TAP Vol 5 Issue 5 by Harborside Press LLC

Metastatic Colorectal Cancer Outcomes 18 | Cutaneous Squamous Cell Carcinoma

| Eight Priorities in Palliative Care

VOLUME 5, ISSUE 5

MARCH 15, 2014

Editor-in-Chief, James O. Armitage, MD | ASCOPost.com

Genitourinary Cancers Symposium

State-of-the-Art Update on Prostate Cancer By Richard J. Boxer, MD, FACS

he 2014 Genitourinary Cancers Symposium, held in San Francisco from January 29 to February 1, brought together more than 3,100 participants from around the world involved in the care of patients with genitourinary malignancies. The abstract presentations and plenary discussions offered the latest clinical and basic science data that will affect patient management immediately and well into the future. During the course of the meeting, The ASCO Post had the opportunity to speak with several of the world’s leading authorities about the state of the art in screening, diagnosis, and treatment for prostate and kidney cancers. In this first installment of our two-part report on genitourinary malignancies, we talked to Peter T. Scardino, MD, FACS, Chair of Surgery and former Chair of Urology at Memorial Sloan Kettering Cancer Center in New York, and Howard M. Sandler, MD, MS, FASTRO, Chair of Radiation Oncology at Cedars-Sinai Medical Center, and a member in the Cedars-Sinai Samuel Oschin Comprehensive Caner Institute, Los Angeles, about the latest approaches to managing prostate cancer.

A Conversation With

By Paul Kalanithi, MD, as told to Jo Cavallo

PETER T. SCARDINO, MD, FACS

continued on page 3

continued on page 129

PSA Screening

The Evolution of U.S. Cooperative Group Trials: Publicly Funded Cancer Research at a Crossroads By Ronald Piana ver the past 5 decades, National Cancer Institute (NCI) Clinical Trials Cooperative Groups have played an enormous role in the fight against cancer, tackling a broad social agenda, including cancer prevention, quality-of-life issues for patients with cancer, and comparison of benefits among different treatment combinations. Given a steady decrease in govern-

ment funding, however, more institutions are turning toward industry-funded trials, which are much less likely to spend resources on important public health issues addressed by the NCI-funded Cooperative Groups. It has become clear that to remain competitive in our challenging fiscal climate, the Cooperative Groups need to rethink their strategy.

We owe it to our cancer patients to make sure that the transition [to the National Clinical Trials Network] does not erode the unique spirit of sheer scientific pursuit, volunteerism, and camaraderie that characterized the cooperative groups’ successes. —Richard L. Schilsky, MD, FASCO

March Is Colorectal Cancer Awareness Month

What is your current perspective on screening for prostate cancer? Screening for prostate cancer with prostate-specific antigen (PSA) will continue to be practiced and will be endorsed by national screening agencies once the problems of current screening methods are resolved. A man’s PSA level at midlife (age 45–50) is a more powerful predictor of his lifetime risk of dying Peter T. Scardino, MD, FACS of prostate cancer than his family history or ethnicity. As the power of PSA to pre-

arly last year, just as I returned to my residency in neurologic surgery at Stanford University after completing 2 years of my postdoctoral fellowship in a laboratory developing optogenetic techniques, I started losing weight—dropping from 180 lb to 160 lb in just 6 months—and I was having fairly significant back pain. The symptoms didn’t sound any alarm bells at first. After all, I had gone from a sedentary job in the laboratory where I was eating three or four meals a day—and had put on a fair amount of weight—to working 90 hours a week at the hospital and grabbing food in between seeing patients and performing surgeries, which also put a lot of stress on my back. Nevertheless, when the symptoms persisted, I saw my primary care physician. She

Issues in Oncology

I Refuse to Capitulate to Cancer

Concept of Cooperation After World War II, scientific and medical research increased exponentially in the United States. In 1950, funding for medical research stood at $161 million. The National Institutes of Health (NIH) opened its clinical

Dr. Kalanithi is Chief Resident in Neurological Surgery at Stanford University in California.

MORE IN THIS ISSUE Oncology Meetings Coverage GU Cancers Symposium �� 1, 4, 10, 11 GI Cancers Symposium �� 15, 16, 18, 20 JADPRO Live Annual Conference �� 40 ASH Highlights of North America ��22 ASH Annual Meeting ��33–37 San Antonio Breast Cancer Symposium �� 29, 30, 32 Prostate Cancer and Melanoma Risk ��43 Nonadherence With Novel Agents ��52 Direct From ASCO �� 62–64 St. Jude Committee on Palliative Care Priorities �� 84 Letters to the Editor �� 127, 129

continued on page 58

A Harborside Press® Publication

The ASCO Post | MARCH 15, 2014

PAGE 2

Harborside Press® Publishing Staff

Editorial Board

Conor Lynch, Executive Editor Conor@harborsidepress.com

James O. Armitage, MD Editor-in-Chief

Bishoy Morris Faltas, MD Weill Cornell Medical College

George W. Sledge, MD Indiana University

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

John A. Fracchia, MD New York Urological Associates

Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Associate Editors Joseph S. Bailes, MD Texas Oncology Laurence H. Baker, DO University of Michigan Comprehensive Cancer Center Richard R. Barakat, MD Memorial Sloan Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Wisconsin School of Medicine and Public Health

Alison Freifeld, MD University of Nebraska Medical Center Louis B. Harrison, MD Continuum Cancer Centers of New York

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Jimmie C. Holland, MD Memorial Sloan Kettering Cancer Center

Lynn D. Wilson, MD Yale University School of Medicine

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

Stanley H. Winokur, MD Singer Island, Florida

Mario E. Lacouture, MD Memorial Sloan Kettering Cancer Center

William C. Wood, MD Winship Cancer Institute, Emory University

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center

Harold J. Burstein, MD Dana-Farber Cancer Institute

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Robert W. Carlson, MD National Comprehensive Cancer Network

Mary S. McCabe, RN, MA Memorial Sloan Kettering Cancer Center

Barrie R. Cassileth, PhD Memorial Sloan Kettering Cancer Center

William T. McGivney, PhD Philadelphia, Pennsylvania

Jay S. Cooper, MD Maimonides Medical Center

James L. Mulshine, MD Rush University Medical Center

John Cox, DO Texas Oncology

Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

E. David Crawford, MD University of Colorado Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

The ASCO Post (ISSN 2154-3283), USPS Publicaton Number 6885, is published semi-monthly, except monthly in January, April, August, and October, by Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Periodicals Postage paid at Cold Spring Harbor, NY, and additional mailing offices. Change of Address: Postmaster send address changes to The ASCO Post, c/o Harborside Press®, LLC, 37 Main Street, Cold Spring Harbor, NY 11724. ASCO Members: If you would like to cancel your subscription to The ASCO Post or need to update your mailing address, please visit your personalized page on ASCO.org. For personalized service, please contact ASCO Member Services at (888) 282-2552, (703) 299-0158, or via email at membermail@asco.org. Non ASCO Members: To initiate or cancel a subscription or to update your mailing address, please email subscriptions@harborsidepress.com or fax (631) 692-0805. Copyright ©2014 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is pro-

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lee S. Schwartzberg, MD University of Tennessee Health Science Center Andrew D. Seidman, MD Memorial Sloan Kettering Cancer Center Samuel Silver, MD, PhD University of Michigan Health System

hibited. For permission inquiries, contact permissions@ harborsidepress.com. Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology. Circulation: The ASCO Post is sent free of charge to approximately 27,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com.

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International Editors Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Nagi El-Saghir, MD American University of Beirut, Lebanon Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital, Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association, Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com Jo Cavallo, Senior Editor and Correspondent Jo@harborsidepress.com Sarah McGullam, Assistant Editor Sarah@harborsidepress.com Michael Buckley, Art Director Michael@harborsidepress.com Terri Caivano, Kristina O’Toole, Layout Artists Terri@harborsidepress.com Kristina@harborsidepress.com Gail Van Koot, Editorial Coordinator Gail@harborsidepress.com Norman Virtue, Production Manager Norman@harborsidepress.com Shannon Meserve, Circulation Manager Shannon@harborsidepress.com Frank Buchner, Chief Technology Officer Frank@harborsidepress.com Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com Anthony Cutrone, President Anthony@harborsidepress.com John A. Gentile, Jr, Chairman Jack@harborsidepress.com

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ASCOPost.com | MARCH 15, 2014

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Genitourinary Cancers Symposium State-of-the-Art Update continued from page 1

dict risk for death from prostate cancer becomes clearer, PSA levels at midlife will be used to risk-adjust screening intensity and duration. Men with a PSA level below the median at age 45 to 50 can be screened every 5 years until age 60. If their PSA level remains below the median at 60, no further screening will be necessary. Men with intermediate PSA levels (1–3 ng/mL) will be screened less frequently than they are today, every 2 to 4 years, to reduce the risk of false-positives. And men with PSA levels greater than 3 ng/ mL will be considered for biopsy after an evaluation that includes the use of new marker panels such as phi (Prostate Health Index, Beckman Coulter) and the 4K (four-kallikrein) panel (in development at OPKO Diagnostics), both of which have been shown to markedly increase the specificity of PSA testing and reduce the need for biopsies. These new testing guidelines will allow many men with elevated PSA levels to avoid a biopsy and yet be followed safely, without the risk of missing highgrade cancers. New urinary molecular markers, in addition to prostate cancer antigen 3 (PCA3), will be developed to better predict which men with an elevated PSA level should have a biopsy.

Imaging Studies What are your thoughts about imaging studies for prostate cancer? Imaging will continue to improve, particularly magnetic resonance imaging (MRI), which when performed as a multiparametric test, is reasonably accurate for the detection of clinically significant cancers. Not only could multiparametric MRI be used in men with an elevated PSA to identify appropriate patients for biopsy, it will also be used with ultrasound fusion or MRI guidance to change the strategy for biopsy from systematic random biopsies back to targeted biopsies, as performed in previous decades when finger guidance was the prime technique for biopsy targeting. Used together with MRI, molecular positron-emission tomography (PET) imaging will provide more accurate detection of clinically significant cancers within the prostate that will allow better local staging and treatment planning with surgery or radiation, as well as accurate tumor localization and characterization for effective focal ablation. Even more exciting, optical imaging of prostate cancer during a surgical procedure will allow more complete excision

of the cancer and of the normal gland (to avoid “benign” PSA relapse requiring salvage radiotherapy), as well as targeted dissection of involved regional lymph nodes, which will become essential once prospective studies document the therapeutic value of lymphadenectomy.

Focal Therapy Could you discuss current concepts in focal therapy for prostate cancer? Technology now exists to ablate regions within the prostate using a variety of modalities, including lasers, photodynamics, high-intensity focused ultrasound, cryotherapy, and electroporation, among others. These approaches have already proven capable of thoroughly ablating regions within the prostate with much less impact on sexual, urinary, and bowel function than radical surgery or radiotherapy. The limiting factor for focal therapy has been our inability to identify the exact location, size, and extent of cancer within the prostate, as well as its biologic potential. But better anatomic imaging (MRI) and molecular imaging will overcome this problem, and partial ablation of the prostate will become as readily accepted as partial nephrectomy for renal tumors, if well designed trials establish the clinical benefit of focal ablation.

Molecular Profiling How is molecular profiling being used in prostate cancer management? Once a cancer is identified within the prostate, the most difficult decision is whether to monitor the patient in an active surveillance program or to proceed immediately with radical surgery or radiotherapy. The decision hinges on the assessment of the biologic potential or level of aggressiveness of the cancer, which can be difficult to determine with standard clinicopathologic measures. Molecular profiling of prostate cancer is now commercially available, with RNA profiles developed by Genomic Health (Oncotype DX) and Myriad (Prolaris), and numerous other techniques currently in development. These profiling strategies provide prognostic information independent of Gleason grade and PSA levels. With improved profiling, patients can be triaged to active surveillance or to radical therapy more appropriately and with greater confidence. I see a rapid expansion of molecular profiling for prostate cancer using such techniques as copy number alteration and mutation analysis, expression arrays, methyl-

ation abnormalities, and metabolomics, as well as microscopic image analysis.

GUEST EDITOR

Active Surveillance Please describe the current role of active surveillance in prostate cancer. As a consequence of these technologic innovations, active surveillance will expand rapidly and be offered to more than half of patients diagnosed with prostate cancer. These patients will be safely monitored over long periods of time, with treatment delayed until evidence of a cancer with aggressive characteristics. Clinical trials will define more clearly the eligibility criteria for active surveillance, both for the patient (age and comorbidity) and the tumor (grade, biologic aggressiveness, and imaging characteristics). Of course, a substantial minority of patients on active surveillance will develop more aggressive prostate cancers that will require definitive therapy, and the risk will likely increase among survivors followed for more than a decade, given the logarithmic growth rate of cancer.

Richard J. Boxer, MD, FACS

Richard J. Boxer, MD, FACS, is Visiting Professor at the David Geffen School of Medicine at UCLA and Clinical Professor at the University of Wisconsin, Madison. He is also an Associate Editor of The ASCO Post. nation with radical surgery for locoregional disease in patients with locally extensive and limited metastatic disease who cannot be cured by local therapy alone. A Conversation With

Radical Prostatectomy

HOWARD M. SANDLER,

How is the use of radical prostatectomy evolving in prostate cancer treatment? Radical prostatectomy procedures will become more complex, as patients with more advanced disease are selected for treatment. More extensive lymphadenectomy will become routine as detection methods improve, including intraoperative imaging of the cancer, and the therapeutic value of lymphadenectomy becomes apparent. Function-preserving radical prostatectomy will become more challenging with complete ablation of large extracapsular tumors; techniques such as nerve grafting to replace resected cavernous nerves and methods to strengthen the distal urinary sphincter will become even more important. Surgery for resection of the primary tumor will become accepted as effective multimodality therapy proves capable of curing many men with locally extensive or limited metastatic prostate cancer. The remarkable advances in systemic therapy for prostate cancer, including potent new antiandrogens (enzalutamide [Xtandi]), inhibitors of testosterone synthesis (abiraterone [Zytiga]), classic chemotherapy (taxanes, including docetaxel and cabazitaxel [ Jevtana Kit]), and immunotherapy (vaccines such as sipuleucel-T [Provenge] and checkpoint blockade with ipilimumab [Yervoy] and anti– PD-1 antibody), will be used in combi-

MD, MS, FASTRO

Evolution of Radiotherapy Dr. Sandler, how has the use of radiation therapy in prostate cancer changed in the new millennium? Radiation oncology for genitourinary tumors, mostly prostate cancer, has evolved over the past 2 decades from relatively crude radiation portals that affected large portions of pelviclocalized bowel uninvolved by prostate cancer (which led to acute and chronic gastrointestinal distress) to current highly targeted radiation treatments that focus with great precision on the prostate itself and a slim margin of surrounding extraprostatic tissue. This has resulted in a marked reduction in acute and chronic complications. Interestingly, despite the older, twodimensional approach using large radiation fields to treat pelvic lymphatic tissue, research showed that those large fields failed to encompass the prostate itself adequately due to uncertainties in prostate localization during the planning and treatment process. Those uncertainties were caused, in part, by the failure to account for prostatic motion due to variations in rectal and bladder filling. With current techniques, we can irradiate a smaller volume with more conformality, more precision, and fewcontinued on page 4

The ASCO Post | MARCH 15, 2014

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Genitourinary Cancers Symposium State-of-the-Art Update continued from page 3

er side effects and simultaneously treat to higher, more effective doses.

Stereotactic Body Radiotherapy What is the role of stereotactic body radiotherapy in prostate cancer treatment? Improvements in radiotherapy techniques led to important changes in the external-beam concept. While traditional radiation biology teaching suggests that fractionated treatment, such as 8 weeks of daily radiation sessions, provides a good risk-benefit ratio, the ability to treat small volumes with precision has led to the development of short, five-fraction approaches using a technique called stereotactic body radiotherapy (SBRT). The “body” is included in the name because this technique evolved from central nervous system or “head” tumor techniques. The intensity of the five-fraction approach can lead to more genitourinary toxicity if the volume treated is too large or if the treatment is delivered imprecisely. However, there have been

enough single-institution studies assessing the benefit of stereotactic body radiotherapy for prostate cancer that in 2013, the American Society for Radiation Oncology (ASTRO) said, “data supporting the use of SBRT for prostate cancer have matured to a point where SBRT could be considered an

Looking Ahead What other changes in radiotherapy for prostate cancer might be coming in the near future? In addition to the increased use of stereotactic body radiotherapy, other new aspects of radiation oncology for prostate cancer include ongoing

Over the next 2 years, one might expect a substantial increase in the use of stereotactic body radiotherapy for prostate cancer, given the convenience of the five-fraction approach compared with longer treatment strategies. —Howard M. Sandler, MD, MS, FASTRO

appropriate alternative for select patients with low- to intermediate-risk disease.” Thus, over the next 2 years, one might expect a substantial increase in the use of stereotactic body radiotherapy for prostate cancer, given the convenience of the five-fraction approach compared with longer treatment strategies.

and future trials that will build on our current template of either short- or long-term androgen deprivation in combination with radiotherapy for intermediate-risk and high-risk cancer, respectively. For example, the Radiation Therapy Oncology Group (RTOG) is examining the potential benefit of inhibiting androgen synthesis with

TAK-700 for high-risk patients above and beyond the conventional androgen deprivation that is provided with luteinizing hormone–releasing hormone (LHRH) agonists or antagonists alone. This trial and others will be exploring how the current enriched environment of medications for the castration-resistant patient population might be beneficial—especially combined with radiotherapy—for the hormone-naive patient. n

Disclosure: Dr. Scardino is a scientific advisor to OPKO, the company that licensed the 4K score from Memorial Sloan Kettering Cancer Center and is developing it for clinical use. Dr. Sandler reported no potential conflicts of interest.

In part 2 of this two-part report, which will appear in the April 15 issue of The ASCO Post, we talk with David I. Quinn, MBBS, PhD, FRACP, Head of Genitourinary Medical Oncology at the USC Norris Comprehensive Cancer Center, Los Angeles, and Arie Belldefrun, MD, FACS, and Allan Pantuck, MD, MS, FACS, Professors of Urologic Oncology at the David Geffen School of Medicine at UCLA, about the present and future care of the patient with renal cell carcinoma.

Role of Immunotherapy Explored in Metastatic Castration-Resistant Prostate Cancer By Alice Goodman

pilimumab (Yervoy) failed to meet the primary endpoint of improving overall survival in the randomized, phase III CA184-043 trial. However, the immunotherapy did improve progression-free survival and prostate-spe-

Charles G. Drake, MD, PhD

cific antigen (PSA) response compared with placebo in postdocetaxel metastatic castration-resistant prostate cancer. Prespecified subset analyses suggested that ipilumumab improves survival in patients with more favorable prognostic factors (ie, no visceral metastasis, lower levels of alkaline phosphatase, and elevated hemoglobin). This finding needs to be validated in future trials.

Immunotherapy Rationale “Although the primary endpoint of this trial was not met, the antitumor activity [of ipilimumab] is suggested by other efficacy endpoints. It appears that patients with more favorable prognostic factors may be more likely to benefit from ipilimumab treatment. Results of this trial support further investigation of ipilimumab in patients with fewer adverse prognostic features than those enrolled in this trial,” said lead author Charles G. Drake, MD, PhD, Assistant Professor of Oncology, Immunology, and Urology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore. Dr. Drake presented the results of the subset analyses of overall survival at the 2014 Genitourinary Cancers Symposium in San Francisco.1 “There are several new therapies in [metastatic castration-resistant prostate cancer],” Dr. Drake noted, “but few that produce long-term responses. Immunotherapy may expand a preexisting anticancer immune response.” The rationale for studying this new

EXPERT POINT OF VIEW

“T

he key thing about this trial is that while the overall study was negative, subset analysis suggests that the patients who appear to benefit from ipilimumab have better prognostic factors, including no visceral disease, lower alkaline phosphatase, and elevated hemoglobin,” commented James Gulley, MD, PhD, Chief of the Clinical Immunotherapy Section and Chief of the Genitourinary Malignancies Branch at the National Cancer InstiJames Gulley, MD, PhD tute, Bethesda, Maryland. “These prognostic factors are consistent with patients earlier in the course of their disease. Eyes will be on the trial just launched in the earlier patient population that excludes visceral metastases,” Dr. Gulley said. n Disclosure: Dr. Gulley reported no potential conflicts of interest.

approach in castration-resistant prostate cancer was based on ipilimumab’s mechanism of action—blockade of the immune checkpoint molecule CTLA-4—as well as the success of this approach in metastatic melanoma, with about 25% of patients alive at 5 years, he said.

Study Details The study included 799 patients with postdocetaxel metastatic castration-resistant prostate cancer. All patients received at least one dose of radiotherapy to bone-directed sites and were randomly assigned in a 1:1 ratio continued on page 8

KADCYLA®: The first antibody-drug conjugate for HER2-positive metastatic breast cancer

Effective Jan 1, 2014

J9354

Indication

KADCYLA® (ado-trastuzumab emtansine), as a single agent, is indicated for the treatment of patients with HER2-positive (HER2+), metastatic breast cancer (MBC) who previously received trastuzumab and a taxane, separately or in combination. Patients should have either: received prior therapy for metastatic disease, or developed disease recurrence during or within six months of completing adjuvant therapy.

Important Safety Information Boxed WARNINGS: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY • Do Not Substitute KADCYLA for or with Trastuzumab • Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function • Embryo-Fetal Toxicity: Exposure to KADCYLA can result in embryo-fetal death or birth defects. Advise patients of these risks and the need for effective contraception Please see the following pages for additional important safety information and brief summary of full prescribing information, including Boxed WARNINGS.

The next era of treatment KADCYLA contains 3 components: the active antibody trastuzumab, the cytotoxic agent DM1, and a stable linker1-3 In preclinical studies:

Trastuzumab (monoclonal antibody) Binds to HER2 at subdomain IV to suppress downstream signaling

DM1* (cytotoxic maytansinoid) Inhibits tubulin polymerization to induce cell-cycle arrest and cell death

MCC* (stable linker) Stabilizes KADCYLA in circulation to release DM1 after entering the target cell

• Maintains the HER2 suppression and anticancer activities of trastuzumab1 • Delivers cytotoxic DM1 to target HER2-expressing cells1 — Many normal cells express HER24 — Some cancer cells overexpress up to 200 times more HER2 than normal cells4

*Emtansine is the combination of DM1, a cytotoxic maytansinoid, and the stable MCC linker.

Additional Important Safety Information

Infusion-Related Reactions, Hypersensitivity Reactions • Treatment with KADCYLA has not been studied in patients who had Left Ventricular Dysfunction (LVD) trastuzumab permanently discontinued due to infusion-related reactions • Patients treated with KADCYLA are at increased risk of developing (IRR) and/or hypersensitivity reactions; treatment with KADCYLA is not LVD. In EMILIA, LVD occurred in 1.8% of patients in the KADCYLArecommended for these patients. In EMILIA, the overall frequency of IRRs treated group and in 3.3% in the comparator group. Permanently in patients treated with KADCYLA was 1.4% discontinue KADCYLA if LVEF has not improved or has declined • KADCYLA treatment should be interrupted in patients with severe further IRR and permanently discontinued in the event of a life-threatening Pregnancy Registry IRR. Patients should be closely monitored for IRR reactions, especially • Advise patients to contact their healthcare provider immediately if during the first infusion they suspect they may be pregnant. Encourage women who may Thrombocytopenia be exposed to KADCYLA during pregnancy to enroll in the MotHER • In EMILIA, the incidence of ≥ Grade 3 thrombocytopenia was 14.5% in Pregnancy Registry by contacting 1-800-690-6720 the KADCYLA-treated group and 0.4% in the comparator group (overall Pulmonary Toxicity incidence 31.2% and 3.3%, respectively) • Cases of interstitial lung disease (ILD), including pneumonitis, some leading to acute respiratory distress syndrome or fatal outcome have • Monitor platelet counts prior to initiation of KADCYLA and prior to each KADCYLA dose. Institute dose modifications as appropriate been reported in clinical trials with KADCYLA. In EMILIA, the overall Neurotoxicity frequency of pneumonitis was 1.2% • In EMILIA, the incidence of ≥ Grade 3 peripheral neuropathy was 2.2% • Treatment with KADCYLA should be permanently discontinued in in the KADCYLA-treated group and 0.2% in the comparator group (overall patients diagnosed with ILD or pneumonitis incidence 21.2% and 13.5%, respectively) • Monitor for signs or symptoms of neurotoxicity. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral © 2013 Genentech USA, Inc. All rights reserved. TDM0002266500 Printed in USA. (12/13) neuropathy until resolution to ≤ Grade 2

Effective Jan 1, 2014

J9354

Superior efficacy with a single agent 1 NEARLY 6-MONTH IMPROVEMENT IN MEDIAN OVERALL SURVIVAL (OS) 100

30.9 months

Proportion surviving (%)

90 80

HR=0.682 95% CI: 0.548, 0.849 P=0.0006

70 60 50

KADCYLA (n=495) No. of events: 149

25.1 months

40 30 20

lapatinib + capecitabine (n=496) No. of events: 182

10 0 0

No. at risk: KADCYLA 495 lapatinib + 496 capecitabine

164 133

136 110

111 86

86 63

62 45

38 27

28 17

13 7

5 4

Months 485 471

474 453

457 435

439 403

418 368

349 297

293 240

242 204

197 159

Results of the randomized, open-label, Phase III EMILIA trial of KADCYLA (3.6 mg/kg IV, Day 1) vs the combination of lapatinib (1250 mg/day oral, once daily) and capecitabine (1000 mg/m2, oral, twice daily, Days 1-14) in 21-day cycles until disease progression in HER2+ MBC patients previously treated with trastuzumab and a taxane. Primary endpoints were OS, progression-free survival (PFS), and safety.1,3

• 50% improvement in median PFS for KADCYLA vs lapatinib + capecitabine (9.6 months vs 6.4 months; HR=0.650; 95% CI: 0.549, 0.771; P <0.0001)1 • The most common NCI-CTCAE (version 3) adverse reactions Grades ≥3 (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy, and fatigue1

HER2 Testing • Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA. Perform using FDA approved tests by laboratories with demonstrated proficiency Extravasation • In KADCYLA clinical studies, reactions secondary to extravasation have been observed and were generally mild. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration. Specific treatment for KADCYLA extravasation is unknown Nursing Mothers • Discontinue nursing or discontinue KADCYLA taking into consideration the importance of the drug to the mother

Please see the following pages for brief summary of full Prescribing Information, including Boxed WARNINGS. References: 1. KADCYLA Prescribing Information. Genentech, Inc. May 2013. 2. Junttila TT, Li G, Parsons K, Phillips GL, Sliwkowski MX. Trastuzumab-DM1 (T-DM1) retains all the mechanisms of action of trastuzumab and efficiently inhibits growth of lapatinib insensitive breast cancer. Breast Cancer Res Treat. 2011;128:347-356. 3. Verma S, Miles D, Gianni L, et al; EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer [published correction appears in N Engl J Med. 2013;368:2442]. N Engl J Med. 2012; 367:1783-1791 and Supplementary Appendix. 4. Hicks DG, Kulkarni S. Review of biologic relevance and optimal use of diagnostic tools. Am J Clin Pathol. 2008;129:263-273.

Adverse Reactions • The most common ADRs seen with KADCYLA in EMILIA (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI-CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue You are encouraged to report side effects to Genentech and the FDA. You may contact Genentech by calling 1-888-835-2555. You may contact the FDA by visiting www.fda.gov/medwatch or calling 1-800-FDA-1088. For more information on KADCYLA, visit KADCYLA.com.

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Genitourinary Cancers Symposium Immunotherapy in Prostate Cancer continued from page 4

to ipilimumab vs placebo. Patients in the experimental arm received maintenance ipilimumab every 12 weeks, and those in the control arm received placebo every 12 weeks. Median overall survival was 11.2

months for ipilimumab vs 10 months for placebo (hazard ratio [HR] = 0.85, 95% confidence interval [CI] = 0.72–1.00, P = .0530). The secondary endpoint of progression-free survival was met, Dr. Drake continued. Median progression-free survival was 4 months in the ipilimumab group and 3 months in the placebo group.

KADCYLA® (ado-trastuzumab emtansine) Injection for intravenous use Initial U.S. Approval: 2013 This is a brief summary of information about KADCYLA. Before prescribing, please see full Prescribing Information. Do Not Substitute KADCYLA for or with Trastuzumab WARNING: HEPATOTOXICITY, CARDIAC TOXICITY, EMBRYO-FETAL TOXICITY

Ipilimumab in Castration-Resistant Prostate Cancer ■■ Ipilimumab failed to meet the primary endpoint of overall survival in a phase III study in metastatic castration-resistant prostate cancer previously treated with docetaxel. ■■ The drug improved progression-free survival and PSA response. S:6.875” ■■ Subgroup analyses suggested that the presence of visceral metastases had a negative impact on survival.

woman. There are no adequate and well-controlled studies of KADCYLA in pregnant women and no reproductive and developmental toxicology studies have been conducted with ado-trastuzumab emtansine. Nevertheless, treatment with trastuzumab, the antibody component of KADCYLA, during pregnancy in the postmarketing setting has resulted in oligohydramnios, some associated with fatal pulmonary hypoplasia, skeletal abnormalities and neonatal death. DM1, the cytotoxic component of KADCYLA, can be expected to cause embryo-fetal toxicity based on its mechanism of action. If KADCYLA is used during pregnancy, or if the patient becomes pregnant while receiving KADCYLA, apprise the patient of the potential hazard to the fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of KADCYLA. Advise patients of the risks of embryo-fetal death and birth defects and the need for contraception during and after treatment. Advise patients to contact their healthcare provider immediately if they suspect they may be pregnant. If KADCYLA is administered during pregnancy or if a patient becomes pregnant while receiving KADCYLA, immediately report exposure to the Genentech Adverse Event Line at 1-888-835-2555. Encourage women who may be exposed during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see Patient Counseling Information (17)].

• Hepatotoxicity: Serious hepatotoxicity has been reported, including liver failure and death in patients treated with KADCYLA. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Reduce dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases or total bilirubin. (2.2, 5.1) • Cardiac Toxicity: KADCYLA administration may lead to reductions in left ventricular ejection fraction (LVEF). Evaluate left ventricular function in all patients prior to and during treatment with KADCYLA. Withhold treatment for clinically significant decrease in left ventricular function. (2.2, 5.2) • Embryo-Fetal Toxicity: Exposure to KADCYLA can result 5.4 Pulmonary Toxicity in embryo-fetal death or birth defects. Advise patients Cases of interstitial lung disease (ILD), including pneumonitis, of these risks and the need for effective contraception. some leading to acute respiratory distress syndrome or fatal (5.3, 8.1, 8.6) outcome have been reported in clinical trials with KADCYLA. Pneumonitis at an incidence of 0.8% (7 out of 884 treated patients) 1 INDICATIONS AND USAGE has been reported, with one case of grade 3 pneumonitis. Signs KADCYLA®, as a single agent, is indicated for the treatment and symptoms include dyspnea, cough, fatigue, and pulmonary of patients with HER2-positive, metastatic breast cancer who infiltrates. These events may or may not occur as sequelae of previously received trastuzumab and a taxane, separately or in infusion reactions. In the randomized trial (Study 1), the overall combination. Patients should have either: frequency of pneumonitis was 1.2% [see Adverse Reactions (6.1)]. • Received prior therapy for metastatic disease, or • Developed disease recurrence during or within six months of Permanently discontinue treatment with KADCYLA in patients diagnosed with ILD or pneumonitis. completing adjuvant therapy. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Hepatotoxicity Hepatotoxicity, predominantly in the form of asymptomatic, transient increases in the concentrations of serum transaminases, has been observed in clinical trials with KADCYLA [see Adverse Reactions (6.1)]. Serious hepatobiliary disorders, including at least two fatal cases of severe drug-induced liver injury and associated hepatic encephalopathy, have been reported in clinical trials with KADCYLA. Some of the observed cases may have been confounded by comorbidities and/or concomitant medications with known hepatotoxic potential. Monitor serum transaminases and bilirubin prior to initiation of KADCYLA treatment and prior to each KADCYLA dose. Patients with known active hepatitis B virus or hepatitis C virus were excluded from Study 1 [see Clinical Studies (14.1)]. Reduce the dose or discontinue KADCYLA as appropriate in cases of increased serum transaminases and/or total bilirubin [see Dosage and Administration (2.2)]. Permanently discontinue KADCYLA treatment in patients with serum transaminases > 3 x ULN and concomitant total bilirubin > 2 x ULN. KADCYLA has not been studied in patients with serum transaminases > 2.5 x ULN or bilirubin > 1.5 x ULN prior to the initiation of treatment. In clinical trials of KADCYLA, cases of nodular regenerative hyperplasia (NRH) of the liver have been identified from liver biopsies (3 cases out of 884 treated patients). Two of these three cases of NRH were observed in the randomized trial (Study 1) [see Adverse Reactions (6.1)]. NRH is a rare liver condition characterized by widespread benign transformation of hepatic parenchyma into small regenerative nodules; NRH may lead to non-cirrhotic portal hypertension. The diagnosis of NRH can be confirmed only by histopathology. NRH should be considered in all patients with clinical symptoms of portal hypertension but with normal transaminases and no manifestations of cirrhosis. Upon diagnosis of NRH, KADCYLA treatment must be permanently discontinued. 5.2 Left Ventricular Dysfunction Patients treated with KADCYLA are at increased risk of developing left ventricular dysfunction. A decrease of LVEF to < 40% has been observed in patients treated with KADCYLA. In the randomized trial (Study 1), left ventricular dysfunction occurred in 1.8% of patients in the KADCYLA-treated group and 3.3% of patients in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. Assess LVEF prior to initiation of KADCYLA and at regular intervals (e.g. every three months) during treatment to ensure the LVEF is within the institution’s normal limits. Treatment with KADCYLA has not been studied in patients with LVEF < 50% prior to initiation of treatment. If, at routine monitoring, LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold KADCYLA and repeat LVEF assessment within approximately 3 weeks. Permanently discontinue KADCYLA if the LVEF has not improved or has declined further [see Dosage and Administration (2.2)]. Patients with a history of symptomatic congestive heart failure (CHF), serious cardiac arrhythmia, or history of myocardial infarction or unstable angina within 6 months were excluded from Study 1 [see Clinical Studies (14.1)].

and 13.5% in the lapatinib plus capecitabine-treated group [see Adverse Reactions (6.1)]. The incidence of ≥ Grade 3 peripheral neuropathy was 2.2% in the KADCYLA-treated group and 0.2% in the lapatinib plus capecitabine-treated group. KADCYLA should be temporarily discontinued in patients experiencing Grade 3 or 4 peripheral neuropathy until resolution to ≤ Grade 2. Patients should be clinically monitored on an ongoing basis for signs or symptoms of neurotoxicity [see Nonclinical Toxicology (13.2)]. 5.8 HER2 Testing Detection of HER2 protein overexpression or gene amplification is necessary for selection of patients appropriate for KADCYLA therapy because these are the only patients studied for whom benefit has been shown [see Indications and Usage (1), Clinical Studies (14.1)]. In the randomized study (Study 1), patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by Dako Herceptest™ or evidence of overexpression defined as FISH amplification ratio ≥ 2.0 by Dako HER2 FISH PharmDx™ test kit. Only limited data were available for patients whose breast cancer was positive by FISH and 0 or 1+ by IHC. Assessment of HER2 status should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specified reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. 5.9 Extravasation In KADCYLA clinical studies, reactions secondary to extravasation have been observed. These reactions, observed more frequently within 24 hours of infusion, were usually mild and comprised erythema, tenderness, skin irritation, pain, or swelling at the infusion site. Specific treatment for KADCYLA extravasation is unknown. The infusion site should be closely monitored for possible subcutaneous infiltration during drug administration.

Patients with dyspnea at rest due to complications of advanced 6 ADVERSE REACTIONS malignancy and co-morbidities may be at increased risk of The following adverse reactions are discussed in greater detail in other sections of the label: pulmonary toxicity. • Hepatotoxicity [See Warnings and Precautions (5.1)] 5.5 Infusion-Related Reactions, Hypersensitivity Reactions • Left Ventricular Dysfunction [See Warnings and Precautions (5.2)] Treatment with KADCYLA has not been studied in patients who • Embryo-Fetal Toxicity [See Warnings and Precautions (5.3)] had trastuzumab permanently discontinued due to infusion-related • Pulmonary Toxicity [See Warnings and Precautions (5.4)] reactions (IRR) and/or hypersensitivity; treatment with KADCYLA is • Infusion-Related Reactions, Hypersensitivity Reactions [See not recommended for these patients. Warnings and Precautions (5.5)] Infusion-related reactions, characterized by one or more of • Thrombocytopenia [See Warnings and Precautions (5.6)] the following symptoms − flushing, chills, pyrexia, dyspnea, • Neurotoxicity [See Warnings and Precautions (5.7)] hypotension, wheezing, bronchospasm, and tachycardia have been reported in clinical trials of KADCYLA. In the randomized 6.1 Clinical Trials Experience trial (Study 1), the overall frequency of IRRs in patients treated with Because clinical trials are conducted under widely varying KADCYLA was 1.4% [see Adverse Reactions (6.1)]. In most patients, conditions, adverse reaction rates observed in the clinical trials of these reactions resolved over the course of several hours to a day a drug cannot be directly compared to rates in the clinical trials of after the infusion was terminated. KADCYLA treatment should be another drug and may not reflect the rates observed in practice.

In clinical trials, KADCYLA has been evaluated as single-agent in 884 patients with HER2-positive metastatic breast cancer. The most common (frequency ≥ 25%) adverse drug reactions (ADRs) seen in 884 patients treated with KADCYLA were fatigue, nausea, One case of a serious, allergic/anaphylactic-like reaction has been musculoskeletal pain, thrombocytopenia, headache, increased observed in clinical trials of single-agent KADCYLA. Medications to transaminases, and constipation. treat such reactions, as well as emergency equipment, should be The ADRs described in Table 6 were identified in patients with HER2positive metastatic breast cancer treated in a randomized trial available for immediate use. (Study 1) [see Clinical Studies (14.1)]. Patients were randomized 5.6 Thrombocytopenia to receive KADCYLA or lapatinib plus capecitabine. The median Thrombocytopenia, or decreased platelet count, was reported in duration of study treatment was 7.6 months for patients in the clinical trials of KADCYLA (103 of 884 treated patients with ≥ Grade KADCYLA-treated group and 5.5 months and 5.3 months for patients 3; 283 of 884 treated patients with any Grade). The majority of these treated with lapatinib and capecitabine, respectively. Two hundred patients had Grade 1 or 2 events (< LLN to ≥ 50,000/mm3) with the and eleven (43.1%) patients experienced ≥ Grade 3 adverse events nadir occurring by day 8 and generally improving to Grade 0 or in the KADCYLA-treated group compared with 289 (59.2%) patients 1 (≥ 75,000 /mm3) by the next scheduled dose. In clinical trials of in the lapatinib plus capecitabine-treated group. Dose adjustments KADCYLA, the incidence and severity of thrombocytopenia were for KADCYLA were permitted [see Dosage and Administration higher in Asian patients. Independent of race, the incidence of (2.2)]. Thirty-two patients (6.5%) discontinued KADCYLA due to an severe hemorrhagic events in patients treated with KADCYLA was adverse event, compared with 41 patients (8.4%) who discontinued low. lapatinib, and 51 patients (10.5%) who discontinued capecitabine In the randomized trial (Study 1), the overall frequency of due to an adverse event. The most common adverse events leading thrombocytopenia was 31.2% in the KADCYLA-treated group and to KADCYLA withdrawal were thrombocytopenia and increased 3.3% in the lapatinib plus capecitabine-treated group [see Adverse transaminases. Eighty patients (16.3%) treated with KADCYLA had Reactions (6.1)]. The incidence of ≥ Grade 3 thrombocytopenia was adverse events leading to dose reductions. The most frequent 14.5% in the KADCYLA-treated group and 0.4% in the lapatinib plus adverse events leading to dose reduction of KADCYLA (in ≥ 1% of capecitabine-treated group. In Asian patients, the incidence of patients) included thrombocytopenia, increased transaminases, ≥ Grade 3 thrombocytopenia was 45.1% in the KADCYLA-treated and peripheral neuropathy. Adverse events that led to dose delays occurred in 116 (23.7%) of KADCYLA treated patients. The most group and 1.3% in the lapatinib plus capecitabine-treated group. Monitor platelet counts prior to initiation of KADCYLA and prior frequent adverse events leading to a dose delay of KADCYLA (in to each KADCYLA dose [see Dosage and Administration (2.2)]. ≥ 1% of patients) were neutropenia, thrombocytopenia, leukopenia, KADCYLA has not been studied in patients with platelet counts fatigue, increased transaminases and pyrexia. interrupted in patients with severe IRR. KADCYLA treatment should be permanently discontinued in the event of a life-threatening IRR [see Dosage and Administration (2.2)]. Patients should be observed closely for IRR reactions, especially during the first infusion.

<100,000/mm3 prior to initiation of treatment. In the event of decreased platelet count to Grade 3 or greater (< 50,000/mm3) do not administer KADCYLA until platelet counts recover to Grade 1 (≥ 75,000/mm3) [see Dosage and Administration (2.2)]. Patients with thrombocytopenia (< 100,000/mm3) and patients on anti-coagulant treatment should be closely monitored during treatment with KADCYLA.

5.7 Neurotoxicity Peripheral neuropathy, mainly as Grade 1 and predominantly sensory, was reported in clinical trials of KADCYLA (14 of 884 treated patients with ≥ Grade 3; 196 of 884 treated patients with any 5.3 Embryo-Fetal Toxicity Grade). In the randomized trial (Study 1), the overall frequency of KADCYLA can cause fetal harm when administered to a pregnant peripheral neuropathy was 21.2% in the KADCYLA-treated group

Table 6 reports the ADRs that occurred in patients in the KADCYLAtreated group (n=490) of the randomized trial (Study 1). Selected laboratory abnormalities are shown in Table 7. The most common ADRs seen with KADCYLA in the randomized trial (frequency > 25%) were nausea, fatigue, musculoskeletal pain, thrombocytopenia, increased transaminases, headache, and constipation. The most common NCI–CTCAE (version 3) ≥ Grade 3 ADRs (frequency >2%) were thrombocytopenia, increased transaminases, anemia, hypokalemia, peripheral neuropathy and fatigue.

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Genitourinary Cancers Symposium The investigators conducted further analyses to determine if any subgroups had a survival benefit from ipilimumab. The only factor that appeared to be of importance was the presence of visceral metastases. Median overall survival was 14.4 months with ipilimumab in patients with no visceral metastases vs 5.7 months with the immune checkpoint

Table 6 Summary of Adverse Drug Reactions Occurring in Patients on the KADCYLA Treatment Arm in the Randomized Trial (Study 1)

Adverse Drug Reactions (MedDRA) System Organ Class

KADCYLA (3.6 mg/kg) n=490 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2) n=488 Frequency rate % All grades (%)

Grade 3 – 4 (%)

Blood and Lymphatic System Disorders

inhibitor in the presence of visceral metastases. Dr. Drake acknowledged that the trial was underpowered to show an interaction between ipilimumab and visceral metastases, but he noted that the S:6.875” hazard ratio (HR = 1.644, 95% CI = 1.157–2.336, P = .0056) “is clearly in the wrong direction…. The bottom line

Table 7 Selected Laboratory Abnormalities

Increased bilirubin

Lapatinib (1250 mg) + Capecitabine (2000 mg/m2)

KADCYLA (3.6 mg/kg)

Parameter

All Grade %

Grade 3 %

Grade 4 %

All Grade %

Grade 3 %

Grade 4 %

Neutropenia

6.7

2.0

9.0

4.3

Increased AST

Anemia

14.3

4.1

10.5

2.5

Increased ALT

Thrombocytopenia

31.2

14.5

3.3

0.4

Decreased platelet count

Decreased hemoglobin

Decreased neutrophils

Decreased potassium

Cardiac Disorders Left ventricular dysfunction

1.8

0.2

3.3

0.4

Lacrimation increased

3.3

2.5

Dry eye

3.9

3.1

Vision blurred

4.5

0.8

Conjunctivitis

3.9

2.3

0 0.4

Eye Disorders

Gastrointestinal Disorders Dyspepsia

9.2

11.5

Stomatitis

14.1

0.2

32.6

2.5

Dry Mouth

16.7

4.9

0.2

Abdominal pain

18.6

0.8

17.6

1.6

Vomiting

19.2

0.8

29.9

4.5 20.7

Diarrhea

24.1

1.6

79.7

Constipation

26.5

0.4

11.1

Nausea

39.8

0.8

45.1

2.5

General Disorders and Administration 8.2

0.2

3.1

Pyrexia

18.6

0.2

8.4

0.4

Asthenia

17.8

0.4

17.6

1.6

Fatigue

36.3

2.5

28.3

3.5

Nodular regenerative hyperplasia*

0.4

Portal hypertension*

0.4

0.2

0.8

0.2

9.4

0.6

3.9

Blood alkaline phosphatase increased

4.7

0.4

3.7

0.4

Increased transaminases

28.8

8.0

14.3

2.5

2.7

9.4

4.7

Hepatobiliary Disorders

Immune System Disorders Drug hypersensitivity

2.2

Injury, Poisoning, and Procedural Infusion-related reaction

1.4

Infections and Infestations Urinary tract infection Investigations

Metabolism and Nutrition Disorders Hypokalemia

10.2

Musculoskeletal and Connective Tissue Disorders Myalgia

14.1

0.6

3.7

Arthralgia

19.2

0.6

8.4

Musculoskeletal pain

36.1

1.8

30.5

1.4

Nervous System Disorders Dysgeusia

8.0

4.1

0.2

Dizziness

10.2

0.4

10.7

0.2

Peripheral neuropathy

21.2

2.2

13.5

0.2

Headache

28.2

0.8

14.5

0.8

12.0

0.4

8.6

0.2

Psychiatric Disorders Insomnia

Respiratory, Thoracic, and Mediastinal Disorders Pneumonitis

1.2

Dyspnea

12.0

0.8

8.0

0.4

Cough

18.2

0.2

13.1

0.2

Epistaxis

22.5

0.2

8.4

Skin and Subcutaneous Tissue Disorders Pruritus

5.5

0.2

9.2

Rash

11.6

27.5

1.8

5.1

1.2

2.3

0.4

Vascular Disorders Hypertension

* Nodular Regenerative Hyperplasia and Portal Hypertension occurred in the same patient. ND = Not determined

the placental barrier during the early and late phases of gestation. The resulting concentrations of trastuzumab in fetal blood and amniotic fluid were approximately 33% and 25%, respectively, of those present in the maternal serum but were not associated with adverse findings. 8.3 Nursing Mothers It is not known whether KADCYLA, specifically, is excreted in human milk, but IgG is known to be excreted in human milk. In lactating monkeys, trastuzumab was excreted in small amounts (about 0.3% of maternal serum concentrations) in breast milk after post-partum doses of 25 mg/kg (about 7 times the clinical dose of KADCYLA). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from KADCYLA, a decision should be made whether to discontinue nursing or discontinue KADCYLA, taking into account the importance of the drug to the mother [see Warnings and Precautions (5.3)]. 8.4 Pediatric Use Safety and effectiveness of KADCYLA have not been established in pediatric patients.

8.5 Geriatric Use Of 495 patients who were randomized to KADCYLA in the randomized 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune trial (Study 1) [see Clinical Studies (14.1)], 65 patients (13%) were ≥ 65 years of age and 11 patients (2%) were ≥ 75 years of age. In patients response to KADCYLA. ≥ 65 years old (n=138 across both treatment arms) the hazard ratios A total of 836 patients from six clinical studies were tested at for progression-free survival (PFS) and Overall Survival (OS) were multiple time points for anti-therapeutic antibody (ATA) responses 1.06 (95% CI: 0.68, 1.66) and 1.05 (95% CI: 0.58, 1.91), respectively. to KADCYLA. Following KADCYLA dosing, 5.3% (44/836) of patients tested positive for anti-KADCYLA antibodies at one or more post- Population pharmacokinetic analysis indicates that age does not dose time points. The presence of KADCYLA in patient serum at have a clinically meaningful effect on the pharmacokinetics of the time of ATA sampling may interfere with the ability of this assay ado-trastuzumab emtansine [see Clinical Pharmacology (12.3)]. 8.6 Females of Reproductive Potential KADCYLA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective Immunogenicity data are highly dependent on the sensitivity and contraception while receiving KADCYLA and for 6 months following specificity of the test methods used. Additionally, the observed the last dose of KADCYLA. incidence of a positive result in a test method may be influenced If KADCYLA is administered during pregnancy or if the patient by several factors, including sample handling, timing of sample becomes pregnant while receiving KADCYLA, immediately report collection, drug interference, concomitant medication and the exposure to the Genentech Adverse Event Line at 1-888-835-2555. underlying disease. Therefore, comparison of the incidence of Encourage women who may be exposed during pregnancy to enroll antibodies to KADCYLA with the incidence of antibodies to other in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see products may be misleading. Clinical significance of anti-KADCYLA Patient Counseling Information (17)]. antibodies is not yet known. 8.7 Renal Impairment No dedicated renal impairment trial for KADCYLA has been 7 DRUG INTERACTIONS No formal drug-drug interaction studies with KADCYLA have conducted. Based on the population pharmacokinetics, as well been conducted. In vitro studies indicate that DM1, the cytotoxic as analysis of Grade 3 or greater adverse drug reactions and dose component of KADCYLA, is metabolized mainly by CYP3A4 and modifications, dose adjustments of KADCYLA are not needed in to a lesser extent by CYP3A5. Concomitant use of strong CYP3A4 patients with mild (creatinine clearance [CLcr] 60 to 89 mL/min) inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, or moderate (CLcr 30 to 59 mL/min) renal impairment. No dose atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, adjustment can be recommended for patients with severe renal telithromycin, and voriconazole) with KADCYLA should be avoided impairment (CLcr less than 30 mL/min) because of the limited data due to the potential for an increase in DM1 exposure and toxicity. available [see Clinical Pharmacology (12.3)]. Consider an alternate medication with no or minimal potential to 8.8 Hepatic Impairment inhibit CYP3A4. If concomitant use of strong CYP3A4 inhibitors is In vitro studies in human liver microsomes indicates that DM1 is unavoidable, consider delaying KADCYLA treatment until the strong metabolized by CYP3A4/5. The influence of hepatic impairment on CYP3A4 inhibitors have cleared from the circulation (approximately the pharmacokinetics of ado-trastuzumab emtansine conjugate has 3 elimination half-lives of the inhibitors) when possible. If a strong not been determined. CYP3A4 inhibitor is coadministered and KADCYLA treatment cannot be delayed, patients should be closely monitored for adverse 10 OVERDOSAGE There is no known antidote for overdose of KADCYLA. In clinical reactions. trials, overdose of KADCYLA has been reported at approximately 8 USE IN SPECIFIC POPULATIONS two times the recommended dose which resulted in Grade 2 thrombocytopenia (resolved 4 days later) and one death. In the fatal 8.1 Pregnancy case, the patient incorrectly received KADCYLA at 6 mg/kg and died Pregnancy Category D [see Warnings and Precautions (5.3)] approximately 3 weeks following the overdose; a cause of death and Risk Summary a causal relationship to KADCYLA were not established. KADCYLA can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies of 17 PATIENT COUNSELING INFORMATION KADCYLA in pregnant women. No reproductive and developmental • Inform patients of the possibility of severe liver injury and advise toxicology studies have been conducted with ado-trastuzumab patients to immediately seek medical attention if they experience emtansine. Nevertheless, two components of KADCYLA symptoms of acute hepatitis such as nausea, vomiting, abdominal pain (trastuzumab and DM1) are known or suspected to cause fetal harm (especially RUQ abdominal pain), jaundice, dark urine, generalized or death when administered to a pregnant woman. If KADCYLA is pruritus, anorexia, etc. [see Warnings and Precautions (5.1)]. to detect anti-KADCYLA antibodies. As a result, data may not accurately reflect the true incidence of anti-KADCYLA antibody development. In addition, neutralizing activity of anti-KADCYLA antibodies has not been assessed.

administered during pregnancy, or if a patient becomes pregnant • Advise patients to contact a health care professional immediately while receiving KADCYLA, apprise the patient of the potential for any of the following: new onset or worsening shortness of breath, hazard to the fetus. Patients should be advised to use effective cough, swelling of the ankles/legs, palpitations, weight gain of contraception during treatment with KADCYLA and for 6 months more than 5 pounds in 24 hours, dizziness or loss of consciousness [see Warnings and Precautions (5.2)]. following the last dose of KADCYLA. If KADCYLA is administered during pregnancy or if a patient • Advise pregnant women and females of reproductive potential that becomes pregnant while receiving KADCYLA, immediately report KADCYLA exposure can result in fetal harm, including embryo-fetal exposure to the Genentech Adverse Event Line at 1-888-835-2555. death or birth defects [see Warnings and Precautions (5.3), Use in Encourage women who may be exposed during pregnancy to enroll Specific Populations (8.1, 8.6)]. in the MotHER Pregnancy Registry by contacting 1-800-690-6720 [see • Advise females of reproductive potential to use effective Patient Counseling Information (17)]. contraception while receiving KADCYLA and for 6 months following the last dose of KADCYLA [See Warnings and Precautions (5.3) and Human Data Use in Specific Populations (8.1, 8.6)]. In the post-marketing setting, treatment with trastuzumab during pregnancy has resulted in cases of oligohydramnios, some • Advise nursing mothers treated with KADCYLA to discontinue associated with fatal pulmonary hypoplasia, skeletal abnormalities nursing or discontinue KADCYLA, taking into account the importance and neonatal death. These case reports described oligohydramnios of the drug to the mother [see Use in Specific Populations (8.3)]. in pregnant women who received trastuzumab either alone or in • Encourage women who are exposed to KADCYLA during pregnancy combination with chemotherapy. In some case reports, amniotic to enroll in the MotHER Pregnancy Registry by contacting fluid index increased after trastuzumab was stopped. In one 1-800-690-6720 [see Warnings and Precautions (5.3) and Use in case, trastuzumab therapy resumed after the amniotic fluid index Specific Populations (8.1, 8.6)]. improved, and oligohydramnios recurred. KADCYLA® (ado-trastuzumab emtansine) Animal Data There were no reproductive and developmental toxicology studies conducted with ado-trastuzumab emtansine. DM1, the cytotoxic component of KADCYLA, disrupts microtubule function. DM1 is toxic to rapidly dividing cells in animals and is genotoxic, suggesting it has the potential to cause embryotoxicity and teratogenicity. In studies where trastuzumab was administered to pregnant monkeys at doses up to 25 mg/kg (about 7 times the clinical dose), trastuzumab crossed

Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080-4990 U.S. License No: 1048

Disclosure: The study was funded by BristolMyers Squibb. Dr. Drake is a consultant/advisor for Bristol-Myers Squibb, Compugen, Costim Pharmaceuticals, Dendreon, and Pfizer, owns stock in Amplimmune, and has received research funding from Bristol-Myers Squibb and Janssen. For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Drake CG, Kwon ED, Fizazi K, et al: Results of subset analyses on overall survival (OS) from the study CA184-043: Ipilimumab versus placebo in post-docetaxel metastatic castration-resistant prostate cancer. 2014 Genitorurinary Cancers Symposium. Abstract 2. Presented January 30, 2014.

Contact

The ASCO Post T:10.5”

7.6

Multivariate analysis identified the following favorable prognostic factors for overall survival: age under 70 years,

B:11.5”

7.1

Chills

Multivariate Analysis

alkaline phosphatase < 1.5 times the upper limit of normal, hemoglobin ≥ 11 g/dL, and the absence of visceral metastases. The safety of ipilimumab was consistent with that of other trials with this agent. Another phase III trial of ipilimumab has been launched (CA184095) in chemotherapy-naive castration-resistant prostate cancer, and it excludes patients with visceral metastases. n

S:9.875”

Peripheral edema

is that visceral metastases interfere with the treatment effect.” He added, “This is a retrospective analysis and hypothesis-generating.”

Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com Cara H. Glynn Director of Editorial e-mail: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash Assoc. Director of Editorial e-mail: Andrew@harborsidepress.com Phone: 631.935.7657

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

The ASCO Post | MARCH 15, 2014

PAGE 10

Genitourinary Cancers Symposium Genitourinary Oncology

Five Key Studies in Prostate Cancer and Renal Cell Carcinoma By Richard J. Boxer, MD, FACS

he 10th Genitourinary Cancers Symposium, sponsored by ASCO, the American Society for Radiation Oncology, and the Society of Urologic Oncology, was held January 29–February 1, 2014, in San Francisco. The more than 630 abstracts presented addressed essential research in genitourinary malignancies, including data on some of the newest, most cutting-edge treatments available. Several papers stand out in my mind as important, possibly groundbreaking, and may alter the approach to treating genitourinary malignancies. The five following abstracts were among the most noteworthy.

Enzalutamide for Prostate Cancer Abstract LBA1. Beer TM, Armstrong AJ, Sternberg CN, et al: Enzalutamide in men with chemotherapy-naive metastatic prostate cancer: Results of phase III PREVAIL study. The authors performed a randomized, double-blind, placebo-controlled phase III (PREVAIL) study in patients with metastatic castration-resistant prostate cancer. The patients were either asymptomatic or mildly symptomatic. They received enzalutamide (Xtandi), an androgen-receptor blocker (160 mg/d) or placebo, and had never received any other chemotherapy. A total of 1,717 men (1,715 treated) were randomly assigned to the two arms between September 2010 and September 2012. The investigators found a 29% reduction in deaths in the enzalutamide group compared to the placebo group, and an 81% reduction in disease progression. The two primary endpoints in this trial were overall survival and radiographic progression-free survival. Enzalutamide treatment resulted in 20% complete responses and 39% partial responses, compared with a 5% objective response rate in the placebo arm. Enzalutamide also significantly delayed the need for chemotherapy. On average, patients on enzalutamide needed chemotherapy 17 months later than placebo recipients. The Independent Data Monitoring Committee deemed the benefit-risk ratio Dr. Boxer is Visiting Professor at the David Geffen School of Medicine at UCLA, Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin (Milwaukee).

to favor enzalutamide and recommended stopping the study and allowing placebo patients to cross over to enzalutamide. The authors concluded, “Treatment with enzalutamide significantly improves overall survival and radiographic progressionfree survival in men with chemotherapy-naive metastatic castration-resistant prostate cancer.”

Radium-223 in Prostate Cancer Abstract 9. Nilsson S, Vogelzang NJ, Sartor AO, et al: 1.5-year post-treatment follow-up of radium-223 dichloride (Ra-223) in patients with castration-resistant prostate cancer and bone metastases from the phase 3 ALSYMPCA study. In follow-up to the ALSYMPCA study

followed for a median of 10.7 years. Among the 439 men receiving hormone therapy only, 118 died of prostate cancer, whereas of the 436 receiving combination therapy, only 45 died. For patients receiving androgen ablation alone, cancerspecific mortality at 10 and 15 years was 18.9% and 30.7%. Patients receiving both radiotherapy and androgen ablation had a 10- and 15-year prostate cancer-specific mortality of 8.3% and 12.4%, respectively. The authors concluded, “Addition of local radiotherapy to hormonal treatment in patients with non-metastatic locally advanced or high-risk prostate cancer more than halved the 10- and 15- year prostate cancer-specific mortality and substantially decreased overall mortality.”

The more than 630 abstracts presented addressed essential research in genitourinary malignancies, including data on some of the newest, most cutting-edge treatments available. —Richard J. Boxer, MD, FACS

of radium Ra 223 dichloride (Xofigo), the first alpha-emitting pharmaceutical approved by the U.S. Food and Drug Administration for treatment of patients with castration-resistant prostate cancer with symptomatic bone metastases, the investigators found the agent significantly improved overall survival by 3.6 months vs placebo. They concluded, “Ra-223 is an effective and well-tolerated treatment for castration-resistant prostate cancer with symptomatic bone metastases.”

Androgen Blockade in Prostate Cancer Abstract 4. Fossa SD, Widmark A, Klepp OH, et al: Ten- and 15-year prostate cancer-specific survival in patients with nonmetastatic high-risk prostate cancer randomized to lifelong hormone treatment alone or combined with radiotherapy (SPCG VII). This important Scandinavian trial, a follow-up to previous study of the same group of patients [Widmark et al: Lancet 373:301-308, 2009], demonstrated a significant reduction in prostate cancer–specific mortality among patients with locally advanced or histologically aggressive prostate cancer who received total androgen blockade and radiotherapy followed by antiandrogen therapy compared to patients given hormonal treatment only. Patients in the total androgen blockade arm had a 12% reduction in deaths. The patients were

Impact of Angiotensin System Inhibitors on Renal Cell Cancer Abstract 437. McKay RR, Rodriguez GE, Lin X, et al: Impact of angiotensin system inhibitors on outcomes in patients with metastatic renal cell carcinoma: Results from a pooled clinical trials database. Treatment of metastatic renal cell carcinoma has been the focus of intense research using new and exciting vascular endothelial growth factor (VEGF)-targeted agents such as sunitinib (Sutent), sorafenib (Nexavar), axitinib (Inlyta), bevacizumab (Avastin); mammalian target of rapamycin (mTOR)-targeted agents such as temsirolimus (Torisel); and interferon alfa. However, accumulating evidence has implicated common antihypertensive angiotensin system inhibitors (angiotensin-converting enzyme inhibitors and angiotension-receptor blockers such as lisinopril, captopril, and losartan) in the modulation of angiogenesis and tumorigenesis. The authors of this important retrospective study evaluated the role of these medications in the survival outcomes of patients with metastatic renal cell carcinoma. The study evaluated the mortality outcomes of 4,736 patients on one or a combination of the above-mentioned targeted therapy medications, also treated with an angiotensin system inhibitor (n = 1,383) or without additional angiotensin system inhibitor treatment (n = 3,353). The overall survival for patients receiv-

ing angiotensin system inhibitors was 27 months, compared with 17 months for those not using these agents. In addition, cancer was more likely to shrink in patients taking angiotensin system inhibitors. The researchers also analyzed data from patients taking any type of antihypertensive agent (n = 2,000) and found that overall survival for patients using angiotensin system inhibitors was 27 months compared to 18 months for those on other types of antihypertensive agents. The authors stated, “This is the largest retrospective study to date evaluating the role of angiotensin system inhibitors on outcomes in cancer patients. In this analysis, we demonstrate that concomitant use of angiotensin system inhibitors may improve survival outcomes in patients with metastatic renal cell carcinoma treated in the era of targeted therapy.”

Prognostic Model for Renal Cell Carcinoma Abstract 398. Ko JJ, Xie W, Heng DY, et al: The International Metastatic Renal Cell Carcinoma Database Consortium model as a prognostic tool in metastatic renal cell carcinoma patients previously treated with firstline targeted therapy. Prognostic models may be helpful in the treatment of any disease, especially in metastatic renal carcinoma. The authors of this international study sought to validate the International Metastatic Renal Cell Carcinoma Database Consortium (IMDC) model in predicting the value of second-line targeted therapy in patients with disease progression on first-line targeted therapy. Their study included 1,021 patients on second-line targeted therapy in 19 international centers. The IMDC identified five (of six) predefined factors (anemia, thrombocytopenia, neutrophilia, Karnofsky performance status less than 80%, and interval less than 1 year from diagnosis to treatment), measured at the time of second-line targeted therapy, as independent predictors of poorer overall survival. The sixth predefined factor, hypercalcemia, was not a statistically significant predictor in multivariable analysis. The authors concluded, “The IMDC prognostic model has been validated in and can be applied to patients previously treated with targeted therapy, in addition to previously validated populations in first-line targeted therapy and non-clear cell setting.” n

Disclosure: Dr. Boxer reported no potential conflicts of interest.

ASCOPost.com | MARCH 15, 2014

PAGE 11

Genitourinary Cancers Symposium Genitourinary Oncology

Fine-Tuning Bladder-Preservation Trimodality Therapy for Patients With Muscle-Invasive Bladder Cancer By Alice Goodman

rgan preservation is a hallmark of progress in the world of cancer management. For patients with muscle-invasive bladder cancer, the bladder-sparing approach is a wellestablished alternative to radical cystectomy. Patients undergo cystoscopic evaluation between the induction and consolidation phases of chemoradiation, and patients with an incomplete response to the induction phase are promptly offered cystectomy. A retro-

bladder-preservation approach, used in the United States, includes maximal transurethral resection of bladder tumor (TURBT), followed by radiation with concurrent chemotherapy, Dr. Mitin explained. Patients undergo cystoscopic evaluation with biopsies after the first phase of chemoradiation induction. Patients with complete response go on to receive a consolidation phase of chemoradiotherapy. Otherwise patients undergo radical cystectomy, he said.

Relaxed Criteria

Timur Mitin, MD, PhD

spective pooled analysis of two multiinstitutional trials found no difference in disease-specific, bladder-intact, and overall survival between patients with a complete response or near-complete response to induction chemoradiation.1

Pooled Analysis “These results suggest that it is appropriate to recommend that patients with near-complete response to induction chemoradiation be continued on bladder-preserving therapy,” said lead author Timur Mitin, MD, PhD, of the Department of Radiation Medicine at the Oregon Health and Science University, Portland. The study was based on a pooled analysis of two Radiation Therapy Oncology Group (RTOG) trials (9906 and 0233) to determine long-term outcomes among patients with muscleinvasive bladder cancer who achieve either complete or a near-complete response after induction chemoradiotherapy. Results were presented at the 2014 Genitourinary Cancers Symposium in San Francisco. Bladder-conservation therapy has been around in Europe and North America for about 4 decades, but the current backbone of the trimodality

“Historically, complete response after cystoscopic evaluation has been defined as T0 (no tumor), but many physicians have been reluctant to offer radical cystectomy to patients with only a small amount of noninvasive tumor (Ta) or carcinoma in situ (Tis), following induction chemoradiation,” Dr. M itin told the audience. Both trials had relaxed criteria for requiring salvage cystectomy and allowed patients with Ta or Tis after the induction to continue with consolidation chemoradiation. RTOG 9906 was a single-arm trial of 80 patients who received paclitaxel/cisplatin plus twicedaily radiation following transurethral resection of bladder tumor. RTOG 0233 was a phase II trial that randomly assigned 97 patients post–transurethral resection of bladder tumor to twicedaily radiation with either paclitaxel/ cisplatin or fluorouracil/cisplatin. The radiation dose and techniques were the same in the two trials. The pooled analysis of outcomes in-

EXPERT POINT OF VIEW

“T

his study has the potential to expand the number of patients who can benefit from organ-sparing therapy,” said Thomas W. Flaig, MD, Associate Professor in the Division of Medical Oncology at the University of Colorado Denver, commenting on the pooled analysis of RTOG 9906 and 0233 presented at the Genitourinary Cancers Symposium. “This is an important question that comes up in clinical practice. Even Thomas W. Flaig, MD though we have good options such as the creation of a surgical neobladder for select patients once their bladders are removed, it is a very important decision for patients to remove the bladder,” he noted. “This study provides a rationale for continuing with organ-sparing therapy in patients with near-complete response, who are now frequently on their way to having their bladders removed. The study gives us new information to discuss with patients when making this decision. The decision should be individualized from patient to patient,” Dr. Flaig commented. n Disclosure: Dr. Flaig reported no potential conflicts of interest.

cluded 119 eligible patients: 101 with complete response (85%) and 18 with near-complete response (Ta or Tis, 15%). Median age was 65 years among complete responders and 70 years among nearcomplete responders. The majority of patients had clinical stage T2 at diagnosis.

Major Findings At a median follow-up of 5.9 years, 5-year survival was 72% among complete responders and 61% among nearcomplete responders, which was not statistically significant. Disease-free survival was also not statistically different between the two groups of patients.

Evolving Approach to Bladder Cancer ■■ A pooled analysis of two RTOG bladder cancer trials suggests that patients with near-complete response (defined as Ta or Tis) to induction chemoradiotherapy can proceed with a bladder-preservation approach. ■■ Long-term follow-up showed no significant difference in overall and disease-free survival, as well as similar low salvage cystectomy rates between patients who achieved complete response (defined as no tumor) and those who achieved near-complete response (defined as Ta or Tis) after the induction phase of combined-modality therapy. ■■ These findings suggest that a fifth of patients with muscle-invasive bladder cancer who elect to be treated with a trimodality bladder-preservation approach and achieve a near-complete response to the induction phase of chemoradiotherapy do not need to have an immediate cystectomy.

Among 101 patients with complete response after induction, 13 developed invasive bladder recurrence (13%), eventually requiring salvage cystectomy. Among 18 patients with near-complete response, there was one invasive bladder recurrence (6%), and this patient required salvage cystectomy. “Although this is a small retrospective analysis, there is no apparent difference in bladder recurrence and salvage cystectomy rates between complete responders and near-complete responders as judged at the time of cystoscopic evaluation after the induction phase of bladder-preserving trimodality therapy,” Dr. Mitin emphasized. n Disclosure: Dr. Mitin reported no potential conflicts of interest. For full disclosures of the study authors, visit abstracts.asco.org.

Reference 1. Mitin T, George A, Zietman AL, et al: Long-term outcomes among patients who achieve complete or near-complete responses after the induction phase of bladder-preserving combined modality therapy for muscle-invasive bladder cancer: A pooled analysis of RTOG 9906 and 0233. 2014 Genitourinary Cancers Symposium. Abstract 284. Presented January 31, 2014.

Take a bite out of G-CSF acquisition costs*

*Based on wholesale acquisition cost (WAC) of all short-acting G-CSF products as of November 11, 2013. WAC represents published catalogue or list prices and may not represent actual transactional prices. Please contact your supplier for actual prices.

Indication » GRANIXTM (tbo-filgrastim) Injection is a leukocyte growth factor indicated for reduction in the duration of severe neutropenia in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia.

Important Safety Information » Splenic rupture: Splenic rupture, including fatal cases, can occur following the administration of human granulocyte colony-stimulating factors (hG-CSFs). Discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture in patients who report upper abdominal or shoulder pain after receiving GRANIX.

» Acute respiratory distress syndrome (ARDS): ARDS can occur in patients receiving hG-CSFs. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS.

» Allergic reactions: Serious allergic reactions, including anaphylaxis, can occur in patients receiving hG-CSFs. Reactions can occur on initial exposure. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim.

GRANIX is another option in short-acting G-CSF therapy TM

» GRANIX demonstrated a 71% reduction in duration of severe neutropenia (DSN) vs placebo1 – GRANIX significantly reduced DSN when compared to placebo (1.1 days vs 3.8 days; p<0.001)1 – Efficacy was evaluated in a multinational, multicenter, randomized, controlled, Phase III study of chemotherapy-naïve patients with high-risk breast cancer receiving doxorubicin (60 mg/m2 IV bolus)/docetaxel (75 mg/m2)1

» Safety was evaluated in 3 Phase III clinical trials1

Important Safety Information (continued) » Use in patients with sickle cell disease: Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving hG-CSFs. Consider the potential risks and benefits prior to the administration of GRANIX in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis.

» Potential for tumor growth stimulatory effects on malignant cells: The granulocyte colonystimulating factor (G-CSF) receptor, through which GRANIX acts, has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded.

» Most common treatment-emergent adverse reaction: The most common treatment-emergent adverse reaction that occurred in patients treated with GRANIX at the recommended dose with an incidence of at least 1% or greater and two times more frequent than in the placebo group was bone pain.

Please see brief summary of Full Prescribing Information on adjacent page. For more information, visit GRANIXhcp.com. Reference: 1. GRANIX TM (tbo-filgrastim) Injection Prescribing Information. North Wales, PA: Teva Pharmaceuticals; 2013.

The ASCO Post | MARCH 15, 2014

PAGE 14

Cancer Prevention Gastrointestinal Oncology

Colorectal Cancer Screening: Quality Measures Should Focus on Patient Benefit Over Age Alone, Study Reports

creening for colorectal cancer based on age alone may contribute to both underuse and overuse of colonoscopy, sigmoidoscopy, and fecal occult blood testing among older people, according to

a study by investigators at the University of Michigan and the Veterans Affairs Center for Clinical Management Research (VA- CCMR). The use of simple age cutoffs in quality measures may contribute to unde-

ruse of screening in healthy, older people and overuse in unhealthy, older people, Eve Kerr, MD, MPH, Sameer Saini, MD, and colleagues reported recently in BMJ.1 Dr. Kerr, senior study author, is Direc-

Eve Kerr, MD, MPH

BRIEF SUMMARY OF PRESCRIBING INFORMATION FOR GRANIX™ (tbo-filgrastim) Injection, for subcutaneous use SEE PACKAGE INSERT FOR FULL PRESCRIBING INFORMATION 1 INDICATIONS AND USAGE GRANIX is indicated to reduce the duration of severe neutropenia in patients with non-myeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Splenic Rupture Splenic rupture, including fatal cases, can occur following administration of human granulocyte colony-stimulating factors. In patients who report upper abdominal or shoulder pain after receiving GRANIX, discontinue GRANIX and evaluate for an enlarged spleen or splenic rupture. 5.2 Acute Respiratory Distress Syndrome (ARDS) Acute respiratory distress syndrome (ARDS) can occur in patients receiving human granulocyte colony-stimulating factors. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving GRANIX, for ARDS. Discontinue GRANIX in patients with ARDS. 5.3 Allergic Reactions Serious allergic reactions including anaphylaxis can occur in patients receiving human granulocyte colony-stimulating factors. Reactions can occur on initial exposure. The administration of antihistamines‚ steroids‚ bronchodilators‚ and/or epinephrine may reduce the severity of the reactions. Permanently discontinue GRANIX in patients with serious allergic reactions. Do not administer GRANIX to patients with a history of serious allergic reactions to filgrastim or pegfilgrastim. 5.4 Use in Patients with Sickle Cell Disease Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disease receiving human granulocyte colony-stimulating factors. Consider the potential risks and benefits prior to the administration of human granulocyte colony-stimulating factors in patients with sickle cell disease. Discontinue GRANIX in patients undergoing a sickle cell crisis. 5.5 Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte colony-stimulating factor (G-CSF) receptor through which GRANIX acts has been found on tumor cell lines. The possibility that GRANIX acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which GRANIX is not approved, cannot be excluded. 6 ADVERSE REACTIONS The following potential serious adverse reactions are discussed in greater detail in other sections of the labeling: • Splenic Rupture [see Warnings and Precautions (5.1)] • Acute Respiratory Distress Syndrome [see Warnings and Precautions (5.2)] • Serious Allergic Reactions [see Warnings and Precautions (5.3)] • Use in Patients with Sickle Cell Disease [see Warnings and Precautions (5.4)] • Potential for Tumor Growth Stimulatory Effects on Malignant Cells [see Warnings and Precautions (5.5)] The most common treatment-emergent adverse reaction that occurred at an incidence of at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group was bone pain. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice. GRANIX clinical trials safety data are based upon the results of three randomized clinical trials in patients receiving myeloablative chemotherapy for breast cancer (N=348), lung cancer (N=240) and non-Hodgkin’s lymphoma (N=92). In the breast cancer study, 99% of patients were female, the median age was 50 years, and 86% of patients were Caucasian. In the lung cancer study, 80% of patients were male, the median age was 58 years, and 95% of patients were Caucasian. In the non-Hodgkin’s lymphoma study, 52% of patients were male, the median age was 55 years, and 88% of patients were Caucasian. In all three studies a placebo (Cycle 1 of the breast cancer study only) or a non-US-approved filgrastim product were used as controls. Both GRANIX and the non-US-approved filgrastim product were administered at 5 mcg/kg subcutaneously once daily beginning one day after chemotherapy for at least five days and continued to a maximum of 14 days or until an ANC of ≥10,000 x 106/L after nadir was reached.

Bone pain was the most frequent treatment-emergent adverse reaction that occurred in at least 1% or greater in patients treated with GRANIX at the recommended dose and was numerically two times more frequent than in the placebo group. The overall incidence of bone pain in Cycle 1 of treatment was 3.4% (3.4% GRANIX, 1.4% placebo, 7.5% non-US-approved filgrastim product). Leukocytosis In clinical studies, leukocytosis (WBC counts > 100,000 x 106/L) was observed in less than 1% patients with non-myeloid malignancies receiving GRANIX. No complications attributable to leukocytosis were reported in clinical studies. 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving GRANIX has not been adequately determined. 7 DRUG INTERACTIONS No formal drug interaction studies between GRANIX and other drugs have been performed. Drugs which may potentiate the release of neutrophils‚ such as lithium‚ should be used with caution. Increased hematopoietic activity of the bone marrow in response to growth factor therapy has been associated with transient positive bone imaging changes. This should be considered when interpreting bone-imaging results. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of GRANIX in pregnant women. In an embryofetal developmental study, treatment of pregnant rabbits with tbo-filgrastim resulted in adverse embryofetal findings, including increased spontaneous abortion and fetal malformations at a maternally toxic dose. GRANIX should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. In the embryofetal developmental study, pregnant rabbits were administered subcutaneous doses of tbo-filgrastim during the period of organogenesis at 1, 10 and 100 mcg/kg/day. Increased abortions were evident in rabbits treated with tbo-filgrastim at 100 mcg/kg/day. This dose was maternally toxic as demonstrated by reduced body weight. Other embryofetal findings at this dose level consisted of post-implantation loss‚ decrease in mean live litter size and fetal weight, and fetal malformations such as malformed hindlimbs and cleft palate. The dose of 100 mcg/kg/day corresponds to a systemic exposure (AUC0-24) of approximately 50-90 times the exposures observed in patients treated with the clinical tbo-filgrastim dose of 5 mcg/kg/day. 8.3 Nursing Mothers It is not known whether tbo-filgrastim is secreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when GRANIX is administered to a nursing woman. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. 8.4 Pediatric Use The safety and effectiveness of GRANIX in pediatric patients have not been established. 8.5 Geriatric Use Among 677 cancer patients enrolled in clinical trials of GRANIX, a total of 111 patients were 65 years of age and older. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. 8.6 Renal Impairment The safety and efficacy of GRANIX have not been studied in patients with moderate or severe renal impairment. No dose adjustment is recommended for patients with mild renal impairment. 8.7 Hepatic Impairment The safety and efficacy of GRANIX have not been studied in patients with hepatic impairment. 10 OVERDOSAGE No case of overdose has been reported. ©2013 Cephalon, Inc., a wholly owned subsidiary of Teva Pharmaceutical Industries Ltd. All rights reserved. GRANIX is a trademark of Teva Pharmaceutical Industries Ltd. Manufactured by: Distributed by: Sicor Biotech UAB Teva Pharmaceuticals USA, Inc. Vilnius, Lithuania North Wales, PA 19454 U.S. License No. 1803 Product of Israel GRX-40189 January 2014 This brief summary is based on TBO-003 GRANIX full Prescribing Information.

Sameer Saini, MD

tor of the VA-CCMR and Professor of Internal Medicine, and Dr. Saini is a Research Scientist at VA-CCMR and Assistant Professor of Internal Medicine, both at the University of Michigan Health System, Ann Arbor. The researchers found that an unhealthy 75-year-old, whose life expectancy is estimated at less than 5 years, was significantly more likely to undergo screening than a 76-year-old in good health.

Implications of Quality Measures “The way quality measures are defined has important implications for how care is delivered,” Dr. Saini said. “By focusing on age alone we’re not screening everyone who’s likely to benefit and some people who are not likely to benefit are being screened unnecessarily. If quality measures focused on age and health status, rather than age alone, we would have better outcomes,” Dr. Saini added. In elderly patients, life expectancy varies considerably according to health status. A 74-year-old man in excellent health has a life expectancy of almost 15 years. The study suggests the upper age cutoff could unintentionally discourage colorectal cancer screening in healthy, older individuals. Dr. Kerr said, “Future patient-centered quality measures should focus on clinical benefit rather than age to ensure that patients who are likely to benefit from screening receive it, regardless of age, and that those who are likely to incur harm are spared unnecessary and costly care.” n Reference 1. Saini SD, Vijan S, Kerr EA, et al: Role of quality measurement in inappropriate use of screening for colorectal cancer. BMJ. February 26, 2014 (early release online).

ASCOPost.com | MARCH 15, 2014

PAGE 15

Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Aspirin Use Not Associated With Survival in PIK3CA-Mutant Colorectal Cancer By Caroline Helwick

ontrary to emerging data from other studies, the regular use of aspirin was not associated with improved survival in patients with PIK3CA-mutant metastatic colorectal cancer in a study reported at the 2014 Gastrointestinal Cancers Symposium in San Francisco.1

Large Dataset “We did not validate survival benefits associated with aspirin in [patients with PIK3CA-mutant disease] across all stages, despite having a larger data-

Nishi Kothari, MD

set” than previously reported studies, reported Nishi Kothari, MD, of Moffitt Cancer Center in Tampa, Florida. “We were also not able to validate

the recurrence-free survival benefits associated with aspirin in [patients with PIK3CA-mutant] stage II and III colorectal cancer,” she added. In a meta-analysis of five randomized trials involving more than 14,000 patients followed for at least 20 years, published in the Lancet, the use of aspirin was associated with a 24% reduction in colorectal cancer occurrence and a 35% reduction in mortality associated with the disease.2 In the Nurses’ Health Study and the Health Professionals Follow-up Study, reported in The New England Journal of Medicine, patients with PIK3CA-mutated tumors who were regular aspirin users had an 82% reduction in colorectal cancer deaths and a 45% reduction in deaths from all causes.3 Most recently, in the VICTOR trial, aspirin use was associated with an 89% reduction in recurrence in patients with PIK3CA mutations.4

No Benefit in Current Study The study reported at the Gastrointestinal Cancers Symposium involved

Expert Point of View

eal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Seidman Cancer Center and Case Western Reserve University, Cleveland, discussed the study by Kothari et al presented at the Gastrointestinal Cancers Symposium. He noted that complex interactions exist between PIK3CA and other signaling pathways, including pathways for prostaglandin synthesis, and this contributes to the growth and Neal J. Meropol, MD development of colorectal cancer. “So, the natural question is whether mutations in PIK3CA will influence the potential benefit from aspirin in patients with colorectal cancer,” he said. “Aspirin’s effects are not only on cell signaling. Aspirin also has myriad effects on the tumor microenvironment that may play a role in this context.”

All Available Data Limited In contrast to previous studies with “very impressive hazard ratios” that support the underlying hypothesis, the Kothari study found no clear survival benefit for aspirin users with PI3KCA mutations,” Dr. Meropol suggested. But he pointed out that all available datasets are limited by challenges, including lack of randomization between aspirin use and no use, reliance on patient reports of aspirin use, variations in dosing of aspirin, variation in cancer stages, and small samples sizes. “A prospective evaluation of aspirin and COX2 inhibition in the PIK3CAmutated colorectal cancer population is definitely needed,” he said, predicting that “meaningful data” will emerge from ongoing randomized studies of aspirin and celecoxib (Celebrex) in the adjuvant setting. n Disclosure: Dr. Meropol has received consulting fees from Precision Therapeutics.

Aspirin in PIK3CA-Mutated Colorectal Cancer ■■ In metastatic colorectal cancer harboring the PIK3CA mutation, regular use of aspirin was not associated with improved recurrence-free or overall survival in a retrospective study of 185 patients with mutated tumors. ■■ The findings are in contrast to several other large studies that have found a positive association, but sample sizes remain small.

a review of 1,019 colorectal cancer patients from the Royal Melbourne Hospital in Australia diagnosed between 1996 and 2009, and 468 similar patients from Moffitt Cancer Center and consortium sites diagnosed between 1998 and 2010. Genetic sequencing revealed 185 patients with mutations in the PIK3CA gene. Among these, 49 were regular aspirin users and 136 were not. “To date this is the largest PIK3CAmutant study population looking at aspirin therapy,” Dr. Kothari indicated. At baseline, aspirin users had significantly fewer right-sided tumors (41% vs 64%, P = .006), were older (median age, 74 vs 70; P = .009), and tended to have more advanced cancers (stage IV in 26% vs 18%, P = .52), compared to nonusers. “Unlike previous studies, we did not confirm a relationship between aspirin use and improved overall survival across the cohort,” Dr. Kothari reported. At 10 years, almost 50% of both groups were alive (hazard ratio [HR] = .96; P = .86). Aspirin users had more medical comorbidities, which could worsen overall survival, and the researchers attempted to account for this by using cancer-specific survival as an outcome. “We still found no improvement in survival among aspirin users (HR = .60; P = .24),” she said. “Because of the differences in our work and previously published data, we looked to ensure the validity of our study population,” she said. In the multivariate analysis, as expected, increasing age was associated with worse survival and increasing stage was associated with worse overall and cancer-specific survival. However, aspirin use was not associated with improved overall survival (HR = .94; P = .83) or cancerspecific survival (HR .64; P = .24). “Because our population had a different stage breakdown than previously published work, we stratified patients by stage,” she continued, “but did not find decreased risk of recurrent disease for stage II and III patients who used aspirin. We did find a trend toward improved overall survival for stage IV patients

(HR = .40; P = .06), but this trend was not sustained in the multivariate analysis.”

Potential Explanations Dr. Kothari proposed that the differences between her findings and those of others could be attributed to the smaller proportion of right-sided cancers in this study (which were associated with worse survival), to the more advanced stage of the patients (which may have a different biology), and to the fact that this was a largely unselected community-based population. The follow-up is also shorter (46 months) than previous studies. “We may see different trends as the data mature,” she acknowledged. As a retrospective study, the current research also lacks information about colorectal cancer treatment and duration of aspirin use. Moreover, the Moffitt population included mutations outside of exons 9 and 20, which have not yet been studied regarding their biologic relevance, she said. “To help resolve these issues, we will contribute data to the individual patient analysis from the Oxford group, which will combine our data with the VICTOR trial as well as the study by Liao et al,” Dr. Kothari added. n

Disclosure: Dr. Kothari reported no potential conflicts of interest.

References 1. Kothari N, Kim RD, Gibbs P, et al: Regular aspirin use and survival in patients with PIK3CA-mutated metastatic colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract 386. Presented January 18, 2014. 2. Rothwell PM, Wilson M, Elwin CE, et al: Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials. Lancet 376:1741-1750, 2010. 3. Liao X, Lochhead P, Nishihara R, et al: Aspirin use, tumor PIK3CA mutation, and colorectal-cancer survival. N Engl J Med 367:1596-1606, 2012. 4. Domingo E, Church DN, Sieber O, et al: Evaluation of PIK3CA mutation as a predictor of benefit from nonsteroidal antiinflammatory drug therapy in colorectal cancer. J Clin Oncol 31:4297-305, 2013.

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

More Support for ‘All-RAS’ Testing in Metastatic Colorectal Cancer By Caroline Helwick

ultiple studies reported at the 2014 Gastrointestinal Cancers Symposium add further support for widening the genetic analysis of colorectal cancer tumors. In fact, experts predict that more extensive genetic testing for RAS gene mutations (in KRAS and NRAS) beyond the routine analysis of KRAS exon 2 will become the standard of care for identifying patients for treatments targeting the epidermal growth factor receptor (EGFR).

Predicting Response to Panitumumab Marc Peeters, MD, PhD, Professor of Oncology at Antwerp University Hospital in Belgium, reported that activating mutations in less common exons of both KRAS and NRAS all predicted a lack of response to panitumumab (Vectibix) in the second-line setting.1 The findings cor-

Marc Peeters, MD, PhD

roborate recent findings from the PRIME and PEAK trials regarding the efficacy of panitumumab in first-line therapy, he said. The study was a retrospective analysis from the randomized phase III 20050181 trial comparing the addition of panitumumab to second-line treatment with FOLFIRI (leucovorin/fluorouracil [5FU]/irinotecan) in 1,186 patients. Investigators reanalyzed tumor specimens previously classified as wild-type KRAS exon 2, detecting additional mutations in exons 3 and 4 of KRAS and exons 2, 3, and 4 of NRAS. These new mutations occurred in 18% of patients with wild-type KRAS exon 2 disease and predicted a lack of response to the drug, Dr. Peeters reported. Clinical outcomes were associated with these newly identified mutations. The overall survival hazard ratio (HR) of 0.850 (P = .12) in the previously defined KRAS wild-type population improved to 0.803 in the new analysis of all-RAS wildtype patients (P = .08). Median overall survival was 16.2 months in the panitumumab arm and 13.9 months with FOLFIRI alone. The progression-free survival hazard ratio improved from 0.73 (P = .004) to 0.695 (P = .006) when including all-RAS wild-type patients.

“If patients have a [RAS] mutant tumor, I don’t think there is a benefit to adding panitumumab to the chemotherapy backbone of FOLFIRI, but there is no deleterious effect,” he said. In the mutant RAS group, both arms had a median overall survival of approximately 11 months. In the new analysis, the objective response rate to panitumumab/FOLFIRI also increased to 41% in the all-RAS wild-type patients, from 35% in the initial analysis. “Based on all the data that’s been generated, it’s clear that today we need RAS testing instead of KRAS exon 2 testing before embarking on anti-EGFR treatment in patients with metastatic colorectal cancer,” he suggested.

Similar Findings With Cetuximab The same conclusions were drawn with regard to cetuximab (Erbitux) in new analyses from three other studies: FIRE-3, OPUS, and CECOG/CORE2. “Patients with all-RAS wild-type tumors have a clinically relevant survival benefit when first-line treatment with FOLFIRI plus cetuximab is offered,” said Sebastian Stintzing, MD, of the Klinikum Grosshadern and the Comprehensive Cancer Center at LMU Munich in Germany, who reported the FIRE-3 findings.2 The study compared cetuximab and bevacizumab (Avastin), added to FOLFIRI, as first-line treatment in 592 wild-type KRAS exon 2 metastatic colorectal cancer patients. New mutations were found in 16% of KRAS exon 2 wild-type patients, including KRAS exons 3 and 4 and NRAS exons 2, 3, and 4. Frequency of BRAF V600E mutation was 10%. PIK3CA mutations in exons 9 and 20 mutations were found in 7.3% and AKT mutations in 1%. The median overall survival was signifi-

EXPERT POINT OF VIEW

eal J. Meropol, MD, Chief of Hematology and Oncology at University Hospitals Case Medical Center at Case Western Reserve University, Cleveland, discussed the various findings in RAS mutations at the Gastrointestinal Cancers Symposium. “RAS mutations beyond exon 2 are common, occurring in about 15% to 18% of patients, and patients with any RAS mutations do not appear to benefit—at least in a major way—from anti-EGFR treatment,” he emphasized. “I do believe it’s time to adopt more extensive RAS testing in our patients with colorectal cancer.” “Among patients with no RAS mutations, a clinically meaningful survival benefit was observed with cetuximab [Erbitux] compared with bevacizuimab [Avastin] in FIRE-3, but no difference in progression-free survival. Results of the ongoing Alliance 80405 trial are of great interest in this regard,” he added. “Currently, the incomplete data regarding potential biologic differences when combining different EGFR inhibitors with different chemotherapy backbones, and between different RAS mutations, awaits further augmentation of the dataset. Pooled analysis of all available studies is encouraged.” n Disclosure: Dr. Meropol has received consulting fees from Precision Therapeutics.

cantly higher with cetuximab than bevacizumab in patients without RAS mutations, suggesting that the exclusion of patients with RAS mutations identifies a population more likely to benefit from cetuximab. “No benefit was observed when pa-

Sebastian Stintzing, MD

tients with RAS-mutant tumors were treated with FOLFIRI plus cetuximab as compared to FOLFIRI plus bevacizumab,” Dr. Stintzing said.

All-RAS Testing in Metastatic Colorectal Cancer ■■ There is mounting support for testing metastatic colorectal patients for mutations in the RAS gene (KRAS and NRAS) beyond KRAS exon 2; approximately 15% of patients have relevant mutations beyond KRAS exon 2. ■■ In a retrospective analysis of the 20050181 trial of panitumumab plus FOLFIRI, all-RAS wild-type patients receiving the EGFR inhibitor had a 20% reduction in deaths; median overall survival was 16.2 months in the panitumumab arm and 13.9 months with FOLFIRI alone among patients with wild-type RAS. ■■ In a new analysis of FIRE-3, which compared cetuximab and bevacizumab plus FOLFOX4, among all-RAS wild-type patients, cetuximab provided an overall survival benefit over bevacizumab. ■■ Additional analyses of OPUS and CECOG/CORE2 confirmed the benefit of cetuximab among all-RAS wild-type patients.

An absolute overall survival benefit of 7.5 months was revealed when the analysis was done on the all-RAS wild-type population: Median overall survival was 33.1 months in the cetuximab arm and 25.6 months in the bevacizumab arm (HR = 0.70; P = .011). Interestingly, overall response rate and progression-free survival were not superior with cetuximab, and in the patients with RAS-mutant disease, bevacizumab actually led to better progression-free survival. Though subsets of the more rare mutations were small, the study found comparable effects on overall survival for cetuximab and bevacizumab. Patients with BRAF mutations had a very poor progression-free and overall survival regardless of treatment designation. “The BRAF mutation is a very bad prognostic factor,” he noted. Among PIK3CA-mutated patients, there was a trend toward longer median progression-free survival with bevacizumab (13.3 vs 7.8 months), but it was not statistically significant (P = .18). Median overall survival was about 26 months in each arm. The findings from FIRE-3 and the 20050181 trial were upheld by mutational analyses from OPUS3 and the phase II CECOG/CORE2 trial,4 presented at the meeting. Describing the OPUS analysis, Sabine Tejpar, MD, PhD, Associate Professor at the University Hospital Gasthuisberg in Leuven, Belgium, reported the breakdown of new RAS mutations be-

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Gastrointestinal Cancers Symposium yond KRAS exon 2: KRAS exon 3 (6.8%), KRAS exon 4 (9.3%), NRAS exon 2 (7.6%), NRAS exon 3 (5.1%), and NRAS exon 4 (3.4%). Patients harboring any of these activating mutations were unlikely to benefit from cetuximab, she said. “In the RAS wild-type population, there was significant benefit associated with the addition of cetuximab to FOLFOX4 [leucovorin/5-FU/oxaliplatin] in relation to progression-free survival and objective response rates, while

FIRI for second-line treatment of metastatic colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract LBA387. Presented January 18, 2014. 2. Stintzing S, et al: Mutations within the EGFR signaling pathway. 2014 Gastrointestinal Cancers Symposium. Abstract 445. Presented January 18, 2014. 3. Tejpar S, et al: Effect of KRAS and NRAS mutations on treatment outcomes in patients

from Bristol-Myers Squibb, Merck Serono, and Roche/Genentech. Dr. Tejpar is a consultant for and has received honoraria from Merck Serono. Dr. Brodowicz has received honoraria from Amgen and Merck Serono. For full disclosures of all study authors, visit meetinglibrary.asco.org.

References 1. Peeters M, et al: Analysis of KRAS/ NRAS mutations in phase 3 study 20050181 of panitumumab plus FOLFIRI versus FOL-

with metastatic colorectal cancer treated firstline with cetuximab plus FOLFOX4. 2014 Gastrointestinal Cancers Symposium. Abstract LBA444. Presented January 18, 2014. 4. Brodowicz T, et al: FOLFOX4 plus cetuximab administered weekly or every two weeks in first-line treatment of patients with KRAS and NRAS wild-type metastatic colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract LBA391. Presented January 18, 2014.

Genentech is investigating the potential of selectively blocking PD-L1. Explore the role of cancer immunotherapy and PD-L1 inhibition at ResearchCancerImmunotherapy.com

Sabine Tejpar, MD, PhD

the hazard ratio for overall survival also favored the FOLFOX4/cetuximab arm,” she said. “In the RAS mutant population, there was less favorable clinical outcome and no benefit—even harm—from the addition of cetuximab.” Overall survival was approximately 4 months shorter in the cetuximab arm, among patients with RAS-mutant colorectal cancer, in the new OPUS analysis. In the randomized phase II CECOG/ CORE2 trial, investigators evaluated 148 KRAS exon 2 wild-type patients treated with first-line FOLFOX4 plus cetuximab and found that patients with RAS/BRAF wild-type disease had a significant prolongation of overall survival as compared to patients with mutant RAS/BRAF. “This analysis supports the findings of other trials that RAS mutational analyses in metastatic colorectal disease is recommended prior to the initiation of an EGFR-targeted monoclonal antibody therapy,” said Thomas Brodowicz, MD,

Exploring the PD-L1 network: a new frontier in oncology PD-L1 plays a central role in cancer’s ability to evade the immune system1 Cancer cells use various mechanisms to circumvent the immune system, including certain ligands such as programmed death-ligand 1 (PD-L1) that can deactivate T-cell–mediated cytotoxicity. This deactivation inhibits the immune system, thereby enabling tumor growth.1

Inhibition of the PD-L1 network requires careful consideration of its components The complex PD-L1 network is comprised of several interactions, including: • PD-1/PD-L1: PD-1, expressed on activated T cells, binds to PD-L1 to inhibit immune activation and reduce T-cell–mediated cytotoxicity2 • PD-1/PD-L2: PD-1 also binds to PD-L2, a ligand expressed on antigenpresenting cells (APCs), which can result in inhibition of some immune responses and play a vital role in maintaining immune homeostasis2-4 • B7.1/PD-L1: B7.1, found on both activated T cells and APCs, binds to PD-L1 and can contribute to suppression of antitumor T-cell responses2 Because of the complexity of the PD-L1 network, blockade strategies must be carefully considered.

Dendritic cell

PD-L1

PD-1

T cell

PD-L2

B7.1 TCR PD-L1

MHC Thomas Brodowicz, MD

Associate Professor of Hematology/Oncology at the Medical University of Vienna and Central European Cooperative Oncology Group. n

Disclosure: Dr. Peeters is a consultant for and has received honoraria and research funding from Amgen. Dr. Stintzing is a consultant for Merck KGaA and Roche/Genentech and has received honoraria

Tumor cell

References: 1. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480:480-489. 2. Keir ME, Butte MJ, Freeman GJ, Sharpe AH. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677-704. 3. Loke P, Allison JP. PD-L1 and PD-L2 are differentially regulated by Th1 and Th2 cells. Proc Natl Acad Sci U S A. 2003;100:5336-5341. 4. Chen DS, Irving BA, Hodi FS. Molecular pathways: next-generation immunotherapy—inhibiting programmed death-ligand 1 and programmed death-1. Clin Cancer Res. 2012;18:6580-6587.

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Outcomes in Metastatic Colorectal Cancer: Studies Examine Relative Merits, Cost-Effectiveness By Caroline Helwick

argeted biologic agents have improved long-term outcomes in metastatic colorectal cancer, but debate continues as to their relative efficacy and proper sequencing. At the 2014 Gastrointestinal Cancers Symposium, a number of studies attempted to answer these questions by interrogating the clinical trial databases to assess not only efficacy, but “value.” A summary of their key findings is reported here.

Relative Merits of Targeted Agents “Biologic therapies used in treating metastatic colorectal cancer are expensive, and debate continues about their ideal place in the therapeutic pathway.

David Chan, MD

Individual trials inconsistently show their potential to improve outcomes. A meta-analysis was therefore performed to assess the impact in patients progressing after first-line therapy,” said David Chan, MD, of the Royal North Shore Hospital in St. Leonards, Australia. Dr. Chan and colleagues evaluated the value of agents targeting the vascular endothelial growth factor (VEGF) receptor and epidermal growth factor receptor (EGFR) beyond the first-line setting by identifying trials comparing standard treatment to chemotherapy plus a biologic agent.1 They used several established databases as well as The Cochrane Library, proceedings of major oncology meetings, and unpublished data on trials of EGFR inhibitors (cetuximab [Erbitux], panitumumab [Vectibix]), VEGF receptor tyrosine kinase inhibitors (regorafenib [Stivarga]), anti-VEGF monoclonal antibodies (bevacizumab [Avastin]), and VEGF Trap (ziv-aflibercept [Zaltrap]). The key results were as follows: • All of the targeted drug classes improve progression-free survival and increase response rates in relapsed/refractory metastatic colorectal cancer. • Bevacizumab and aflibercept are also associated with improved overall survival (as one class, hazard ratio

[HR] = 0.79; P < .00001). • EGFR inhibitors as single agents or combined with chemotherapy, as well as regorafenib, have less certain effects on overall survival in random-effects modeling, likely due to crossover in some trials. Recent data regarding extended RAS testing may alter the results for cetuximab and panitumumab. • All classes increased grade 3/4 toxicity (more than twofold), but not grade 5 toxicity.

EGFR Inhibitors vs Bevacizumab The FIRE-3 trial compared cetuximab and bevacizumab, showing improved overall survival, but not progression-free survival, with cetuximab.2 A systematic review of randomized controlled trials of first-line treatment, presented by Alexander Kumachev, MSc, BSc (Hons), a medical student at the University of Toronto, compared these agents and found that the results depended on the method of analysis.3 For their evaluation of 15 randomized trials involving 6,960 patients, the researchers used Bayesian pairwise and network meta-analyses to estimate the direct, indirect, and combined progression-free and overall survival hazard ratios comparing EGFR inhibitors to bevacizumab. The direct pairwise analysis evaluated two trials—FIRE-3, which compared bevacizumab and cetuximab, and PEAK, which compared bevacizumab and panitumumab. In this analysis, the hazard ratio for progression-free survival was 1.00, while the hazard ratio for overall survival was 0.76 in favor of EGFR inhibitors. The investigators combined this direct comparison with the indirect comparisons (13 trials of biologic vs chemotherapy alone) and the network meta-analysis (15 trials) and found the overall progression-free survival hazard ratio to be 1.10, a trend favoring bevacizumab. The hazard ratio for overall survival was 0.95, indicating no difference, ie, no overall survival benefit for the EGFR inhibitors. “The results of direct pairwise metaanalysis, dominated by FIRE-3, suggested that EGFR inhibitors improved overall survival, without progression-free survival benefits, when compared to bevacizumab,” Mr. Kumachev noted. “However, the results from indirect or combined network meta-analyses, synthesizing all relevant data from the existing literature, did not confirm those findings,” he added.

“The findings of FIRE-3 may be due to chance or trial-specific reasons,” Mr. Kumachev suggested. “The results of the upcoming [Cancer and Leukemia Group B] (CALGB) 80405 trial will provide further direct evidence to help refine these estimates.”

worth the cost, or we need new third-line regimens, because historically we are not deriving a survival benefit,” he said. “Insurers will soon be passing along accountability not just to patients but to physician groups, and physicians will start asking, ‘Are we shifting survival

Benefit Beyond Second Line? Proceeding from first-line to secondline treatment with a chemotherapy regimen plus biologic significantly prolongs survival (HR = 0.659; P < .001) and colon cancer–specific survival (HR = 0.614; P < .001) in elderly patients, but treating beyond the second line does not. The findings are based on data from 5,129 metastatic colorectal cancer patients in the SEER-Medicare database, diagnosed between 2003 and 2007, prior to the advent of newer third-line agents.4 Investigators from the University of Maryland, Baltimore, conducted this large analysis and found that untreated patients had an adjusted median survival time of 6.8 months, but each line of chemotherapy/biologic led to longer survival: 11.9 months, 23.2 months, and 26.4 months for first-line treatment only, second-line treatment, and subsequent treatments, respectively. The respective colon cancer–specific mortality hazard ratios were 0.637, 0.398, and 0.364 (P < .001), in the study led by Nader N. Hanna, MD, of the University of Maryland team. In an interview, senior author C. Daniel Mullins, PhD, questioned whether additional survival benefits of fewer than 3 months in elderly patients warrants the use of expensive new drugs. “Either the third-line treatment is not

C. Daniel Mullins, PhD

enough to make third- and fourth-line regimens worth it?’” he continued.

Importance of First-Line Therapy Dr. Mullins also led a study that evaluated the options recommended by the National Comprehensive Cancer Network, and found that “real-world survival benefits” of second-line treatments varied greatly, depending upon the first-line regimen, and so did cost-effectiveness.5 The study identified 3,211 patients at least 66 years old diagnosed with metastatic colorectal cancer between 2003 and 2009. Compared to patients who received first-line treatment, those who went on to receive second-line treatment lived longer, but the additional gain varied by the type of first-line regimen. Additional days associated with second-line treatment, according to their first-line therapy, were 172 for fluorouracil (5-FU)/leucovorin,

Treating Metastatic Colorectal Cancer ■■ A meta-analysis found that the use of EGFR inhibitors, VEGF receptor tyrosine kinase inhibitors, anti-VEGF monoclonal antibodies, and VEGF trap all improve progression-free survival and increase response rates in relapsed/refractory metastatic colorectal cancer. ■■ Bevacizumab and aflibercept also improve overall survival; the randomeffects model did not sustain a survival benefit for the EGFR inhibitors or regorafenib. ■■ A meta-analysis of trials evaluating EGFR inhibitor and bevacizumab as firstline treatment found no overall survival benefit for the EGFR inhibitor. ■■ Another systematic review found that overall survival benefits are limited to the first and second lines of treatment, with no survival benefit with thirdline treatment in the elderly. ■■ The efficacy and cost-effectiveness of second-line treatment appears to depend on which regimen elderly patients received in the first line; more aggressive first-line regimens were associated with better outcomes from second-line regimens.

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Gastrointestinal Cancers Symposium 126 for oxaliplatin, 210 for irinotecan, and 220 for “others,” which included irinotecan/oxaliplatin or a biologic agent without oxaliplatin or irinotecan. Cost also varied. Patients who received irinotecan/oxaliplatin or biologics without first receiving oxaliplatin or irinotecan gained higher survival benefits from further treatment, at a relative-

ly lower cost. The highest incremental cost-effectiveness ratio of second-line treatment was for oxaliplatin in the firstline setting ($247,799), and the lowest was for “other” regimens ($92,422). “Increasingly, the value proposition is something the health-care system is struggling with. Our paper broadens the discussion to show that it’s not as

Infusion reactions: The incidence of infusion reactions was 69% with the first infusion of GAZYVA. The incidence of Grade 3 or 4 infusion reactions was 21% with 8% of patients discontinuing therapy. The incidence of reactions with subsequent infusions was 3% with the second 1000 mg and <1% thereafter. No Grade 3 or 4 infusion reactions were reported beyond the first 1000 mg infused.

effects in animals. The high dose results in an exposure (AUC) that is 2.4 times the exposure in patients with CLL at the recommended label dose. When first measured on Day 28 postpartum, obinutuzumab was detected in offspring and B cells were completely depleted. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months after birth.

Of the first 53 patients receiving GAZYVA on the trial, 47 (89%) experienced an infusion reaction. After this experience, study protocol modifications were made to require pre-medication with a corticosteroid, antihistamine, and acetaminophen. The first dose was also divided into two infusions (100 mg on day 1 and 900 mg on day 2). For the 45 patients for whom these mitigation measures were implemented, 21 patients (47%) experienced a reaction with the first 1000 mg and <2% thereafter [see Dosage and Administration (2)].

8.3 Nursing Mothers It is not known whether obinutuzumab is excreted in human milk. However, obinutuzumab is excreted in the milk of lactating cynomolgus monkeys and human IgG is known to be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from GAZYVA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the importance of the drug to the mother.

Neutropenia: The incidence of neutropenia reported as an adverse reaction was 40% in the GAZYVA treated arm and 18% in the chlorambucil alone arm with the incidence of serious adverse events being 1% and 0%, respectively (Table 3). Cases of late onset neutropenia (occurring 28 days after completion of treatment or later) were 16% in the GAZYVA treated arm and 12% in the chlorambucil alone arm.

8.4 Pediatric Use The safety and effectiveness of GAZYVA in pediatric patients has not been established.

Infection: The incidence of infections was similar between arms. Thirty-eight percent of patients in the GAZYVA treated arm experienced an infection, 9% were Grade 3-4, and none were fatal. Thrombocytopenia: The incidence of thrombocytopenia reported as an adverse reaction was 15% in the GAZYVA treated arm and 7% in the chlorambucil alone arm (Table 3). Five percent of patients in the GAZYVA treated arm experienced acute thrombocytopenia (occurring within 24 hours after the GAZYVA infusion). Tumor Lysis Syndrome: The incidence of Grade 3 or 4 tumor lysis syndrome was 2% in the GAZYVA treated arm versus 0% in the chlorambucil arm. Musculoskeletal Disorders: Adverse events related to musculoskeletal disorders, including pain (System Organ Class) have been reported with GAZYVA with higher incidence than in the comparator arm (17% vs. 13%). 6.2 Immunogenicity Serum samples from patients with previously untreated CLL were tested during and after treatment for antibodies to GAZYVA. Approximately 13% (9/70) of GAZYVA treated patients tested positive for anti-GAZYVA antibodies at one or more time points during the 12 month follow-up period. Neutralizing activity of anti-GAZYVA antibodies has not been assessed. Immunogenicity data are highly dependent on the sensitivity and specificity of the test methods used. Additionally, the observed incidence of a positive result in a test method may be influenced by several factors, including sample handling, timing of sample collection, drug interference, concomitant medication and the underlying disease. Therefore, comparison of the incidence of antibodies to GAZYVA with the incidence of antibodies to other products may be misleading. Clinical significance of anti-GAZYVA antibodies is not known. 6.3 Additional Clinical Trial Experience Progressive multifocal leukoencephalopathy: PML has been reported with GAZYVA [see Warnings and Precautions (5.2)]. Worsening of Pre-Existing Cardiac Conditions: Fatal cardiac events have been reported in patients treated with GAZYVA. Hepatitis B reactivation: Hepatitis B virus reactivation has been reported with GAZYVA [see Warnings and Precautions (5.1)]. 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with GAZYVA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C Risk Summary There are no adequate and well-controlled studies of GAZYVA in pregnant women. Women of childbearing potential should use effective contraception while receiving GAZYVA and for 12 months following treatment. GAZYVA should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Animal Data In a pre- and post-natal development study, pregnant cynomolgus monkeys received weekly intravenous doses of 25 or 50 mg/kg obinutuzumab from day 20 of pregnancy until parturition. There were no teratogenic

8.5 Geriatric Use Of 240 previously untreated CLL patients who received GAZYVA in combination with chlorambucil, 196 patients (82%) were ≥ 65 years of age and 109 patients (45%) were ≥ 75 years of age. The median age was 74 years. Of the 109 patients ≥ 75 years of age, 49 (45%) experienced serious adverse events and 5 (5%) experienced adverse events leading to death. For 131 patients <75 years of age, 39 (30%) experienced a serious adverse event and 3 (2%) an adverse event leading to death. Similar rates were observed in the comparator arm. No significant differences in efficacy were observed between patients ≥ 75 years of age and those <75 years of age [see Clinical Studies (14.1)]. 8.6 Renal Impairment Based on population pharmacokinetic analysis, a baseline creatinine clearance (CLcr) >30mL/min does not affect the pharmacokinetics of GAZYVA. GAZYVA has not been studied in patients with a baseline CLcr<30mL/min. [see Clinical Pharmacology (12.3)]. 8.7 Hepatic Impairment GAZYVA has not been studied in patients with hepatic impairment. 10 OVERDOSAGE There has been no experience with overdose in human clinical trials. Doses ranging from 50 mg up to and including 2000 mg per infusion have been administered in clinical trials. For patients who experience overdose, treatment should consist of immediate interruption or reduction of GAZYVA and supportive therapy. 17 PATIENT COUNSELING INFORMATION Advise patients to seek immediate medical attention for any of the following: • Signs and symptoms of infusion reactions including dizziness, nausea, chills, fever, vomiting, diarrhea, breathing problems, or chest pain [see Warnings and Precautions (5.3) and Adverse Reactions (6.1)]. • Symptoms of tumor lysis syndrome such as nausea, vomiting, diarrhea and lethargy [see Warnings and Precautions (5.4) and Adverse Reactions (6.1)]. • Signs of infections including fever and cough [see Warnings and Precautions (5.5) and Adverse Reactions (6.1)]. • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.1)]. • New or changes in neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.2)]. Advise patients of the need for: • Periodic monitoring of blood counts [see Warnings and Precautions (5.6, and 5.7) and Adverse Reactions (6.1)]. • Avoid vaccinations with live viral vaccines [see Warnings and Precautions (5.8)]. • Patients with a history of hepatitis B infection (based on the blood test) should be monitored and sometimes treated for their hepatitis [see Warnings and Precautions (5.1)].

simple as asking whether we pay for second- or third-line treatment in the elderly patient, because the value of that second line is clinically interdependent on the first line,” Dr. Mullins explained. “From the study, it appears that patients initially treated with more aggressive regimens (not just 5-FU/leucovorin) derive greater value from their second line

of treatment than those treated less aggressively. While at this point, it’s hypothesis-generating only, this could challenge the way we historically treat the elderly, which is with a bias toward very simple regimens,” he suggested. n Disclosure: Dr. Chan has received a travel grant from Amgen. Mr. Kumachev and Dr. Mullins reported no potential conflicts of interest.

References 1. Chan D, Segelov E, Shapiro J, et al: Meta-analysis of outcomes of VEGF and EGFR targeted biological therapy in relapsed metastatic colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract 534. Presented January 18, 2014. 2. Heinemann V, von Weikersthal LF, Decker T, et al: Randomized comparison of FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment of KRAS-wildtype metastatic colorectal cancer: German AIO study KRK-0306 (FIRE3). 2013 ASCO Annual Meeting. Abstract LBA3506. Presented June 1, 2013. 3. Kumachev A, Yan M, Berry SR, et al: A comparison of biologics in first-line advanced colorectal cancer: A Bayesian network meta-analysis of EGFR inhibitors and bevacizumab. 2014 Gastrointestinal Cancers Symposium. Abstract 543. Presented January 18, 2014. 4. Hanna N, Woods C, Zheng Z, et al: Survival benefit associated with the number of chemotherapy/biologic treatment lines in 5,129 metastatic colon cancer patients. 2014 Gastrointestinal Cancers Symposium. Abstract 559. Presented January 18, 2014. 5. Mullins CD, Woldemichael A, Zheng Z, et al: Does first-line treatment impact the cost-effectiveness of second-line treatment for elderly metastatic colon cancer patients? 2014 Gastrointestinal Cancers Symposium. Abstract 585. Presented January 18, 2014.

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The ASCO Post | MARCH 15, 2014

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

Colorectal Cancer Survivors Face Challenges With Bowel Regulation By Caroline Helwick

he fight against colorectal cancer leaves many survivors with battle wounds, according to studies that show a high incidence of assorted morbidities that can affect quality of life. Clinicians, in fact, may be unaware of the struggles with bowel function that occur during survivorship, researchers said at the 2014

tile function than before treatment, and 42% of women reported sexual changes such as vaginal dryness. The participants found the survivorship plan beneficial, stating that it improved their knowledge of late treatment effects (90%) and their knowledge of which tests and treatments are needed

Colorectal cancer survivors use a multitude of adaptive strategies to control their bowel function. Many struggle with unpredictable bowel function for the rest of their lives, and many never find management strategies to achieve regularity. —Virginia Sun, RN, PhD

Gastrointestinal Cancers Symposium in San Francisco. A study from the University of Pennsylvania, Philadelphia, described patientreported outcomes for 657 colorectal cancer survivors who answered questions regarding late effects of treatment. The participants used a publically available Internet-based tool for the creation of survivorship care plans (www. livestrongcareplan.com).

Altered Bowel Patterns The late effects of treatment—which involved surgery for 97%, chemotherapy for 89%, and radiation for 37%—included chronic changes in bowel patterns (63%), chronic diarrhea (38%), bowel obstruction (9%), hernia development (18%), radiation colitis (8%), and fistula formation (2%). Of 249 survivors who graded their gastrointestinal toxicity, 23% reported having four to six stools per day, and 18% reported having more than six stools or incontinence, according to James M. Metz, MD, Professor of Radiation Oncology at the Hospital of the University of Pennsylvania, Philadelphia. Queries about sexual function revealed that 35% of men had worse erec-

during the survivorship period (83%). “The data reported here may have a significant impact on future studies of quality of life, as well as on patient counseling and survivor care,” Dr. Metz said.

Dietary and Behavioral Adjustments Loss of bowel control results in persistent problems, with difficulty controlling gas, fecal incontinence, and incomplete bowel evacuation. While patients must learn to manage these effects of treatment, little has been learned about how patients accomplish that. Researchers from the University of Arizona, City of Hope, and Kaiser Permanente Northwest and Northern California, therefore, studied the dietary and behavioral adjustments that long-term colorectal cancer survivors must make to regulate their bowel function. The study presented by Virginia Sun, RN, PhD, Assistant Professor, Nursing Research and Education, at City of Hope, Duarte, California, used a mixedmethods analysis of survey, focus group, and interview data from four studies that assessed health-related quality of life. The population involved 919 patients from three Veterans Affairs (VA) Centers and three Kaiser Permanente (KP)

Bowel Regulation in Colorectal Cancer Survivors ■■ Colorectal cancer survivors face challenges in bowel regulation.

regions diagnosed with colorectal cancer at least 5 years earlier and who were living with ostomies or anastamoses. “Many survivors in both samples reported making dietary adjustments following surgery, and many never became comfortable with their diet,” Dr. Sun reported. Survivors in both the VA and KP samples who reported decreases in health-related quality of life made the most dietary adjustments and were more likely to report that they had never become comfortable with these alterations. The key adjustments included the following: • Of all patients surveyed, 40% to 46% said they had adjusted their diet because of ostomy or surgery. • Overall, 28% to 43% had made dietary adjustments within the first 12 months of treatment; the fewest adjustments were made by VA patients with ostomies and the most were observed within the VA sample with anastomosis. • Only about 11% of patients had never needed to make dietary adjustments. • 50% of patients with lower quality-of-life scores (< 7) reported making dietary adjustments, compared to 35% to 41% of patients with better scores (≥ 7). “Most dietary and behavioral adjustments were made to counter their negative effects on bowel function,” Dr. Sun said.

The comments related to the patients’ strategies for bowel function regulation were interesting (see sidebar below). From these, the researchers developed a framework that illustrates the strategies that survivors used for regulating bowel function and coping with bowel dysfunction. “Colorectal cancer survivors use a multitude of adaptive strategies to control their bowel function. Many struggle with unpredictable bowel function continually for the rest of their lives, and many never find any set of management strategies to achieve regularity,” she said. Better understanding of the adjustments these individuals find to be necessary should inspire evidence-based recommendations, she suggested. n

Disclosure: Dr. Metz has received research funding from the LiveSTRONG Foundation. Dr. Sun reported no potential conflicts of interest. For full disclosures of the study authors, visit meetinglibrary.asco.org.

References 1. Metz JM, et al: Updated patient reported outcomes and survivorship care plan use by survivors of colorectal cancer. 2014 Gastrointestinal Cancers Symposium. Abstract 527. Presented January 18, 2014. 2. Sun V, et al: Dietary and behavioral adjustments to control bowel function by long-term colorectal cancer survivors. 2014 Gastrointestinal Cancers Symposium. Abstract 573. Presented January 18, 2014.

Colorectal Cancer Survivors’ Comments on Strategies to Regulate Bowel Function Avoiding Foods • I don’t eat beans, I don’t eat onions. I’m kind of careful on greens because they just don’t digest well. • I don’t eat as many salads. I couldn’t because they went right through.

Behavioral Adjustments • You learn, over the years, what you can and can’t do. And you can’t overeat. It’s good to graze. • I try to chew my food slowly, and I don’t ever drink until after I eat. • You just plan your schedule and figure out when you’re going to eat what, and when. • I don’t choose to be around groups of people I do not know. I suppose there are times when I have cut myself off from something that might be an enjoyable activity. • I try not to drive as much as I used to. When I drive, I want to make sure that I know where I’m going.

Medications

■■ Nearly two-thirds report chronic changes in bowel function, and almost 40% have chronic diarrhea.

• I live on stool softeners in the morning and a laxative at night…. And even then, sometimes it all blocks up.

■■ Survivors adjust their diet and, sometimes, social behavior to meet these new patterns.

Adapted, with permission, from Sun V, et al.2

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Gastrointestinal Cancers Symposium Gastrointestinal Oncology

For Progressive Neuroendocrine Tumors, Clinical Benefit Is High With Capecitabine Plus Temozolomide By Caroline Helwick

n an interim analysis of a phase II trial, 97% of patients with progressive metastatic neuroendocrine tumors achieved clinical benefit with the combination of capecitabine and temozolomide (CAPTEM). The results were reported at the 2014 Gastrointestinal Cancers Symposium by Robert L. Fine, MD, Director of the Experimental Therapeutics Program and Irving Association Professor of Medicine at Columbia University College of Physicians and Surgeons, Pancreas Center at Columbia, New York.1 “There is a great need for new treatments in well-differentiated neuroendocrine tumors, and there are a number of reasons why CAPTEM is an exciting combination,” Dr. Fine said in an interview with The ASCO Post. “First, it’s an oral regimen of generic drugs. This will not cost a lot, yet it’s 5 to 10 times more efficacious than sunitinib [Sutent] or everolimus [Afinitor] and much less toxic. Second, it’s the first regimen to ever produce responses in all neuroendocrine subtypes, including carcinoid, a tumor that has a 0% to 5% response rate to chemotherapy.” The ongoing median progressionfree survival in this study—more than 22 months—is more than 150% greater than that reported with everolimus and sunitinib, he noted. Dr. Fine and his team previously found that capecitabine and temozolomide are synergistic in inducing apoptosis in neuroendocrine tumor cell lines. “We first reported in 2005 the use and mechanism of action of CAPTEM, and have since then seen promising retrospective results in patients who have failed all prior available therapies. This is our first prospective study.”

Small Study, Robust Result The phase II study included patients with metastatic, well-to-moderately differentiated neuroendocrine tumors who had disease progression on long-acting octreotide (Sandostatin LAR), 60 mg, or who had

negative octreotide scans, which is a negative prognostic factor. Patients received capecitabine at 1,500 mg/ m2 per day on days 1 to 14, and temozolomide at 150 to 200 mg/m2 per day on days 10 to 14 (capped at 2,500 mg per day), in a 28-day cycle. The primary endpoint was response rate by RECIST criteria, with imaging performed after two cycles by two Columbia University radiologists with expertise in neuroendocrine cancer. The study has accrued 38 patients with various neuroendocrine cancer subtypes, including carcinoid (typical and atypical), pituitary, pancreatic neuroendocrine, and medullary thyroid

Capecitabine/Temozolomide in Neuroendocrine Tumors ■■ In patients with progressive metastatic neuroendocrine tumors, the combination of capecitabine and temozolomide produced a response rate of 43% and a stable disease rate of 54%, therefore conveying clinical benefit to 97% of patients. ■■ Patients with carcinoid tumors, typically resistant to chemotherapy, had a 100% clinical benefit rate; all patients with pituitary tumors responded. ■■ Median progression-free survival was almost 2 years.

tumors (typical and atypical), the response rate was 42%, including 8% complete responses, and 58% of this group achieved stable disease. The median progression-free survival for this group exceeded 22 months.

The most important thing is that [capecitabine/temozolomide] works so well in carcinoid tumors, for which nothing else really works. —Robert L. Fine, MD

tumors. Of these patients, 28 of whom could be assessed for efficacy in the interim analysis. The overall response rate was 43%, including 11% complete responses, and 54% of patients achieved stable disease, resulting in a clinical benefit rate of 97%, Dr. Fine reported. CAPTEM was very effective in tumors that are traditionally chemoresistant. For patients with carcinoid

“The most important thing is that CAPTEM works so well in carcinoid tumors, for which nothing else really works,” he said.

Response in Pituitary Tumors The three patients with pituitary tumors all responded, and two (67%) had complete responses; their median progression-free survival exceeded 41

EXPERT POINT OF VIEW

ebecca A. Miksad, MD, MPH, Assistant Professor of Medicine at Harvard Medical School and Physician-Investigator at Beth Israel Deaconess Medical Center, Boston, who discussed the paper by Fine et al at the Gastrointestinal Cancers Symposium, said, “the study reports that a range of neuroendocrine tumor types responded to the capecitabine/temozolomide regimen studied. Prospective randomized, controlled data are needed to confirm these findings.” n

months. For all subtypes, ongoing median progression-free survival was 22 months, he reported. The inclusion of pituitary tumors occurred as the result of Dr. Fine’s effort to treat a challenging patient who was referred to him. “I treat untreatable tumors, and I was called in to see this patient who had a tracheotomy and was ready to go on respiratory support. Her pituitary tumor was compressing the brain stem. She had had six surgeries, two radiation treatments, and chemotherapy.” “I thought that since the pituitary gland secretes endocrine hormones and is derived from neural cells, we should try CAPTEM, and the tumor just melted away,” he noted. “She has had a complete response for 42 months, as has the second patient. The third pituitary tumor patient had a 75% reduction in tumor and died of other causes.” Of the 28 assessable patients, 12 had died at the time of interim analysis, with a median overall survival of more than 29 months. The most common grade 3/4 toxicities were lymphopenia (35%), hyperglycemia (65%, unlikely to be related), thrombocytopenia (3%), and diarrhea (3%). No hospitalizations, opportunistic infections, or deaths occurred from CAPTEM treatment. n

Disclosure: Dr. Fine reported no potential conflicts of interest.

Rebecca A. Miksad, MD, MPH

Disclosure: Dr. Miksad reported no potential conflicts of interest.

Reference 1. Fine RL, Gulati AP, Tsushima D, et al: Prospective phase II study of capecitabine and temozolomide (CAPTEM) for progressive, moderately, and well-differentiated metastatic neuroendocrine tumors. 2014 Gastrointestinal Cancers Symposium. Abstract 179. Presented January 17, 2014.

The ASCO Post | MARCH 15, 2014

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ASH Highlights of North America Hematology

Minimal Residual Disease Before and After Transplant: What Does It Mean? By Caroline Helwick

n patients with acute leukemia, outcomes after hematopoietic stem cell transplantation are negatively impacted by the presence of minimal residual

the Division of Cellular Therapy at Duke University in Durham, North Carolina, and Matthew J. Wieduwilt, MD, PhD, Assistant Clinical Profes-

Detection of any tumor in the first 90 days after transplant by this method is also highly predictive of relapse and survival. —Nelson J. Chao, MD, MBA

disease. However, transplant can prolong survival in patients with minimal residual disease after consolidation, according to two studies presented at the American Society of Hematology (ASH) Annual Meeting, and further discussed at the ASH Highlights of North America meeting in Miami. The discussants were Nelson J. Chao, MD, MBA, Professor of Medicine and Immunology and Chief of

sor of Medicine at the University of California, San Diego, Moores Cancer Center in La Jolla.

Deep-Sequencing Studies in Children A new method of evaluating for minimal residual disease—immunoglobulin heavy light chain (IGH) variable, diversity, and joining (VDJ) DNA sequencing—was used in the ASCT0431 study

of the Children’s Oncology Group/ Pediatric Blood and Marrow Transplant Consortium. The study involved patients aged 1 to 21 years undergoing stem cell transplantation for high-risk acute lymphoblastic leukemia (ALL) in first complete remission or second. Bone marrow samples were taken within 2 weeks of the preparative regimen and at 1 month, 3 months, and 9 to 12 months after transplant, and were subjected to IGH VDJ sequencing. The initial analysis showed strong power to predict relapse and lower event-free survival by the presence of minimal residual disease > 0.1% in the bone marrow, both pre- and posttransplant. The new subanalysis tested whether the high level of sensitivity of minimal residual disease detection offered by deep sequencing would increase the predictive power.1 Deep-sequencing techniques were able to define clones in more than 95% of patients. Detection of blasts at any level, either pre- or post-transplant, predicted for worse event-free survival. “With any tumor present, there was

a high risk of relapse,” Dr. Chao reported. Evidence of tumor in the pretransplant sample was associated with significantly higher 36-month cumulative incidence of relapse, compared with no evidence of tumor (57% vs 4.5%, P = .008), and a significantly increased risk of the composite of relapse and death. Tumor in the post-transplant sample was also significantly associated with increased relapse or death, compared to no tumor cells. Additionally, a negative result by deep sequencing predicted a lower risk of relapse compared with a negative result by flow cytometry (4.5% vs 25%). The authors of the study concluded, “Patients with no detectable leukemia by deep sequencing pretransplant relapsed less than 5% of the time, a striking improvement compared to our previous ability to predict relapse.… Detection of any tumor in the first 90 days after transplant by this method is also highly predictive of relapse and survival.” Dr. Wieduwilt also included this continued on page 28

Novel Therapies May Help Wipe Out Residual Acute Lymphoblastic Leukemia By Caroline Helwick

inimal residual disease after induction and consolidation for the treatment of acute leukemia might be eradicated by novel therapies, thus obviating the need for stem cell transplantation. That is the prediction of Matthew J. Wieduwilt, MD, PhD, Assistant Clinical Professor of Medicine at the University of California, San Diego, Moores Cancer Center in La Jolla, who described emerging treatments at the 2014 Highlights of ASH in North America meeting, held recently in Miami. In multiple studies, the presence of minimal residual disease pre- and posttransplant has been associated with worse prognosis. Used as front-line agents, a number of compounds now in clinical trials may ameliorate this problem, he said. The most promising drugs are chimeric antigen receptor–modified T cells (CAR-T), inotuzumab ozogamicin, blinatumomab, and tyrosine kinase inhibitors. Although still limited to small pilot studies in small numbers of patients, the findings for engineered T cells—so

called CAR-T therapy—are impressive, and the excitement over this new class of agents was palpable at the American Society of Hematology (ASH) Annual Meeting. The cellular therapy involves isolating T cells from the patient and genetically modifying them with a chimeric antigen receptor construct. Expression of the CAR by a T-cell promotes binding of the CD19 antigen and triggers cytotoxicity, cytokine release, and T-cell proliferation, Dr. Wieduwilt explained.

CAR-T Therapy A phase I study of 16 patients (two in first remission [treated at relapse] and 14 relapsed at enrollment) was presented by Memorial Sloan Kettering investigators.1 Unfavorable cytogenetics were present in 44% of patients, and 25% were positive for the Philadelphia chromosome. After CAR-T cell infusion, more than 80% of patients achieved complete remission, compared to 52% who had this outcome after chemotherapy reinduction chemotherapy. In these groups, 70% were

negative for minimal residual disease after CAR-T therapy, compared to only 10% after chemotherapy. Approximately half the patients developed fevers, hypotension, hypoxia, neurologic changes, and/or malaise— ie, cytokine release syndrome—but this responded well to the anti–interleukin-6 antibody tocilizumab (Actemra).

Inotuzumab Ozogamicin Also producing “impressive early results” were early studies of inotuzumab ozogamicin, a CD22 monoclonal antibody combined with a toxin conjugate that was used in combination with lowintensity chemotherapy in a small study of 17 patients ≥ 60 years old with newly diagnosed B-cell acute lymphoblastic leukemia (ALL).2 The patients received a low-intensity modification of the hyper-CVAD regimen referred to as mini-hyper-CVD (cyclophosphamide and dexamethasone at 50% dose reduction, no anthracycline, methotrextate at 75% dose reduction, cytarabine at 0.5 g/m2 for four doses), plus inotuzumab on day 3 of

each of the first four courses. Overall survival at 1 year was significantly improved over historical controls receiving full-dose hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone): 87% vs 60% (P = .04). Of 14 patients evaluable for response, 13 (93%) achieved complete response or complete response with incomplete platelet recovery. All patients with complete response also achieved flowcytometric minimnal residual disease– negative status. Additionally, the rate of deaths due to adverse events was 6%, considerably less than the 34% observed with hyper-CVAD. Randomized front-line trials are now in development for younger adults, he said.

Blinatumomab Results were a little less impressive with blinatumomab, a bispecific T-cell engaging antibody binding to CD3 and CD19, in relapsed pediatric acute lymphoblastic leukemia compared with continued on page 28

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The ASCO Post | MARCH 15, 2014

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ASH Highlights of North America Minimal Residual Disease continued from page 22

study in his “highlights” in ALL. He noted that event-free survival at 2 years was only 28% for patients with minimal residual disease. “Breaking the group out according to level of minimal residual disease, they found quantitation was not predictive,” he added. “So minimal residual disease was a sensitive predictor of relapse. These newer methods should lead to the standardization of detection of minimal residual disease.”

Studies in Adults With ALL Most studies of minimal residual disease have focused on pediatric ALL, all showing a prognostic effect, but data in adults have been limited. Several studies of minimal residual disease in Philadelphia chromosome–negative adult ALL patients were described by Dr. Wieduwilt. French investigators reported the results of a large study in 522 high-risk patients in first complete remission, of whom approximately half went on to stem cell transplantation and half did not.2 They assessed the impact of transplant according to level of minimal residual disease at complete remission, and concluded that residual tumor could be “a powerful tool” to select patients who might benefit from the procedure. The study showed that patients with < 104 cells postinduction had a re-

Novel Therapies continued from page 22

CAR-T cells or inotuzumab ozogamicin, according to Dr. Wieduwilt. The drug acts independently of the T-cell receptor and allows T-cell recognition of tumorassociated surface antigen, without requiring major histocompatibility complex class I and/or peptide antigen. In a study of 41 patients, the best response within two cycles was complete remission or complete remission with incomplete hematologic recovery in 37%, with 30% of those patients having no detectable minimal residual disease.3 Partial responses were observed in 7%. Randomized

lapse-free survival rate of almost 80%, regardless of whether they went on to transplant. For those with disease ≥ 10–4, however, transplant mattered, with a relapse-free survival probability of about 55%, compared to about 30% without a transplant (P = .04 for the interaction). In a study from China, the amount of minimal residual disease was im-

ated just prior to the procedure. “Within the whole cohort, there was no difference in overall survival at 3 years, but breaking it out by minimal residual disease subgroup, you did see a difference,” Dr. Wieduwilt added. “Only patients with ‘intermediate’ level of minimal residual disease had benefits from transplant.” For patients with disease ≤ 0.02%

Measuring Minimal Residual Disease in Leukemia

tion for long-term survival” of patients with persistent minimal residual disease following consolidation. Minimal residual disease–positive patients potentially benefit from allogeneic transplant, whereas those who are minimal residual disease–negative do not, he noted. n

Disclosure: Dr. Chao reported no potential conflicts of interest. Dr. Wieduwilt reported consultancy for Cellerant and research funding from Sigma Tau.

portant.3 The study included 107 adult patients, of whom 62 underwent transplant and 45 had chemotherapy only; all received induction and consolidation and had minimal residual disease evaluated by flow cytometry. In chemotherapy-only patients, the researchers used the time point of first complete remission, while patients undergoing transplant were also evalu-

and for those with disease > 0.2%, transplant offered no survival benefit over chemotherapy, but for patients with minimal residual disease between these extremes, transplant was associated with an overall survival rate of more than 60%, compared with about 20% for chemotherapy only (P = .008). From these studies, Dr. Wieduwilt concluded, “Transplant may be the op-

References 1. Pulsipher MA, Carlson CS, Mark K, et al: Striking predictive power for relapse and decreased survival associated with detectable minimal residual disease by IGH VDJ deep sequencing of bone marrow pre- and post-allogeneic transplant in children with B-lineage ALL: A subanalysis of The COG ASCT0431/PBMTC ONC051 study. 2013 ASH Annual Meeting. Abstract 919. Presented December 10, 2013. 2. Dhedin N, Huynh A, Maury S, et al: Allogeneic hematopoietic stem cell transplantation in adults with Philadelphia chromosome-negative acute lymphoblastic leukemia: Results from the Group for Research on Adult ALL (GRAALL). 2013 ASH Annual Meeting. Abstract 552. Presented December 9, 2013. 3. Zhang M, Luo Y, Lai X, et al: Minimal residual disease levels at time of CRI and transplant predict outcome in Philadelphia chromosome-negative adult ALL. 2013 ASH Annual Meeting. Abstract 713. Presented December 9, 2013.

trials are in development in children and adults with ALL. n

blastic leukemia. 2013 ASH Annual Meeting. Abstract 1432. Presented December 7, 2013. 3. Von Stackelberg A, Zugmaier G, Handgretinger R, et al: A phase 1/2 study

of blinatumomab in pediatric patients with relapsed/refractory B-cell precursor acute lymphoblastic leukemia. 2013 ASH Annual Meeting. Abstract 70. Presented December 8, 2013.

■■ A new method of evaluating minimal residual disease—immunoglobulin heavy light chain (IGH) variable, diversity, and joining (VDJ) DNA sequencing—may be a more sensitive measure than flow cytometry. ■■ Patients with no detectable leukemia by deep sequencing pretransplant relapsed less than 5% of the time. ■■ Patients with < 10–4 tumor cells postinduction had a relapse-free survival rate of almost 80%, regardless of whether they went on to transplant, but in patients with ≥ 10–4 tumor cells, allogeneic transplant significantly increased the relapse-free survival probability. ■■ Patients with an “intermediate” level of minimal residual disease benefited from transplant, but no benefit was observed in patients with very low levels and little benefit was see with high levels.

Disclosure: Dr. Wieduwilt reported consultancy for Cellerant and research funding from Sigma Tau.

References 1. Davilla M, Riviere I, Wang X, et al: Safe and effective re-induction of complete remissions in adults with relapsed B-ALL using 19-28z CAR DC19-targeted T cell therapy. 2013 ASH Annual Meeting. Abstract 69. Presented December 8, 2013. 2. Jain N, O’Brien S, Thomas D, et al: Inotuzumab ozogamicin in combination with low-intensity chemotherapy (minihyper-CVD) as frontline therapy for older patients (≥ 60 years) with acute lympho-

Innovative Approaches to ALL ■■ CAR-T therapy induced complete remissions in 80% of acute lymphoblastic leukemia (ALL) patients who relapsed ■■ Inotuzumab ozogamicin, given in combination with a low-intensity chemotherapy regimen, yielded an 87% overall survival rate at 1 year, in relapsed ALL patients, with an improved toxicity profile over full-dose regimens ■■ Blinatumomab produced complete remissions in approximately one third of relapsed pediatric ALL patients.

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San Antonio Breast Cancer Symposium Breast Cancer

Immune Modulation May Aid Some Breast Cancer Subtypes By Caroline Helwick

here may be an immunogenic phenotype in breast cancer that could benefit from immune modulation as part of treatment, according to results from studies that correlated high levels of tumor-infiltrating lymphocytes with both pathologic complete responses and long-term outcomes. Studies presented at the 2013 San Antonio Breast Cancer Symposium lent support to this concept by linking tumor-infiltrating lymphocytes to response to neoadjuvant trastuzumab (Herceptin), response to neoadjuvant carboplatin, and longterm outcomes after adjuvant therapy.

lymphocytes), finding 20% of HER2- lymphocytes, and for each 10% increWe are actively investigating this.” Results of genetic profiling in the positive tumors to be lymphocyte- ment in stromal tumor-infiltrating lymstudy suggested that trastuzumab is predominant breast cancer, and 28% of phocytes at diagnosis there was an 18% reduction in the risk of distant recurrelieving tumor-mediated immuno- triple-negative tumors. Comparing pathologic complete re- rence (P = .04) and a 19% reduction in suppression. High levels of immunenegative regulators (CTLA-4, PD1) were associated with higher benefit from trastuzumab. In a HER2driven mammary mouse model, the combination of T-cell checkpoint inhibitors with trastuzumab was Sherene Loi, MD, PhD Carsten Denkert, MD Sylvia Adams, MD Lisa M. Coussens, PhD synergistic. Biomarkers of Response The data provide the rationale sponse rates for lymphocyte-predomi- mortality (P = .01), at a median followSherene Loi, MD, PhD, Head of the to evaluate whether the anti–PD-1 nant vs non–lymphocyte-predominant up of 10.6 years. Translational Breast Cancer Genom- agents—currently showing impressive patients, they found that 60% of paIn the multivariate analysis, a 10% ics Lab at the Peter MacCallum Cancer results in melanoma, non–small cell tients with lymphocyte-predominant increase in tumor-infiltrating lymphoCentre in Melbourne, Australia, report- lung cancer, and renal cell carcinoma— breast cancer (ie, high levels of tumor- cytes remained a highly significant ed that for every 10% increase in the lev- when added to trastuzumab can further infiltrating lymphocytes) achieved a independent predictor of disease-free els of tumor-infiltrating lymphocytes, improve clinical outcomes in HER2- pathologic complete response, com- survival (P = .005), distant recurrence– there was a 16% increase (P = .038) positive disease, she added. pared with 40% of all participants and free survival (P = .01), and overall surin the number of patients achieving a “This study confirms that higher lev- 34% of non–lymphocyte-predominant vival (P = .003). As a binary variable, pathologic complete response to neo- els of [tumor-infiltrating lymphocytes] breast cancer patients (P < .0005). the hazard ratios for disease-free suradjuvant therapy among HER2-positive are significantly associated with higher “The predictive effect of [tumor-in- vival were 0.62 when stromal tumor-inpatients in the GeparQuattro trial.1 clinical benefit from trastuzumab plus filtrating lymphocytes] was particularly filtrating lymphocytes were present (P Dr. Loi suggested that levels of tumor- chemotherapy, and while further vali- high in patients treated with carboplatin,” = .007) and 0.76 when intraepithelial reported Carsten Denkert, MD, Head tumor-infiltrating lymphocytes were of the Translational Cancer Research present (P = .07). Tumor-Infiltrating Lymphocytes in Breast Cancer Group at Charité University in Berlin. The results in patients with tripleFor patients with lymphocyte-pre- negative breast cancer validate previous ■■ High levels of tumor-infiltrating lymphocytes in breast tumors are dominant breast cancer treated with findings by Loi et al in 256 patients with associated with high pathologic complete response rates to trastuzumab in carboplatin plus paclitaxel/doxorubicin, triple-negative disease in the BIG 02-98 patients with HER2-positive breast cancer and to carboplatin in those with the pathologic complete response rate study,3 which showed that every 10% HER2-positive or triple-negative cancer. reached 74% for lymphocyte-predomi- increase in intratumoral and stromal ■■ Tumor-infiltrating lymphocytes also are prognostic in triple-negative breast nant, triple-negative breast cancer patients lymphocytic infiltrations was associated cancer for better long-term outcomes after adjuvant therapy. with 17% and 15% reduced risk of reand 78% for HER2-positive patients. ■■ These findings suggest that immune modulation may have value in treating “In [lymphocyte-predominant breast lapse (P = .10 and P = .025), respectively, these breast cancer phenotypes. cancer], an increased pathologic com- and 27% and 17% reduced risk of death plete response rate with carboplatin (P = .035 and P = .023), respectively. infiltrating lymphocytes may serve as dation is needed, the data suggest that was observed not only in triple-negative Dr. Adams said this study provides biomarkers of response to trastuzumab trastuzumab acts not only directly on breast cancer but also in HER2-positive a prospective validation study to BIG in primary breast cancer, “something that the tumor but may help antitumor im- breast cancer,” Dr. Denkert said. “Tu- 02-98, and thus culminates in level 1 researchers have been looking for with munity,” Dr. Loi concluded. mor-infiltrating lymphocytes are predic- evidence for tumor-infiltrating lympholittle success for some time,” she said. tive for response to neoadjuvant chemo- cytes as a prognostic factor for tripleThe researchers examined breast Triple-Negative Breast Cancer therapy, and the prediction is especially negative breast cancer. In other studies presented in San good with carboplatin treatment.” cancer tissue from 445 women and identified 156 whose tumors had high Antonio, investigators reported that Similar results came from an analysis Looking Ahead Lisa M. Coussens, PhD, Professor, levels of tumor-infiltrating lympho- tumor-infiltrating lymphocytes were of 481 participants in Eastern Cooperacytes. Of those with high levels, 47.4% prognostic and also predictive in wom- tive Oncology Group (ECOG) 2197 Chair, and Associate Director of Basic achieved a pathologic complete re- en with triple-negative breast cancer. and ECOG 1199, two randomized tri- Research at the Knight Cancer Institute German investigators reported on als of adjuvant chemotherapy in breast of Oregon Health and Science Universisponse, compared with 31.7% of the a prospective evaluation in 580 pa- cancer.3 Sylvia Adams, MD, Associ- ty, Portland, emphasized the finding by entire cohort. “These data indicate that a patients who had either triple-negative or ate Professor of Medicine at New York Dr. Loi and colleagues that high levels tient’s immune system influences HER2-positive disease, from the neoad- University, and colleagues identified of CTLA-4 and PD-1 correlated with a outcome and trastuzumab response,” juvant GeparSixto trial.2 They stratified stromal tumor-infiltrating lymphocytes survival benefit after trastuzumab treatshe said. “What we don’t know is why patients according to the lymphocyte- in 80% of tumors, which were all triple- ment in a mouse model. “This suggests that immune checkpoint inhibition is a some patients have [tumor-infiltrat- predominant breast cancer phenotype, negative. In this group, at least 10% of all cells plausible approach to take, in what has ing lymphocytes] in their breast tu- which contains more lymphocytes than continued on page 30 mor at diagnosis and others do not. tumor cells (≥ 60% tumor-infiltrating in the stroma were tumor-infiltrating

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San Antonio Breast Cancer Symposium Breast Cancer

Adding Bevacizumab to Adjuvant Chemotherapy/Trastuzumab Fails to Improve Survival in HER2-Positive Breast Cancer By Alice Goodman

he addition of bevacizumab (Avastin) to adjuvant chemotherapy did not improve invasive disease-free survival or overall survival in patients with high-risk HER2-positive breast cancer in the large randomized phase III BETH trial. Although not specifically designed to answer this question, BETH also demonstrated that a non– anthracycline-containing chemotherapy arm was as effective in prolonging survival as an anthracycline-containing arm. The study results were presented at the 2013 San Antonio Breast Cancer Symposium.1 “In this trial, bevacizumab added virtually nothing to chemotherapy, but it did increase safety concerns. To date, all the antiangiogenic strategies studied show no impact on survival in breast cancer. Unless we can find a biomarker to identify a subgroup of patients who will benefit, bevacizumab does not warrant further study in this setting,” stated BETH study lead author Dennis Slamon, MD, PhD, Director of Clinical/Translational Research at UCLA’s Jonsson Comprehensive Cancer Center and Chief of the Division of Hematology/Oncology at UCLA.

were randomly assigned to anthracycline-based therapy with T-FEC-H (docetaxel, fluorouracil, epirubicin, cyclophosphamide, plus trastuzumab) with or without bevacizumab. Dr. Slamon noted that anthracyclines are an established chemotherapy backbone treatment in breast cancer, including HER2-positive breast cancer. However, the combination of trastuzumab plus anthracycline increases the risk of cardiotoxicity—in particular, congestive heart failure— and secondary leukemia. About 130 centers had the option to select an anthracycline-based regimen. Dr. Slamon noted that he was disappointed that fewer than 300 patients were assigned to anthracyclines, resulting in less power to compare the anthracycline vs nonanthracycline regimen. Treatment arms were well

Immune Modulation continued from page 29

been considered a nonimmunogenic type of cancer,” she said, adding that “cytotoxic and targeted therapy alone

Jennifer Litton, MD

■■ In the BETH trial, bevacizumab added to adjuvant chemotherapy plus trastuzumab did not improve outcomes in HER2-positive breast cancer but did increase safety concerns. ■■ A non–anthracycline-containing adjuvant regimen led to similar outcomes as an anthracycline-based regimen in high-risk HER2-positive breast cancer.

free survival in cohort 1 was 92% in both TCH arms (with and without bevacizumab), and in cohort 2, 89% in the anthracycline-containing arms without bevacizumab vs 91% with bevacizumab. This difference between the anthracycline and non–anthracycline-containing arms was not statistically significant. Dr. Slamon pointed out that the 92% invasive disease–free survival achieved in both TCH treatment arms surpassed results of other large

While there is some small room for improvement [in response rates], we now need to concentrate further on improving the safety of adjuvant treatment regimens.

Two-Cohort Design The BETH trial, conducted at 576 sites around the world, enrolled 3,509 women with HER2-positive, nodepositive, or high-risk node-negative breast cancer. Patients were treated in two cohorts. Cohort 1 included 3,231 patients randomly assigned to receive the nonanthracycline regimen TCH (docetaxel, carboplatin, and trastuzumab [Herceptin]) or TCH plus bevacizumab. In cohort 2, 278 patients

Role of Bevacizumab in HER2-Positive Breast Cancer

—Dennis Slamon, MD, PhD

balanced for age, number of positive lymph nodes, breast-conserving surgery, and hormone receptor status. Median age was 51 years.

Key Data At a median follow-up of 38 months, the rate of invasive disease– won’t get us where we need to go.” She added, “Fortunately, there are many of these inhibitors as well as antibodies to PD-1 and PD-L1 in the pipeline.” Jennifer Litton, MD, Associate Professor of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, Houston, moderated a press briefing where Dr. Loi’s study was presented and commented that the findings could impact how breast cancer is treated. The prognostic value of tumor-infiltrating lymphocytes, she said, could possibly “change the paradigm of breast cancer treatment.” Research is also needed to de-

randomized trials in HER2-positive breast cancer. For example, 3-year disease-free survival was about 87% in both the Herceptin Adjuvant (HERA) trial2 and the N9831 trial.3 He noted that the negative showing for adjuvant bevacizumab in BETH might be partly attributable to the termine “how to bring [tumor-infiltrating lymphocytes] into tumors where they are not currently expressed,” she added. n

Disclosure: Drs. Loi, Adams, Coussens, and Litton reported no potential conflicts of interest. Dr. Denkert is cofounder of Sividon Diagnostics. and his research was funded by the European FP7 Project Responsify.

References 1. Loi S, Michiels S, Salgado R, et al: Tumor infiltrating lymphocytes (TILs) indicate trastuzumab benefit in early-stage HER2-positive breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-05. Presented December 11, 2013.

excellent 92% disease-free survival in the TCH control arm. “It is going to be difficult to develop treatment regimens that have even better response rates than that. While there is some small room for improvement, we now need to concentrate further on improving the safety of adjuvant treatment regimens,” Dr. Slamon commented.

Safety Concerns No new safety concerns about bevacizumab were raised in BETH, but bevacizumab significantly increased the risk of any-grade and grade 3/4 adverse events, as well as adverse events of special interest such as hypertension and proteinuria (all P < .0001). Patients enrolled in BETH will be followed prospectively to determine longer-term outcomes. Dr. Slamon said he believes that the TCH regimen is driving the diseasefree survival benefit, and he doubted whether bevacizumab would make a significant difference over the longer term. Experts—including Dr. Slamon— pretty much agree that bevacizumab has no role in adjuvant therapy of breast cancer. continued on page 31

2. Denkert C, Loibl S, Salat C, et al: Increased tumor-associated lymphocytes predicts benefit from addition of carboplatin to neoadjuvant therapy for triple-negative and HER2-positive early breast cancer in the GeparSixto trial (GBG 66/AGO-B). 2013 San Antonio Breast Cancer Symposium. Abstract S1-06. Presented December 11, 2013. 3. Loi S, Sirtaine N, Piette F, et al: Prognostic and predictive value of tumor-infiltrating lymphocytes in a phase III randomized adjuvant breast cancer trial in node-positive breast cancer comparing the addition of docetaxel to doxorubicin with doxorubicin-based chemotherapy: BIG 02-98. J Clin Oncol 31:860-867, 2013.

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San Antonio Breast Cancer Symposium “Although the data are somewhat mixed, with one previous trial in metastatic disease and a recent neoadjuvant trial showing a slight advantage for bevacizumab, the cumulative data including the BETH adjuvant trial suggest minimal

to show a difference between anthracyclines vs no anthracyclines. n

Disclosure: The BETH study was supported by Roche/Genentech. Dr. Slamon is a consultant for and receives research support from Novartis, and has ownership interests in Amgen.

References 1. Slamon DL, Swain SM, Buyse M, et al:

Anthracycline vs Nonanthracycline Use of an anthracycline in early breast cancer is controversial, and experts are basically divided into camps on this issue. “Trastuzumab combined with anthracyclines increases cardiac toxicity three- to fivefold,” Dr. Slamon explained. “Our new results, which surpassed our expectations, show that it is not necessary to include an anthracycline as part of the treatment regimen to obtain ideal results for patients with HER2-positive breast cancer, even if they have a large tumor or node-positive disease,” Dr. Slamon told listeners at a press conference during the San Antonio meeting. “The importance of these results lies in the fact that TCH has a much better safety profile than anthracycline/trastuzumab combinations and has now been shown to be equally effective.” He continued, “No single trial has shown an incremental benefit for anthracyclines…. At our institution, we don’t use anthracyclines as adjuvant therapy for early HER2-positive breast cancer.” Press conference moderator Jennifer Litton, MD, a breast medical oncologist at The University of Texas MD Anderson Cancer Center, Houston, expressed a different opinion. “We could debate this for 5 hours. I am on the other side of the aisle on this question, and I don’t think anthracyclines should be thrown away.” She pointed out that the BETH trial was designed to evaluate the role of bevacizumab in early HER2-positive breast cancer, not

adjuvant trastuzumab for HER2-positive breast cancer (HERA): An open-label, randomized controlled trial. Lancet 382:10211028, 2013. 3. Romond EH, Perez EA, Bryant J, et al: Trastuzumab plus adjuvant chemotherapy for operable HER2-positive breast cancer. N Engl J Med 353:16731684, 2005.

Now Enrolling

C. Kent Osborne, MD

if any value for this drug in breast cancer,” said C. Kent Osborne, MD, Director of the Dan L. Duncan Cancer Center and the Lester and Sue Smith Breast Center at Baylor College of Medicine, Houston.

Primary results from BETH, a phase 3 controlled study of adjuvant chemotherapy and trastuzumab ± bevacizumab in patients with HER2-positive, node-positive, or high-risk node-negative breast cancer. 2013 San Antonio Breast Cancer Symposium. Abstract S1-03. Presented December 11, 2014. 2. Goldhirsch A, Geler RD, PiccartGebhart M, et al: 2 years versus 1 year of

BIRCH

A Study of MPDL3280A (an engineered anti-PDL1 antibody) in Patients With PD-L1–positive Locally Advanced or Metastatic Non-small Cell Lung Cancer (NCT02031458, Study ID GO28754)

For more information, please call the Genentech Trial Information Support Line at 1-888-662-6728 (US only), visit clinicaltrials.gov, or e-mail global.rochegenentechtrials@roche.com.

Locally advanced or metastatic NSCLC PD-L1–positive patients

N=300

MPDL3280A1 (an engineered anti-PDL1 antibody)

Central testing for PD-L1 IHC status

Primary Endpoints:

Secondary Endpoints:

• Objective response rate (ORR), IRF-assessed,

• Duration of response

according to RECIST v1.1

• Progression-free survival

• ORR, investigator-assessed, according to

• Overall survival

modified RECIST

• Safety: incidence of AEs • Pharmacokinetics: maximum serum concentration • Pharmacokinetics: minimum serum concentration

under steady-state conditions within a dosing interval

Key Inclusion Criteria2:

Key Exclusion Criteria2:

• Locally advanced or metastatic NSCLC (stage IIIB,

stage IV, or recurrent)

• History of autoimmune disease • Active hepatitis B or hepatitis C

• Representative FFPE tumor specimens

• HIV-positive

• PD-L1–positive status by IHC tested at a

• Prior treatment with CD137 agonists, anti-CTLA4,

central laboratory • Measurable disease, defined by RECIST v1

anti-PD1, or anti-PDL1 antibodies or pathwaytargeting agents

• ECOG performance status of 0 or 1 1. Product under investigation has not been approved for use outside of the clinical trial setting. This information is presented only for the purpose of providing an overview of the clinical trial and should not be construed as a recommendation for use of any product for unapproved purposes. 2. For more information on trial inclusion and exclusion criteria, visit clinicaltrials.gov.

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San Antonio Breast Cancer Symposium Breast Cancer

Zoledronic Acid Fails to Benefit Women With Chemoresistant Breast Cancer By Alice Goodman

oledronic acid does not improve outcomes in patients with early breast cancer who do not have a full response to neoadjuvant anthracycline/ taxane–based chemotherapy, according to results of the Neo-Adjuvant Trial Add-On (NATAN) study presented at the 2013 San Antonio Breast Cancer Symposium.1 A trend was observed for some benefit of zoledronic acid in women over 55 years old, consistent with the Early Breast Cancer Trialists’ Collaborative Group (EBCTCG) meta-analysis (aka “Oxford Overview”) on the effects of bisphosphonates, reported at the same meeting.2 “There are not a lot of postsurgery options for patients with residual disease after neoadjuvant chemotherapy who we consider chemoresistant. In this first randomized postneoadjuvant study investigating zoledronic acid in patients without a pathologic complete response after neoadjuvant chemotherapy, no benefit was observed,” stated lead author Gunter von Minckwitz, MD, PhD, Chairman of the German Breast Group and Professor of Gynecology at the University of Frankfurt, Germany.

NATAN Trial Details The phase III NATAN trial enrolled 693 women with early breast cancer and residual tumor after two cycles of neoadjuvant chemotherapy with anthracycline and taxane between 2005 and 2009. After surgery, the women were randomly assigned to receive or not receive treatment with intravenous zoledronic acid every 4 weeks for 6 months, then every 3 months for

2 years, then every 6 months for 2.5 years, for a total of 5 years. Treatment arms were well balanced for demographic and disease characteristics. Mean age was about 50; about one-third were over age 55 years; about 72% had ductal invasive carcinoma; 31% had grade 3 disease; about 79% were hormone receptor–positive, and 17% were HER2-positive; 15% had stable disease or progressive disease following neoadjuvant chemotherapy.

cant advantage with zoledronic acid. However, a nonsignificant trend favored zoledronic acid in women over age 55, showing a 17% reduction in risk of progression. “This is consistent with the risk reduction in postmenopausal women shown in the Oxford meta-analysis presented at this meeting. It is the older women who benefit from zoledronic acid,” Dr. von Minckwitz said. “Better patient selection is needed to study future compounds in

We experienced a number of challenges while conducting this study and are sharing what we have learned with other researchers considering running these extremely complicated trials. —Gunter von Minckwitz, MD, PhD

Prior and/or simultaneous trastuzu mab (Herceptin), endocrine therapy, and radiotherapy were allowed. A preplanned interim analysis was undertaken because the observed event rate at 48 months was 148, which was only 50% of the required rate. It would have taken another 6 to 8 years to reach the required 316 events for a final analysis, Dr. von Minckwitz explained.

Key Outcomes No significant difference in diseasefree survival (P = .7885) or overall survival (P = .4082) was observed between the two treatment arms. Furthermore, no subgroup had a signifi-

Role of Zoledronic Acid in Early Breast Cancer ■■ Zoledronic acid does not improve disease-free or overall survival in the population of all women with early breast cancer who have residual tumor following standard neoadjuvant therapy. ■■ Zoledronic acid appears to benefit postmenopausal women in this setting. ■■ The trend toward improved outcomes in postmenopausal women taking zoledronic acid is consistent with the large Oxford meta-analysis showing improved survival in postmenopausal women on the drug. ■■ A take-home message from both studies is that zoledronic acid is of no added value in premenopausal women.

this setting,” he added. “We would need a very large trial to show the benefit of zoledronic acid. The Oxford meta-analysis included 7,000 patients and 36 randomized controlled trials,” Dr. von Minckwitz noted.

Complicated Trials Other postneoadjuvant treatment options under study in chemoresistant breast cancer patients include rucapa-

rib (an oral PARP inhibitor) for triplenegative breast cancer, palbociclib in women with hormone receptor–positive/HER2-negative disease, and adotrastuzumab emtansine (Kadcyla) in patients with chemoresistant HER2positive disease. “We experienced a number of challenges while conducting this study and are sharing what we have learned with other researchers considering running these extremely complicated trials,” he noted. n

Disclosure: Dr. von Minckwitz has received research grants from Novartis and Roche and consultancy honoraria from Roche.

References 1. von Minckwitz G, Rezai M, Eidtmann H, et al: Postneoadjuvant treatment with zoledronate in patients with tumor residuals after anthracyclinestaxane-based chemotherapy for primary breast cancer: The phase III NATAN study (GBG 36/ABCSG XX). 2013 San Antonio Breast Cancer Symposium. Abstract S5-05. Presented December 13, 2013. 2. Coleman R, Gnant M, Paterson A, et al: Effects of bisphosphonate treatment on recurrence and cause-specific mortality in women with early breast cancer: A meta-analysis of individual patient data from randomised trials. 2013 San Antonio Breast Cancer Symposium. Abstract S4-07. Presented December 12, 2013.

EXPERT POINT OF VIEW

“T

he NATAN study showed that zoledronic acid doesn’t work in that average woman in this trial [one with early breast cancer, residual tumor remaining after neoadjuvant therapy]. There is, however, a trend to modest benefit in women older than 55, which is consistent with statistically significant benefit seen in a meta-analysis for bisphosphonates in adjuvant therapy trials, as was shown by the meta-analysis presented here,” Peter Ravdin, MD stated Peter Ravdin, MD, of San Antonio, Texas. Dr. Ravdin believes that the National Comprehensive Cancer Network will consider the findings of the Oxford m eta-analysis and possibly include bisphosphonates as adjuvant therapy for postmenopausal women. n Disclosure: Dr. Ravdin reported no potential conflicts of interest.

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ASH Annual Meeting Hematology

Promising Results Demonstrated for Brentuximab Vedotin in Cutaneous T-Cell Lymphoma By Alice Goodman

hase II results suggest that brentuximab vedotin (Adcetris) has encouraging activity in CD30-positive cutaneous T-cell lymphomas and lymphoproliferative disorders, including mycosis fungoides, the most common type of cutaneous T-cell lymphoma. High levels of responses were achieved

enrolled 48 patients diagnosed with established CD30-positive cutaneous Tcell lymphoma within the past 3 years. Of these, 28 patients had mycosis fungoides, 9 had lymphomatoid papulosis, 2 had anaplastic T-cell lymphoma, 7 had lymphomatoid papulosis/mycosis fungoides, and 2 had anaplastic T-cell lympho-

[Brentuximab vedotin], a conjugated antibody targeting the CD30 receptor, as expected, had a very rapid and 100% response rate for the CD30positive cutaneous lymphoproliferative disorders. In addition, it produced an unexpectedly high response rate in patients with mycosis fungodies…. —Madeleine Duvic, MD

in a 48-patient trial reported at the 55th American Society of Hematology (ASH) Annual Meeting in New Orleans. “[Brentuximab vedotin], a conjugated antibody targeting the CD30 receptor, as expected, had a very rapid and 100% response rate for the CD30positive cutaneous lymphoproliferative disorders. In addition, it produced an unexpectedly high response rate in patients with mycosis fungodies, irrespective of degree of CD30 expression and including [mycosis fungoides] with large cell transformation or folliculotropic morphology,” said lead author Madeleine Duvic, MD, Professor of Medicine and Dermatology and Deputy Chair of the Dermatology Department at The University of Texas MD Anderson Cancer Center, Houston.

Study Background CD30-positive cutaneous T-cell lymphomas/lymphoproliferative disorders include primary cutaneous anaplastic T-cell lymphomas, secondary cutaneous anaplastic T-cell lymphomas, lymphomatoid papulosis, and transformed CD30-positive mycosis fungoides. Brentuximab vedotin is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Hodgkin lymphoma and anaplastic large cell lymphoma, and is investigational in cutaneous T-cell lymphoma. The single-center, open-label study

ma/ lymphomatoid papulosis. The study included 22 women and 26 men with a median age of 59.5 years (range, 31–86). Brentuximab vedotin was infused over 30 minutes every 21 days for eight cycles; patients who achieved partial remission could get up to 16 doses. Treatment was continued for two doses past complete remission. Responses were defined for each lesion type as follows: lymphomatoid papulosis, 50% decrease in active lesion count; anaplastic T-cell lymphoma, tumor measurements of index lesions; mycosis fungoides, 50% reduction in modified skin weighted assessment tool (mSWAT). Quality of life was evaluated on a visual analog scale with a patient global assessment.

Key Data In 48 evaluable patients, the overall response rate was 73%. Breaking response rates down by tumor type, over-

EXPERT POINT OF VIEW

“T

his study provides proof of principle that different tumor types that express CD30 have a good chance of responding to anti-CD30 treatment. Brentuximab achieves good response rates of about 76% in mycosis fungoides and 85% in [anaplastic T-cell lymphoma]. In [mycosis fungoides] and cutaneous T-cell lymphoma, response rates were slightly lower and duration of response also slightly lower than in other CD30-positive Anas Younes, MD lymphoid malignancies with an FDA-approved indication,” said Anas Younes, MD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center, New York. “Brentuximab vedotin is a promising treatment strategy for [cutaneous Tcell lymphoma] and lymphoproliferative CD30-positive malignancies. The ongoing phase III trial comparing brentuximab vedotin with investigator’s choice in patients with relapsed CD30-positive [cutaneous T-cell lymphoma] will certainly clarify the potential role of brentuximab vedotin in this patient population,” Dr. Younes commented. To move the drug forward, the next steps are to study brentuximab in combination with other drugs to increase response rates and duration of response in cutaneous T-cell lymphoma and other lymphoproliferative CD30positive cutaneous malignancies and/or to identify a biomarker for patients who benefit from the drug within this subgroup. “Identifying a biomarker is a bit more challenging than doing combination studies,” Dr. Younes noted. n Disclosure: Dr. Younes has received honorarium from Seattle Genetics and Millennium.

all other tumor types, overall response rate was 100%. Looking at mycosis fungoides patients, best skin response to treatment on mSWAT increased over time. Response was not correlated with level of CD30 expression at baseline in mycosis fungoides. Median time to response for all patients was 12 weeks. Median duration of response for mycosis fungoides patients was 39 weeks. Six patients experienced grade 3 or higher adverse events, including neutropenia, nausea, unstable angina, infection, fatigue, deep-vein thrombosis, pulmonary embolism, liver function test

New Findings for Brentuximab Vedotin ■■ The antibody-drug conjugate brentuximab vedotin achieves high response rates in cutaneous T-cell lymphomas, including the most common type, mycosis fungoides. ■■ The drug is being evaluated in phase III trials.

all response rate was 54% for mycosis fungoides (13 partial remissions, 2 complete remissions), the most common type of cutaneous T-cell lymphoma; for

abnormalities, dehydration, and arthralgia (some patients experienced multiple events). Six patients withdrew from the study, two due to death.

Peripheral neuropathy was the most common adverse event of concern, occurring in 31 (65%) of 48 patients at least once. Median duration of peripheral neuropathy was 60 weeks. Dose reductions resolved peripheral neuropathy in 14 (45%) of the 31 patients; peripheral neuropathy was unresolved in 17 (55%) of 31 patients at the time of the ASH meeting. Fatigue was reported in 41%, and drug rash in 27%. The phase III ALCANZA trial is comparing brentuximab vedotin vs investigator’s choice of methotrexate or bexarotene (Targretin) in approximately 124 patients with relapsed CD30-positive cutaneous T-cell lymphoma. Results may determine whether FDA approval will be granted for the disease. n

Disclosure: Dr. Duvic has received research funding from Seattle Genetics and Millennium.

Reference 1. Duvic M, Tetzlaff M, Clos AL, et al: Phase II trial of brentuximab vedotin for CD30+ cutaneous T-cell lymphomas and lymphoproliferative disorders. 2013 ASH Annual Meeting. Abstract 367. Presented December 9, 2013.

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ASH Annual Meeting Hematology

Idelalisib Plus Rituximab in Heavily Pretreated Relapsed CLL: ‘Dawn of a New Age’? By Alice Goodman

delalisib plus rituximab (Rituxan) improved progression-free survival, overall response rates, and overall survival compared with rituximab alone in heavily pretreated patients with relapsed chronic lymphocytic leukemia (CLL). Moreover, the combination provided effective, durable disease control in these patients, who were not suitable for cytotoxic chemotherapy.1

A total of 220 patients were randomly assigned between the two arms. At baseline, both treatment arms were well balanced. The median number of prior therapies was three in each arm, 91% in the idelalisib arm and 88% in the placebo arm had received prior rituximab, and time since diagnosis was 7.8 and 8.6 years, respectively.

Highly Selective Oral Agent “This study heralds the dawn of a new age, with the opportunity to treat CLL patients with refractory disease and to treat them much more safely,” stated Richard R. Furman, MD, Richard A. Stratton Associate Professor in Hematology and Oncology at Weill Cornell Medical College, New York. “Idelalisib represents an important addition to the armamentarium for patients living with this life-threatening disease.” Idelalisib is a targeted, highly selective, orally administered inhibitor of the delta isoform of the PI3K enzyme, which is found exclusively in hematopoietic cells and is essential to survival of CLL cells. The drug inhibits cell proliferation and induces apoptosis of CLL cells. It also inhibits homing and retention of CLL cells in lymphoid tissues, reducing cell survival, Dr. Furman explained at a late-breaking abstract session during the 2013 American Society of Hematology (ASH) Annual Meeting in New Orleans. These properties of idelalisib explain the rapid and dramatic reduction in lymphadenopathy seen with this drug, before lymphocyte counts are reduced, he said.

Study 116 Study 116 was a randomized controlled, double-blind study conducted in the United States and Europe investigating the benefit of rituximab plus idelalisib compared with rituximab plus placebo. Eligible patients were considered unfit for chemotherapy, as defined by a Cumulative Illness Rating Scale (CIRS) score > 6, creatinine clearance < 60 mL/min, or myelosuppression secondary to prior chemotherapy.

isib/rituximab over rituximab/placebo (P = .018). A decrease in lymphadenopathy, based upon “nodal response” (which required a > 50% reduction), was seen in 93% of the idelalisib/rituximab arm vs 4% of the placebo/rituximab arm. Adverse events were similar in both arms: 90.9% and 94.4%, respectively, ex-

With drugs like idelalisib, we have a great opportunity to eliminate chemotherapy from the treatment paradigm. —Richard R. Furman, MD

All patients received rituximab at 375 mg/m2, followed by 500 mg/m2 every 2 weeks for four doses, and then every 4 weeks for three doses, for a total of eight doses over 6 months. Idelalisib was administered at a dose of 150 mg twice daily. Patients continued on either idelalisib or placebo until disease progression, at which point they were given idelalisib at 150 mg twice daily in addition to their current therapy. Thus, patients initially on placebo received idelalisib at 150 mg plus placebo twice daily and patients initially on idelalisib at 150 mg received idelalisib at 300 mg twice daily. The study was stopped early based on a prespecified interim analysis by an independent monitoring committee showing a highly statistically significant effect of idelalisib/rituximab on progression-free survival, the primary endpoint. Median progression-free survival was not reached in the idelalisib/rituximab arm vs 5.5 months in the rituximab/placebo arm (P < .0001), representing an 85% improved likelihood of progression-free survival with the novel agent. For all prespecified subgroups, progression-free survival favored idelalisib/ rituximab over placebo/rituximab. Overall survival also favored idelal-

Idelalisib in Chronic Lymphocytic Leukemia ■■ A first-in-class PI3K inhibitor, idelalisib in combination with rituximab extended survival in heavily pretreated CLL patients, including those with poor-risk cytogenetics. The drug was well tolerated. ■■ Idelalisib is an FDA-designated Breakthrough Therapy moving forward in other phase III trials.

perienced any adverse event; 56.4% and 47.7%, respectively, experienced grade 3 or higher adverse events. There were fewer deaths in the idelalisib/rituximab arm: 4 vs 12, respectively. Infusion-related reactions

occurred in 17 patients (16%) in the idelalisib/rituximab arm vs 30 patients (28%) in the rituximab/placebo arm.

Eliminating Chemotherapy Based on these findings, idelalisib was granted Breakthrough Therapy designation for CLL by the U.S. Food and Drug Administration. “With drugs like idelalisib, we have a great opportunity to eliminate chemotherapy from the treatment paradigm. The focus has always been on eliminating chemotherapy for patients who are unfit and likely to suffer toxicities. My hope is that with these novel agents (tyrosine kinase inhibitors), even medically fit patients will be able to avoid chemotherapy and its toxicities, making long-term survival a reality,” Dr. Furman commented. n

Disclosure: Dr. Furman has served as an advisor for Gilead Sciences.

Reference 1. Furman RR, et al: ASH Annual Meeting. Abstract LBA-6. Presented December 10, 2013.

EXPERT POINT OF VIEW

“I

delalisib is being studied in three ongoing registration trials. [Study 116] was stopped early after idelalisib/rituximab demonstrated high efficacy in relapsed chronic lymphocytic leukemia [CLL],” said Jennifer R. Brown, MD, PhD, Director of the CLL Center at Dana-Farber Cancer Institute, Boston. Dr. Brown moderated a press conference at the ASH Annual Meeting, where the results were discussed. She pointed out that patients on this drug have a very rapid nodal re-

The challenge is to decide when patients should receive idelalisib vs other emerging therapies for CLL. —Jennifer R. Brown, MD, PhD

sponse and start to feel better quickly, before their white blood cell counts start to improve. “Over time, the white counts also improve,” she said. All of the new therapies, including idelalisib, make this an exciting time in the field of CLL, Dr. Brown continued. “The challenge is to decide when patients should receive idelalisib vs other emerging therapies for CLL. That’s the $64,000 question, isn’t it?” she said. The next generation of studies will be aimed at evaluating combinations to determine how to sequence and deploy these new therapies, she said. n Disclosure: Dr. Brown has served as a consultant for Gilead Sciences.

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ASH Annual Meeting Hematology

Idelalisib Achieves High Response Rates in ‘Double-Refractory’ Indolent NHL By Caroline Helwick

n patients with indolent B-cell nonHodgkin lymphoma (NHL) refractory to both rituximab (Rituxan) and an alkylating agent, monotherapy with the selective oral PI3K-delta inhibitor idelalisib produced a high response rate, with responses persisting for 1 year in the average patient, according to mature response data from a phase II study presented at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition in New Orleans.1 “Idelalisib may provide meaningful disease control in ‘double-refractory’

that idelalisib’s novel mechanism of action could be efficacious in double-refractory indolent B-cell NHL,” he said. PI3K-delta signaling is critical for the activation, proliferation, and survival of B cells and is hyperactive in many B-cell malignancies. PI3K-delta inhibition impacts many of these critical pathways and suppresses the homing and retention of malignant B-cells in lymphoid tissues, reducing B-cell survival.

Study Details

Study 101-09 included 125 previously treated patients with follicular lymphoma (58%), small lymphocytic lymphoma (22%), marginal zone lymphoma (12%), and lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia (8%). Patients were refractory to both rituximab and an alkylating agent and had reAjay Gopal, MD Bruce D. Cheson, MD ceived a median number of four prior therapies. These were most indolent B-cell NHL patients,” suggest- commonly bendamustine (Treanda)/ ed principal investigator Ajay Gopal, rituximab and rituximab, cyclophosphaMD, of the University of Washington mide, doxorubicin, vincristine, prednisone School of Medicine, Seattle. (R-CHOP); 11% of patients had underBruce D. Cheson, MD, Professor gone prior stem cell transplantation. of Medicine, Deputy Chief of HematolPatients received idelalisib at 150 mg ogy/Oncology, and Head of Hematol- twice daily until disease progression. As ogy at the Georgetown University Hos- of the data cutoff in June 2013, approxipital, Lombardi Comprehensive Cancer mately one-third of patients remained Center, Washington, DC, commented on treatment and two-thirds had disconduring the discussion period, “[These tinued therapy due to disease progresare] very exciting data, and [the results] sion (32%), adverse event (20%), death are potentially practice-changing.” (6.4%), investigator request (5.6%), or withdrawal of consent (3.2%). Why PI3K-Delta Inhibition? Mean duration of idelalisib treatment “Patients with indolent B-cell NHL was 8.1 months; median duration was 6.6 refractory to rituximab and alkylating months, ranging from 0.6 to 23.9 months. agents have few or no remaining viable treatment options and are an under- High Response Rates Seventy-one patients responded for studied population, due to the lack of an effective therapy. We hypothesized an overall response rate of 57%, includ-

Idelalisib in Non-Hodgkin Lymphoma ■■ The oral investigational PI3K-delta inhibitor idelalisib produced an overall response rate of 57% in indolent non-Hodgkin lymphoma patients refractory to both rituximab and an alkylating agent. ■■ Almost all patients had some degree of tumor reduction, and disease was controlled for a year or more in many patients.

ing complete responses in 6%, partial responses in 50%, and a minor response in one patient with Waldenstrom’s macroglobulinemia. Another 34% of patients had stable disease, while 8% had disease progression, and 2% were not evaluated. Responses were consistent across subsets, with the highest response rate (80%) seen in lymphoplasmacytic lymphoma/Waldenstrom’s macroglobulinemia patients. Responses were high, regardless of disease histology, number of prior regimens, refractoriness to bendamustine, or tumor bulk. By number of prior therapies, responses were observed in 50% of patients with fewer than four lines and 62% of those with four or more lines of prior treatment. Time to response was rapid—less than 2 months for the average patient. The median duration of response was 12.5 months, he said. The waterfall plot of lymph node responses showed that 90% of patients had an improvement in lymphadenopathy and 57% had at least a 50% decrease from baseline. “Virtually all patients had some degree of tumor reduction,” Dr. Gopal said. “A number had prolonged stable disease, and this is also what I’ve seen in my clinic.”

Acceptable Safety Profile “Idelalisib was well tolerated and had an acceptable safety profile,” he reported. The primary adverse event

was diarrhea, which occurred in 43% (all grades), including grade ≥ 3 in 13%. Pneumonia ≥ grade 3 developed in 7%. Serious adverse events included pyrexia (10.4%), pneumonia (7.2%), and diarrhea (7.2%), with a few patients developing colitis, dehydration, neutropenic fever, acute renal failure, and pneumonitis. Neutropenia ≥ grade 3 was observed in 27%, but 5% of patients were neutropenic at baseline. Transaminase elevations were fairly common, with grade 1 or 2 observed in 35%, grade 3 in 10%, and grade 4 in 2%. “Grade 1 and 2 transaminase elevation resolved with continued idelalisib treatment, and grade 3 and higher was reversible with drug interruption,” he said. “Fourteen out of 16 patients with grade 3 or 4 transaminase elevations were rechallenged, and 10 of them had no recurrences.” n

Disclosure: The study was funded by Gilead Sciences. For full disclosures of the study authors, view the study abstract at ash. confex.com/ash/2013/webprogram/start. html.

Reference 1. Gopal A, Kahl BS, De Vos S, et al: Mature response data from a phase 2 study of PI3K-delta inhibitor idelalisib in patients with double (rituximab and alkylating agent)-refractory indolent B-cell non-Hodgkin lymphoma (iNHL). 2013 ASH Annual Meeting. Abstract 85. Presented December 8, 2013.

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ASH Annual Meeting Gemtuzumab Ozogamicin Reduces Relapse, Improves Event-Free Survival in Pediatric AML By Caroline Helwick

he monoclonal antibody gemtuzumab ozogamicin (Mylotarg) improved event-free survival and reduced the risk of relapse in children with acute myeloid leukemia (AML) in a study from the Children’s Oncology Group, presented at the 55th American Society of Hematology (ASH) Annual Meeting and Exposition by Alan S. Gamis, MD, MPH, Associate Director of Hematology/ Oncology and Section Chief of Oncology at Children’s Mercy Hospitals and Clinics in Kansas City, Missouri.1 “Gemtuzumab ozogamicin improved event-free survival in children, adolescents, and young adults with AML by reducing the risk of relapse among those achieving remission,” Dr. Gamis reported. Initial findings for gemtuzumab ozogamicin, the first humanized antiCD33 monoclonal antibody, were so promising in treatment-refractory patients that the drug was granted accelerated approval in 2000. Subsequent phase III clinical trials, however, failed to replicate the positive results in newly diagnosed patients, leading to the drug’s withdrawal from the market in 2010. Two subsequent trials were again contradictory, showing that disease-free survival and reduced risk of relapse did, indeed, occur with gemtuzumab ozogamicin, primarily in the low- or intermediate-risk AML subgroups, according to Dr. Gamis. “We know that AML is a very heterogeneous disease, and thus, we don’t expect one single agent to work in all patients,” Dr. Gamis said, “so this endpoint

was designed to look at whether gemtuzumab ozogamicin improves event-free survival from the time of diagnosis, and whether this benefit varied by risk group method of intensification.”

Study Details The phase III AAML0531 trial enrolled 1,070 pediatric and young adult patients (median age, 10 years), randomly assigning them to standard

arm vs 46.9% in the standard treatment arm, representing a reduction in events of 17% (P = .04). “We did not see a significant benefit in complete remissions after induction, but that’s not unusual,” he added. (This phenomenon of an induction randomization only having an impact upon postremission outcome, and not upon the remission rate itself, was also seen in the CCG-2891 trial,

We should revisit the addition of this agent, to further define the patients who would most benefit. It is very promising, and I think this is a treatment that will become more standard in the future. —Alan S. Gamis, MD, MPH

therapy alone or to two doses of gemtuzumab ozogamicin at 3 mg/m2 per dose on day 6 of induction and on day 7 of intensification, with a five-cycle chemotherapy backbone. The use of stem cell transplantation was stratified by risk, with high-risk patients allocated to best allogeneic donor transplant after the first induction, while low-risk patients received chemotherapy only and intermediate-risk patients were assigned to transplant if there was a matched family donor. After a median follow-up of 3.5 years, the 3-year event-free survival rate from time of study entry was 53.1% in the gemtuzumab ozogamicin

Gemtuzumab Ozogamicin in AML ■■ Gemtuzumab ozogamicin was withdrawn from the market in 2010, but a new study suggests it does provide benefit in pediatric and young adult patients with acute myeloid leukemia. ■■ The Children’s Oncology Group AAML0531 trial evaluated the addition of gemtuzumab ozogamicin to standard chemotherapy vs chemotherapy alone (with or without stem cell transplant) and found a benefit in eventfree survival at 3 years. ■■ No increase in complete remission rate or overall survival was observed.

which randomized standard-timing vs intensive-timing chemotherapy, he explained.2)“We did see a reduction in the risk of relapse.” At 3 years from the end of induction, relapses had occurred in 32.8% of the gemtuzumab ozogamicin group vs 41.3% of the standard treatment group, for a 27% reduction in risk (P = .01).

Increased Toxicity “But we also saw an increase in treatment-related mortality,” he added. This was 6.6% in the gemtuzumab ozogamicin arm and 4.1% in the standard treatment arm among those in remission, primarily due to infections in later cycles. “Our current regimen uses four courses, not five, so we think the risk of infectious complications will be less,” he added. “Because of this increase in toxicity, we saw no statistically significant improvement in overall survival,” he said. At 3 years from the end of induction, overall survival was 74.0% with gemtuzumab ozogamicin and 70.1% without gemtuzumab ozogamicin (P = .32). Disease-free survival, however, closely approached a significant im-

provement (hazard ratio = 0.82, 95% confidence interval [CI] = 0.67–1.01, P = .07). At 3 years, disease-free survival was 60.6% vs 54.7% in the two groups, respectively. In multivariate modeling to minimize confounding (controlling for risk group, age, white count at diagnosis, and race), the disease-free survival Cox regression hazard ratio was 0.80 (95% CI = 0.64–0.99, P = .04). By risk subgroup, gemtuzumab ozogamicin markedly reduced relapse risk in the low-risk patient group: 19.7% with gemtuzumab ozogamicin vs 30.3% without gemtuzumab ozogamicin—a 42% reduction—but this group also had a fourfold increased risk of treatment-related mortality (7.5% vs 1.8%). Relapses were consistently reduced in all risk groups, though in the intermediate-risk and high-risk groups the benefit was limited to stem cell transplant recipients. In conclusion, Dr. Gamis said that gemtuzumab ozogamicin and other investigational CD33-directed agents show promise in pediatric AML and merit further investigation. “We should revisit the addition of this agent, to further define the patients who would most benefit. It is very promising, and I think this is a treatment that will become more standard in the future,” he predicted. n

Disclosure: The study authors reported no potential conflicts of interest.

References 1. Gamis AS, Aplenc R, Alonzo TA, et al: Gemtuzumab ozogamicin (GO) in children with de novo acute myeloid leukemia (AML) improves event-free survival (EFS) by reducing relapse risk: Results from the randomized phase III Children’s Oncology Group (COG) trial, AAML0531. 2013 ASH Annual Meeting. Abstract 355. Presented December 9, 2013. 2. Woods WG, Kobrinsky N, Buckley JD, et al: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: A report from the Children’s Cancer Group. Blood 87:49794989, 1996.

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ASH Annual Meeting Hematology

Crizotinib Proves Effective in ALK-Positive Lymphoma By Alice Goodman

rizotinib (Xalkori) produced promising results in patients with ALK-positive lymphoma in two small studies presented at the 2013 American Society of Hematology (ASH) Annual Meeting. Crizotinib exerted potent antitumor activity in advanced ALK-positive lymphoma and achieved durable responses in heavily pretreated patients, with a benign safety profile. Crizotinib was the first ALK inhibitor to be approved by the U.S. Food and Drug Administration for the indication of ALK-positive non–small cell lung cancer. These studies support the concept of targeting the tumor abnormality as an important strategy, not just focusing on the type of cancer. “These data indicate that ALK-positive lymphoma patients have a high chance of responding to crizotinib even when heavily pretreated, with approximately half of them not relapsing within the first months and then enjoying long-lasting responses…. These data will be useful for the management of this aggressive disease,” said Carlo Gambacorti-Passerini, MD, University of Milano Bicocca, Monza, Italy, an investigator in both studies.

These data indicate that ALKpositive lymphoma patients have a high chance of responding to crizotinib even when heavily pretreated, with approximately half of them not relapsing within the first months and then enjoying longlasting responses. —Carlo Gambacorti-Passerini, MD

Compassionate Use Study To test the concept of ALK inhibition in ALK-positive lymphoma, Dr. Gambacorti-Passerini and colleagues evaluated crizotinib monotherapy (250 mg twice daily) in a compassionate use study of 11 patients (7 males, 4 females) with ALKpositive non-Hodgkin lymphoma documented by immunohistochemistry and fluorescence in situ hybridization. “In this study, crizotinib was well tolerated for up to 3 years, with a 91% overall response rate and a 2-year progressionfree survival of 63.7%. Durable responses were seen in about half the patients in this study. These promising results will lead to

EXPERT POINT OF VIEW

nas Younes, MD, Chief of the Lymphoma Service at Memorial Sloan-Kettering Cancer Center in New York, told The ASCO Post, “Of the 800 or so ALK-positive anaplastic large-cell lymphoma patients in the United States, 70% to 80% are cured by CHOP [cyclophosphamide, doxorubicin, vincristine, prednisone]. In the remaining 20% to 30%, second-line therapy with autologous stem cell transplant consolidation cures another Anas Younes, MD 50%. Then brentuximab vedotin [Adcetris] can be used in the remaining patients. Crizotinib [Xalkori] may be effective in patients who have not responded to other therapies such as brentuximab,” he said.

Noteworthy Mechanism Dr. Younes said the excitement over this study relates to the ability to target the oncogenic driver of anaplastic large-cell lymphoma—the ALK gene translocation—as opposed to brentuximab, which delivers a chemotherapylike agent to CD30-expressing lymphomas. “Crizotinib has good activity and safety. The challenge is how to move crizotinib forward in a relatively rare disease with a high cure rate on currently available regimens. You would need a huge randomized trial to compare CHOP vs CHOP plus crizotinib in newly diagnosed patients. An alternative, more efficient strategy would be to use this drug in brentuximab failures, or perhaps combine it with brentuximab,” Dr. Younes stated. n Disclosure: Dr. Younes reported no potential conflicts of interest.

studies of crizotinib earlier in the course of disease and in combinations. Since ALK mutations were identified in relapsed patients, second-generation ALK inhibitors should be tested in relapsed patients,” Dr. Gambacorti-Passerini said. All 11 patients had relapsed or refractory, heavily pretreated disease, with a median of three prior lines of therapy. Median age was 28 years. Response to crizotinib was evaluated by computed tomography and positronemission tomography scans according to RECIST criteria. Overall response rate was 91%, including nine complete remissions and one partial remission. ALK rearrangements were documented in all nine complete remissions. Responses began to emerge as early as 12 days after the first dose of crizotinib. Bulky lymphadenopathy resolved as early as day 16, and bone marrow involvement resolved at 1 month in four patients with bone marrow involvement. B symptoms

relapse and die and half go on to continued complete remission,” he stated.

Registration Study Dr. Gambacorti-Passerini was lead author of a registration study sponsored by Pfizer and reported at the ASH meeting during a poster session. The registration study had a design and enrollment criteria (including advanced pretreated ALK-positive lymphoma) similar to those of the compassionate use study. This open-label, multicenter, exploratory trial enrolled 15 patients with advanced ALK-positive lymphoma; 14 had anaplastic large-cell lymphoma (ALCL) and 1 had diffuse large B-cell lymphoma. Median age was 25 years, and 60% were male. All patients had received prior systemic therapy, and 13% had undergone prior radiation therapy. The median number of previous lines of therapy was three. At the time of data analysis in June 2013, 5 patients had discontinued therapy and 10 were still on treatment. Median duration of treatment was 33 weeks. Overall response rate was 57%, and clinical benefit rate (including complete remission, partial remission, and stable disease) was 64%. Progression-free and overall survival will be reported with longer follow-up. The most common adverse events were diarrhea and nausea, each observed in 47% of patients. Visual impairment was reported in 40%, and asthenia, cough, and neutropenia each occurred in 27%. Most treatment-emergent adverse events were grade 1. “These data suggest that ALK inhibi-

Crizotinib in Lymphoma ■■ Crizotinib showed promising activity in two small studies of ALK-positive lymphoma. ■■ Based on these results, crizotinib will be studied in combination with other drugs to treat lymphoma and earlier in the course of disease.

resolved quickly, normalizing within 30 days, Dr. Gambacorti-Passerini noted. At 2 years, the overall survival rate was 72.7% and the progression-free survival rate is 63.7%. All four cases of crizotinib treatment failure occurred within the first 3 months of therapy. “Four patients relapsed, three were able to undergo bone marrow transplantation, and four are alive and happy.” Dr. Gambacorti-Passerini said. “Our observations suggest that within 2 to 3 months of treatment with crizotinib, approximately half the patients

tion can be effective in patients with ALKpositive hematologic malignancy. Further study is warranted in this setting,” concluded Dr. Gambacorti-Passerini, who was first author of the poster presentation. n

Disclosure: Dr. Gambacorti-Passerini is a consultant for and has received research funding from Pfizer.

References 1. Redaelli S, et al: ASH Annual Meeting. Abstract 368. Presented December 9, 2013. 2. Gambacorti-Passerini C, et al: ASH Annual Meeting. Abstract 4342. Presented December 9, 2013.

The ASCO Post | MARCH 15, 2014

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FDA Update

Omacetaxine Mepesuccinate Receives Full FDA Approval for CML

he U.S. Food and Drug Administration (FDA) has granted full approval to omacetaxine mepesuccinate (Synribo) for injection. The full approval was based on the final analysis of two phase II trials that evaluated the efficacy and tolerability data of omacetaxine. The agent received an accelerated approval in October 2012 for adult patients with chronic-phase or accelerated-phase chronic myeloid leukemia (CML) with resistance or intolerance to two or more tyrosine kinase inhibitors.

patients achieved a major cytogenetic response with a mean time to major cytogenetic response onset of 3.5 months. The median duration of response for these patients was 12.5 months. For accelerated-phase CML, 14% of patients

achieved a major hematologic response, with a mean time to response onset of 2.3 months. The median duration of major hematologic response for these patients was 4.7 months. The most common adverse reac-

tions in chronic- and acceleratedphase patients were thrombocytopenia, anemia, neutropenia, diarrhea, nausea, fatigue, asthenia, injection site reaction, pyrexia, infection, and lymphopenia. n

Phase II Studies The original approval of omacetaxine mepesuccinate was based on an

Activated T Cell Inactivated T Cell

analysis of combined data subsets from two phase II, open-label, multicenter studies. The pooled analysis included patients who had received two or more approved tyrosine kinase inhibitors and, at a minimum, had evidence of resistance or intolerance to dasatinib (Sprycel) and/or nilotinib (Tasigna). Treatment with imatinib (Gleevec), dasatinib, and nilotinib had failed in 47% of chronic-phase patients and 63% of accelerated-phase patients; the majority of patients had also received other treatments including hydroxyurea, interferon, and cytarabine. For chronic-phase CML, 18% of

PD-L1

PD-1 Receptor PD-L2

PD-1 Receptor PD-L1

Oncology Drug Approvals in 2014 • February 12, 2014: Ibrutinib (Imbruvica) receives accelerated approval for patients with chronic lymphocytic leukemia who have received at least one prior therapy. • January 10, 2014: Trametinib (Mekinist) and dabrafenib (Tafinlar) receive approval for use in combination in the treatment of patients with unresectable or metastatic melanoma with a BRAF V600E or V600K mutation.

Artist’s interpretation based on scanning electron microscopy.

ASCOPost.com | MARCH 15, 2014

PAGE 39

FDA Update

FDA Grants Orphan Drug Status to Pracinostat for the Treatment of Acute Myeloid Leukemia

he U.S. Food and Drug Administration (FDA) has granted orphan drug designation to the investigational drug pracinostat for the treatment of acute myeloid leukemia (AML).

The FDA’s Orphan Drug Designation program provides orphan status to drugs defined as those intended for the safe and effective treatment, diagnosis or prevention of rare diseases

that affect fewer than 200,000 people in the United States.

About Pracinostat Pracinostat is an orally available

Discover PD-1: An immune checkpoint pathway1 Some tumor cells can evade the body’s immune response, which may result in disease progression2,3 • One function of the body’s immune response is to detect and destroy tumor cells through activated T cells and other mechanisms; tumor cells express multiple antigens that are not expressed in normal tissue.1—3 • However, some tumor cells may evade the body’s immune response by exploiting the PD-1 checkpoint pathway through expression of the dual PD-1 ligands PD-L1 and PD-L2.1,2,4—7 • PD-L1 and PD-L2 engage the PD-1 receptor on T cells in order to inactivate T cells, which may allow tumor cells to evade the immune response.1,2,8 Merck is committed to furthering the understanding of immunology in cancer, including the role of the PD-1 pathway.

TO DISCOVER MORE ABOUT THE PD-1 CHECKPOINT PATHWAY IN CANCER AND TO REGISTER FOR UPDATES, VISIT WWW.DISCOVERPD1PATHWAY.COM.

PD-1=programmed cell death protein 1; PD-L1=programmed cell death ligand 1; PD-L2=programmed cell death ligand 2. References: 1. Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–264. 2. Keir ME, Butte MJ, Freeman GJ, et al. PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol. 2008;26:677–704. 3. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646–674. 4. Quezada SA, Peggs KS. Exploiting CTLA-4, PD-1 and PD-L1 to reactivate the host immune response against cancer. Br J Cancer. 2013;108(8):1560–1565. 5. Zou W, Chen L. Inhibitory B7-family molecules in the tumour microenvironment. Nat Rev Immunol. 2008;8(6):467–477. 6. Rosenwald A, Wright G, Leroy K, et al. Molecular diagnosis of primary mediastinal B cell lymphoma identifies a clinically favorable subgroup of diffuse large B cell lymphoma related to Hodgkin lymphoma. J Exp Med. 2003;198(6):851–862. 7. Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151–2157. 8. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261–268.

histone deacetylase (HDAC) inhibitor that has been tested in phase I and phase II clinical trials in advanced hematologic disorders and solid tumors in both adult and pediatric patients. The drug has been generally well tolerated, with manageable side effects generally associated the drugs of this class. In a phase I dose-escalation trial, pracinostat demonstrated evidence of single-agent activity in elderly patients with AML, including 2 out of 14 (14%) who achieved a complete remission, with durable responses persisting 206+ and 362 days, respectively. A phase II clinical trial of pracinostat in combination with Vidaza in elderly patients with newly diagnosed AML is currently underway. n

FDA Orders Cessation of Sale, Distribution of Four Tobacco Products

DA has issued orders to stop the further sale and distribution of four tobacco products currently on the market. The action marks the first time the FDA has used its authority under the Family Smoking Prevention and Tobacco Control Act to order a manufacturer of currently available tobacco products to stop selling and distributing them. The products, Sutra Bidis Red, Sutra Bidis Menthol, Sutra Bidis Red Cone, and Sutra Bidis Menthol Cone, were found to be not substantially equivalent to tobacco products commercially marketed as of February 15, 2007. This means they can no longer be sold or distributed in interstate commerce or imported into the United States. “Historically, tobacco companies controlled which products came on and off the market without any oversight,” said Mitch Zeller, JD, Director of the FDA’s Center for Tobacco Products. “But the Tobacco Control Act gave the FDA, a science-based regulatory agency, the authority to review applications and determine which new tobacco products may be sold and distributed under the law in order to protect public health.” For more information, visit www. fda.gov/TobaccoProducts/ n

The ASCO Post | MARCH 15, 2014

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Issues in Oncology

Advanced Practitioners in Oncology: Diverse Experiences, Shared Challenges By Susan Reckling

he professional paths of advanced practitioners (APs) in oncology are as varied as the locations in which they work. The first annual JADPRO Live 2014 educational symposium was held in St. Petersburg, Florida, and hosted by JADPRO, the Journal of the Advanced Practitioner in Oncology. A distinguished panel was assembled to discuss the profile of today’s APs

Jeannine M. Brant, PhD, APRN, AOCN®

from the unique perspectives of a nurse practitioner at a large academic cancer center, a clinical nurse specialist and scientist, a nurse practitioner at a rural cancer institute, a clinical pharmacist at a comprehensive cancer center, and a physician assistant at the oldest private cancer center in the country. The assortment of challenges facing advanced practitioners in oncology requires clear thinking, assistance from those who have already blazed a path, and confidence to discover workable solutions. The panel focused on issues such as fostering the collaborative practice model in oncology, balancing academic education and on-the-job clinical training, establishing advanced practice

groups as a forum for the voice of the APO to be heard, and serving as mentors to younger practitioners and/or students.

nurse practitioners, an attending physician, a fellow, and a clinical pharmacist.

Inpatient and Outpatient Experience

Collaborative Models of Practice While the professional experiences of the panel members were diverse, many of them shared the collaborative nature of their current roles. Jeannine M. Brant, PhD, APRN, AOCN®, was a pain consultant in her first advanced practitioner role, developing a pain service with a group of nurse practitioners who managed pain in patients admitted to the hospital. In another role, Dr. Brant was involved in the development of a supportive care clinic comprised of an interdisciplinary

Christopher J. Campen, PharmD, BCPS, BCOP

and quality of life instead of my disease.” After a general practice residency and an oncology fellowship, Christopher J. Campen, PharmD, BCPS, BCOP, worked as an academic pharmacist in conjunction with an outpatient cancer treatment center. “I was the first pharmacist to work with outpatients in the clinical areas about 5 years ago at our

The panel focused on issues such as fostering the collaborative practice model in oncology, balancing academic education and on-the-job clinical training, establishing advanced practice groups as a forum for the voice of the APO to be heard, and serving as mentors to younger practitioners and/or students. team of nurse practitioners, pharmacists, physician assistants, social workers, dietitians, and occupational therapists. The team meets weekly to help patients struggling with uncontrolled physical and/or psychosocial symptoms. As one patient told her, “I will never miss my symptom management visit, because it is the time I get to talk about my symptoms

Meet the Panel Laura Zitella, MS, RN, ACNP-BC, AOCN®, moderator: Lead Advanced Practice Provider, Inpatient Hematology/Oncology, Stanford University Medical Center, Stanford, California, and Clinical Assistant Professor, D epartment of Physiological Nursing, University of California, San Francisco Jeannine M. Brant, PhD, APRN, AOCN®: Oncology Clinical Nurse Specialist, Nurse Scientist, and Pain Consultant, Billings Clinic Cancer Center, Billings, Montana Christopher J. Campen, PharmD, BCPS, BCOP: Clinical Pharmacist and IT Analyst, University of Arizona Center Center, Tucson, Arizona Heather M. Hylton, MS, PA-C: Lead Physician Assistant, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York Wendy H. Vogel, MSN, FNP, PA-C, AOCNP®: Oncology Nurse Practitioner, Wellmont Cancer Institute, Kingsport, Tennessee

cancer center,” he revealed. Dr. Campen predicted that the model of the future is for pharmacists to work alongside advanced practitioners, physicians, and fellows in outpatient clinics and infusion areas to reduce errors and improve patient safety. In addition to doing a lot of protocol and standard development, Dr. Campen has become involved in direct patient care, counselling patients with lung cancer on the adverse effects of traditional chemotherapy and targeted agents, including erlotinib (Tarceva). “I often grab our oncology pharmacist to go to a pain consult on the inpatient unit,” said Dr. Brant. Pharmacists have been among the staunchest supporters of advanced practitioners in collaborative practice, she noted. This sentiment was echoed by Heather M. Hylton, MS, PA-C. “I could never practice without a clinical pharmacist,” she said. In her administrative role, Ms. Hylton has helped to build programs and integrate APs into different services at her cancer center. In terms of her clinical role in bone marrow and stem cell transplantation, there are two separate inpatient teams, with each team having four to five physician assistants and

Over the past 15 years, panel moderator Laura Zitella, MS, RN, ACNPBC, AOCN®, has seen much change at her academic cancer center. In the bone marrow transplant setting, she

Laura Zitella, MS, RN, ACNP-BC, AOCN®

recognized the importance of caring for patients across the inpatient and outpatient settings. She helped develop a program where the outpatient nurse practitioner and the inpatient fellow switched positions for 2 months of the year. Over the years, this evolved into inpatient and outpatient teams that include both advanced practitioners and fellows year-round. In the hematology/ oncology divisions, she was instrumental in creating a collaborative inpatient service consisting exclusively of advanced practitioners supervised by an attending physician. Turning to her role as a community oncology nurse practitioner, Wendy H. Vogel, MSN, FNP, AOCNP®, called her current practice model a chameleon. She is in a collaborative practice model with seven oncologists, seeing a schedule of patients similar to theirs, she noted. In addition to writing and publishing her own practice protocols, Ms. Vogel transformed her passion for prevention into a high-risk cancer clinic

Heather M. Hylton, MS, PA-C

for patients. In partnering with a genetic counselor, she offers both genetic testing and risk-reduction counseling.

ASCOPost.com | MARCH 15, 2014

Transforming Challenges Into Opportunities The panel agreed that many of the challenges facing today’s advanced practitioners in oncology may also be viewed as opportunities. Two specific areas of concern echoed by the panel and many attendees centered on the need to improve the academic and clinical training/orientation of APs and the importance of promoting the evolving role of advanced practitioners in cancer

Wendy H. Vogel, MSN, FNP, AOCNP®

centers and community settings, as well as in the eyes of the public. The training of advanced practitioners differs from that of physicians. Ms. Zitella noted that most advanced practitioners are trained as generalists, with the oncology coming as an apprenticeship and on-the-job training. Academic training for APs, including educational information from such organizations as ASCO and the Oncology Nursing Society, is part of the

PAGE 41

equation, but so too is adequate time for clinical training, she added. Although the panel and many attendees considered several months to be a reasonable duration of orientation for an advanced practitioner new to oncology, all admitted that in reality, the time is much shorter than that. There is a struggle to obtain administrative support for proper orientation and assignment of a mentor. The value of a strong mentoring relationship between a supervising physician and an advanced practitioner is a critical part of clinical training. The panel acknowledged the ongoing need for more hands-on training programs for APs, postgraduate programs, and resources geared for those in the community setting. Ms. Hylton mentioned ASCO’s Curricula for Advanced Practice Providers (ACAPPTM) offered through ASCO University (http://university.asco. org/app), which offers courses on topics such as basic symptom management, communication with patients, and pharmacology. Clerkships for later-level students were also noted as a possibility, as was the practice of taking on students interested in health care. “Working with students is a good recruitment tool, and I have hired many of my former students for our team,” stated Ms. Zitella. Furthermore, much can be accom-

Evolving Role of Advanced Practitioners in Oncology ■■ At a recent roundtable discussion, a distinguished panel of advanced practitioners (APs) in oncology shared their diverse professional experiences yet similar vision on the value of collaborative practice. ■■ Among the many challenges facing today’s APs are how best to balance academic education with on-the-job clinical training and the need to establish advocacy groups to promote the evolving role of APs.

plished regarding advocacy efforts on behalf of APs. For instance, Ms. Zitella shared her experiences in creating an advanced practice provider council at Stanford. Caught between nursing and medicine and often reporting to nonclinical managers, advanced practitioners found their own forum to effect change through this group, she added. Several recommendations were made by the panel to APs looking to implement changes in their practices and serve as advocates for health policy: Have long-term goals but start with small victories, be patient and line up all of your champions, promote your passion in writing and speaking, and get involved on the local political level.

Improving Patient Outcomes In closing, the panel flagged one particular area in which collaborative practice may improve patient outcomes: adherence to oral oncolytic

agents. Drs. Brant and Campen noted that there are stellar models focusing on oral adherence for multidisciplinary teams, and one of the best is a system that runs through a clinical pharmacist and an advanced practitioner. Through such collaborative efforts, patient questions can be answered, adherence and refills can be tracked either by phone or text, the need for changes in dose can be assessed, and side effects can be identified and managed through follow-up. Ms. Vogel agreed that an oral clinic would be a major benefit to both patients and providers, “because these patients often do not get the education or attention that patients receiving intravenous chemotherapy receive,” she concluded. n Disclosure: Dr. Brant is on the speaker’s bureau for Genentech. Dr. Campen, Ms. Zitella, Ms. Hylton, and Ms. Vogel reported no potential conflicts of interest.

Don’t Miss These Important Reports in This Issue of The ASCO Post Neal J. Meropol, MD, on effect of aspirin on survival in colorectal cancer see page 15

Peter T. Scardino, MD, FACS, and Howard M. Sandler, MD, MS, FASTRO, on trends in prostate cancer see pages 1, 3, and 4

Susan F. Slovin, MD, PhD, on melanoma and prostate cancer see page 43

Richard L. Schilsky, MD, FASCO, and Laurence H. Baker, DO, on U.S. Cooperative Group Trials see pages 1 and 58-59

Clifford A. Hudis, MD, on the costs of noncompliance see page 52

Christopher A. Barker, MD, Bhuvanesh Singh, MD, PhD, and Kishwer S. Nehal, MD, on cutaneous squamous cell carcinoma staging see page 56

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PAGE 43

JCO Spotlight Genitourinary Oncology

History of Prostate Cancer Increases Risk of Melanoma in White Men By Matthew Stenger

istory of severe acne, which is a surrogate for high androgen activity, has been associated with increased risk of prostate cancer, and recent data suggest that severe teenage acne is a risk factor for melanoma. Such findings suggest a role of androgens in etiology for both prostate cancer and melanoma.

melanoma in white men.1 Their findings suggest that personal history of prostate cancer is associated with significantly increased risk of melanoma.

Study Details The study was a prospective evaluation of the association of prostate cancer and incident melanoma among

Our finding of [prostate cancer] diagnosis as a risk predictor for melanoma holds general public health significance, which may inform clinical practice to address the queries and aid the care of patients with [prostate cancer]. —Wen-Qing Li, PhD, and colleagues

In a study reported in the Journal of Clinical Oncology, Wen-Qing Li, PhD, of the National Cancer Institute, and colleagues investigated the potential association between prostate cancer and

42,372 white men in the Health Professionals’ Follow-Up Study (HPFS, 1986–2012). Prostate cancer, melanoma, and nonmelanoma skin cancer diagnoses were self-reported biennially,

and prostate cancer and melanoma diagnoses were pathologically confirmed. The association between prostate cancer diagnosis and melanoma was also examined among 18,603 white men in the Physicians’ Health Study (PHS, 1982–1998).

Increased Risk of Melanoma in HPFS During 747,176 person-years of follow-up, 5,091 prostate cancers and 539 melanomas were identified in the HPFS. Men with prostate cancer were older (mean, 73 vs 61 years) and reported greater ever-use of sildenafil citrate for erectile dysfunction (24% vs 5.5%). They were also somewhat more likely to have greater sun exposure (average ≥ 11 hours per week in 56.5% vs 50% in college/high school, 39% vs 32% at age 25–35 years, 31% vs 27% at age 36–59 years, and 32% vs 27% at age ≥ 60 years) and somewhat less likely to be a current smoker (4.5% vs 7.6%). Burn or blistering due to sun exposure was reported in 65% and 68%, 4.7% vs 3.7% had a

family history of melanoma, natural red or blonde hair was reported in 15% vs 13%, and history of at least six severe or blistering sunburns was reported in 36% and 34%. On multivariate analysis adjusting for age, body mass index, smoking status, alcohol intake, physical activity, ever-use of sildenafil citrate for erectile dysfunction, childhood reaction to sun, number of sunburns, mole count, hair color, family history of melanoma, sun exposures by age, and ultraviolet (UV) index by age, personal history of prostate cancer was significantly associated with increased risk of melanoma (adjusted hazard ratio [HR] = 1.83, 95% confidence interval [CI] = 1.32–2.54). A lag analysis in which prostate cancer diagnosis occurring at least 2 years before melanoma served as the exposure produced similar results (HR = 1.54; 95% CI = 1.03–2.29). Adjustment for midrange UV radiation exposure (UVB flux) and adjustment for severe acne also did not alter continued on page 44

Melanoma and Prostate Cancer: Two Sides of One Coin? By Susan F. Slovin, MD, PhD

n a recent study, reviewed in this issue of The ASCO Post, Li et al present data from two long- term prospective studies—the Physicians Health Study (PHS, from 1982 to 1998), and the Health Professionals’ Follow-up Study (HPFS, from 1986 to 2010)— both of which suggest a strong association between prostate cancer and risk of melanoma.1 Both studies sought to monitor medical history and lifestyle practices. The PHS was a randomized, doubleblind, placebo-controlled trial with annual follow-up for the prevention of cancer and cardiovascular disease. The HPFS used self-reported questionnaires biennially, whereas the PHS incorporated self-reporting of prostate cancer, at which time immediate medical records and pathology reports were requested. Dr. Slovin is a medical oncologist in the Genitourinary Oncology Service at Sidney Kimmel Center for Prostate and Urologic Cancers, Memorial Sloan Kettering Cancer Center, New York.

Androgens and Acne The Li et al study introduces and attempts to support the hypothesis that not only is there a strong association between prostate cancer and

surrogate for high androgen activation, could indirectly be a risk factor for melanoma, thereby leading to an association between melanoma and prostate cancer.

Further characterization of genetic characteristics in these cases will likely help determine whether there is a commonality between the two diseases. Even if these observations are not confirmed, it nevertheless brings awareness of how these associations can impact lifestyle, health maintenance, and treatments. —Susan F. Slovin, MD, PhD

infiltration by intraprostatic Propionibacterium acnes and subsequently may have led to the development of acne vulgaris in youth. Questionnaires that indicated the self-reported use of tetracycline for the treatment of acne for 4 or more years provided data that an association of chronic tetracycline use for acne could lead to a higher risk of prostate cancer. This incorporated a constellation of lifestyles that included increased risk of sun exposure with blistering facial sunburns, increased alcohol consumption, less calcium consumption, and greater alcohol consumption in youth. While not deemed an epiphenomenon, the strength of this association has never been conclusively borne out.

Ironies and Uncertainties the development of melanoma, but there is also an underlying association between androgens and acne as a precursor of prostate cancer. The authors’ prior work has suggested that severe teenage acne, which may be a

Analyses of prostatectomy specimens have shown chronic inflammatory changes that may serve as a precursor for the development of prostate cancer. The inflammatory changes have been associated with

The current study reviews multiple aspects of the HPFS and PHS participants including the personal history of prostate cancer. In the 747,176 person-years reported, 5,091 prostate continued on page 44

The ASCO Post | MARCH 15, 2014

PAGE 44

JCO Spotlight Prostate Cancer and Melanoma

No Increased Risk of Other Cancers

continued from page 43

Personal history of prostate cancer was not significantly associated with risk of other cancers (eg, HR = 1.23, 95% CI = 0.96–1.57, for lung cancer, and HR = 1.16, 95% CI = 0.82–1.63, for colorectal cancer). Risk for melanoma was not significantly associated with history of cancers other than prostate cancer, with few patients with other major cancers developing melanoma during follow-up (eg, three patients with colorectal cancer and none with lung cancer).

the association. Mole counts were not significantly related to risk of prostate cancer, although there was a borderline significant interaction (P = .08 for interaction) between prostate cancer and melanoma risk according to presence of moles. No significant heterogeneity in melanoma risk was found in analyses by prostate cancer subtype, age at diagnosis, or primary treatment. During 692,290 person-years of follow-up, 11,960 nonmelanoma skin cancers (squamous cell or basal cell carcinoma) were identified in the HPFS. Patients with prostate cancer had a slight and nonsignificant increase in risk for nonmelanoma skin cancers (adjusted HR = 1.08, 95% CI = 0.995–1.16). The magnitudes of association of prostate cancer with melanoma and with nonmelanoma skin cancers were significantly different (P =.002 for heterogeneity). Personal history of melanoma was not associated with increased risk of prostate cancer (HR = 0.88, 95% CI = 0.57–1.35).

Two Sides of One Coin? continued from page 43

cancers and 539 melanomas were identified, suggesting that a personal history of prostate cancer was significantly associated with risk of melanoma (hazard ratio = 1.83, 95% confidence interval = 1.32–2.54). While the studies presented were prospective, and suggested a strong association of melanoma with prostate cancer, there is still concern that other factors may play a pivotal role in the association. Among the driving forces in prostate cancer growth is the androgen receptor, while melanoma has BRAF mutations as its main focus for therapeutic targeting. Melanoma is deemed a disease of chronic and severe sun exposure. It is of interest that patients from Scandinavia who experienced markedly fewer months of sunlight were found to be vitamin D deficient and therefore believed to be at higher risk for prostate cancer. In a study by Moan

Confirmation in PHS Cohort The association between prostate cancer diagnosis and increased risk for melanoma was confirmed in the PHS cohort, in which 166 melanomas were identified in 251,850 person-years of follow-up. In a multivariate analysis adjusting for age, body mass index, smoking status, alcohol intake, and physical activity, the hazard ratio for melanoma in patients with history of prostate cancer was 2.17 (95% CI = 1.12–4.21). For et al,2 people living in southern latitudes and who made more vitamin D from sun exposure were less likely to die from those cancers than were the northern latitude residents. Ironically, many men who retire often do so in sunny climes where the sun exposure is high, often promoting near-normal to normal vitamin D levels, but these men still develop prostate cancer in addition to melanoma. It remains unclear as to the stage of the prostate cancer during which melanoma developed in the Li et al report, whether these men were at castrate levels of testosterone for their prostate cancer treatment, what stage the melanoma was at diagnosis, and how many of these patients died of their melanoma rather than of their prostate cancer. The authors acknowledge limitations in the detail of the prostate cancer treatment. Another point of interest is the fact that the PHS revealed that more than two-thirds of the nearly 15,000 study

Prostate Cancer–Melanoma Link ■■ A personal history of prostate cancer was associated with a significantly increased risk of melanoma. ■■ Diagnosis of prostate cancer was not associated with increased risk of other nonskin cancers. ■■ A history of melanoma was not associated with increased risk of prostate cancer.

both cohorts combined, the hazard ratio was 1.89 (95% CI = 1.41–2.54). The investigators concluded: [B]ased on two large, well-established, long-term cohorts, we suggest an association between a diagnosis of [prostate cancer] and risk of subsequent melanoma in white men, which may not be entirely a result of greater medical scrutiny. We postulated a potential role for androgens in the etiology of melanoma, which might contribute to the observed association. Pending biologic investigation, further understanding of the mechanisms that mediate the associations could eventually lead to elucidation of new targets for interventions that may modulate their incidence or activity…. Our finding of [prostate cancer] diag-

participants had suboptimal blood levels of vitamin D in the winter and spring. Among men who developed prostate cancer, those with low levels of vitamin D (aged ≥ 65 years) were more likely to have an aggressive form of the disease.

Broad Implications The authors provide strong statistical data based on two large, wellestablished, long-term cohorts. The speculation that androgens can play a potential role in melanoma and may contribute to its association with prostate cancer is tantalizing.3 The authors point toward the fact that patients with an androgen imbalance during prostate carcinogenesis might be at greater risk for melanoma development. While there exists an increased risk of melanoma in patients with prostate cancer, the converse association did not appear to hold true. The implications for this study are broad and certainly have potential pub-

nosis as a risk predictor for melanoma holds general public health significance, which may inform clinical practice to address the queries and aid the care of patients with [prostate cancer].

They noted that it would be of interest to investigate the effects of continuous androgen deprivation in prostate cancer on the risk for melanoma. n

Disclosure: The study was supported by the National Cancer Institute. The authors reported no potential conflicts of interest.

Reference 1. Li W-Q, Qureshi AA, Ma J, et al: Personal history of prostate cancer and increased risk of incident melanoma in the United States. J Clin Oncol 31:4394-4399, 2013.

lic health impact. Further characterization of genetic characteristics in these cases will likely help determine whether there is a commonality between the two diseases. Even if these observations are not confirmed, it nevertheless brings awareness of how these associations can impact lifestyle, health maintenance, and treatments. n

Disclosure: Dr. Slovin reported no potential conflicts of interest.

References 1. Li W-Q, Qureshi AA, Ma J, et al: Personal history of prostate cancer and increased risk of incident melanoma in the United States. J Clin Oncol 31:4394-4399, 2013. 2. Moan J, Porojnicu AC, Dahlback A, et al: Addressing the health benefits and risks, involving vitamin D or skin cancer, of increased sun exposure. Proc Natl Acad Sci USA 105:668-673, 2008. 3. Rampen FH, Mulder JH: Malignant melanoma: An androgen-dependent tumour? Lancet 1(8168 pt 1):562-564, 1980.

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The ASCO Post | MARCH 15, 2014

PAGE 52

JCO Spotlight Hematology

Higher Copayment Associated With Greater Discontinuation of and Nonadherence to Tyrosine Kinase Inhibitor Treatment in CML By Matthew Stenger

he availability of the tyrosine kinase inhibitor imatinib (Gleevec) has dramatically increased survival in chronic myeloid leukemia (CML). Nonadherence to therapy with imatinib

expenditures from 2002 to 2011 and the association between copayment requirements for imatinib and tyrosine kinase inhibitor adherence.1 They found that patients with higher copay-

Patients with higher copayments are more likely to discontinue or be nonadherent to [tyrosine kinase inhibitors]. Given the importance of these therapies for patients with CML, our data suggest a critical need to reduce patient costs for these therapies. —Stacie B. Dusetzina, PhD, and colleagues

and other tyrosine kinase inhibitors is associated with disease progression and treatment resistance. In a study reported in the Journal of Clinical Oncology, Stacie B. Dusetzina, PhD, University of North Carolina at Chapel Hill, and colleagues evaluated trends in imatinib

ments are significantly more likely to be nonadherent to or discontinue tyrosine kinase inhibitor treatment.

Study Details The study involved review of MarketScan health plan claims to identify

patients aged 18 to 64 years with CML who started imatinib therapy between January 2002 and June 2011 and had insurance coverage for ≥ 3 months before and ≥ 6 months after treatment initiation (N = 1,541). The primary outcomes were tyrosine kinase inhibitor discontinuation and nonadherence. The primary independent variable was out-of-pocket cost for a 30-day supply of imatinib. A propensity-score weighted sample was used to estimate risk of discontinuation and nonadherence for patients with higher (top quartile) vs lower copayments (bottom 3 quartiles). The propensity score was derived by modeling the probability of having higher vs lower copayments as a function of control variables including age, insurance type, region, and enrollee relationship to employee, all assessed in the month prior to starting therapy, as well as the Klabunde modification of the Charlson comorbidity score and number of medication classes used preceding treatment initiation, both assessed during the 3 months prior to the start of therapy.

Copayments Copayment requirements were calculated based on coinsurance or copayments for the first fill for imatinib. Most patients paid copayments (88.5% of imatinib users) rather than coinsurance (6% of imatinib users). Costs varied substantially, with 6% of patients paying > $500 for a 30-day supply. Over the study period, the mean copayment for a 30-day supply of imatinib was $108 and the median copayment was $30, with a range of $0 to $4,792. Although mean monthly copayments varied widely (from $0 to $4,792 for a 30day supply), patients in the lowest 25th percentile were paying $17 and those in the upper 75th percentile were paying $53. Monthly copayments increased from an average of $55 in 2002 to $145 in 2010. Mean monthly total expenditure for imatinib increased from $2,798 in 2002 to $4,892 in 2011 ($2,846 to $4,954 for median expenditure). Before propensity-score weighting, patients with relatively lower imatinib copayment requirements (lowest 3 quartiles, n =1,134) and those with higher

Who Pays for Noncompliance? The Hidden Costs of Our Current System By Clifford A. Hudis, MD

he development of novel targeted therapies that capitalize on our growing understanding of the molecular underpinnings and vulnerabilities of specific malignancies has to rank among the most important advances we have seen in the 50 years since the American Society of Clinical Oncology was founded. We have, of course, had truly targeted therapies—dating to the performance of bilateral oophorectomies to deprive estrogen receptor–positive breast cancers of their ligand— since the end of the 19th century, but now we are witnessing and driving an unprecedented expansion in such agents.1 The new agents that have been Dr. Hudis is President, ASCO; Chief, Breast Cancer Medicine Service, Memorial Sloan Kettering Cancer Center; and Professor of Medicine, Weill Cornell Medical College, New York.

Ultimately, we share the costs of everyone’s illnesses directly or indirectly, and it costs all of us when patients with a treatable serious illness are inadequately treated because of avoidable challenges. The question is this: What are we going to do about it? —Clifford A. Hudis, MD

most successful have truly changed the expected outcomes and treatment course for historically poorprognosis diseases. Before the development of imatinib (Gleevec), the treatment of chronic myelogenous leukemia (CML) consisted of chemotherapy, bone marrow transplant, and supportive care.2,3 After the development of this agent, a

large number of patients have been able to enjoy prolonged periods of disease control with minimal symptoms and without the earlier generation of cytotoxic agents. Moreover, this success has begotten further success with the development of related agents for resistant disease and for other malignancies with related pathophysiology.

Reasons for Noncompliance One of the seeming advantages of many newly developed agents is their oral bioavailability. Avoiding inpatient or outpatient parenteral treatment is, or should be, less expensive and generally appeals to patients and families. There is, however, an ever-present concern about compliance. We have studied this for years in the postoperative, adjuvant setting for breast cancer, where compliance with oral antiestrogen treatments is documented to decline over time.4 The reasons for noncompliance include toxicity, cost, convenience, and other factors, all of which we try to confront, given the evidence that prolonged therapy (now up to 10 years in many settings) is associated with further improvements in outcomes. One would think that CML would not be subject to the same lack of compliance as has been seen

ASCOPost.com | MARCH 15, 2014

PAGE 53

JCO Spotlight

copayment requirements (upper quartile, n = 407) were generally balanced for age (mean, 49 and 48 years), sex (44% and 46% female), relationship of patient to employee (66.5% and 69% employee), starting imatinib dose (≤ 400 mg in 89% in both), number of medications in the 3 months before start of treatment (mean, 5.5 and 5.3), and Charlson comorbidity score (0 in 94% and 95%). Patients with higher copayment requirements were significantly less likely to live in the Northeast (13% vs 8%, P = .01 for trend) and significantly more likely to have a preferred provider organization health plan (57% vs 68%, P < .001 for trend). After propensity-score weighting, there were no significant differences between groups in any of these characteristics.

tiation, representing a 70% increase in risk of discontinuing tyrosine kinase inhibitors in those with higher copayments (adjusted risk ratio [RR] = 1.70, 95% confidence interval [CI] = 1.30–2.22). Similarly, patients with higher copayments were significantly more likely to be nonadherent with tyrosine kinase inhibitor therapy, defined as < 80% of days with drug available (21% vs 30%, adjusted RR = 1.42, 95% CI = 1.19–1.69). Patients with lower copayments had a significantly greater number of days covered by medication supply (87% vs 82%, adjusted risk difference = −0.05, 95% CI = −0.07 to −0.02), but there was no difference between groups when patients who discontinued medication were excluded from analysis (93% vs 92%, adjusted risk difference = −0.01, P = .15).

Discontinuation and Nonadherence

Sensitivity Analyses

On adjusted analysis, 10% of patients with lower copayment requirements and 17% with higher requirements discontinued therapy during the first 180 days after treatment iniin early-stage breast cancer. CML is potentially lethal in the short-term, and the treatment that imatinib replaces was generally far more debilitating and toxic, as well as less effective.

Health-Care Challenge The recent study by Dusetzina and colleagues,5 reported in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post, highlights a challenge for our current health-care system. Simply put, the investigators correlated the out-ofpocket expenses for imatinib with compliance. They showed that as the personal cost in dollars increases, compliance decreases. This is not a surprise, since the finding is consistent with the rest of conventional economic thinking, modeling, and

Sensitivity analyses excluding patients who were hospitalized after starting imatinib, excluding patients who paid drug deductibles, excluding patients who were enrolled for < 6 months without tyrosine kinase inhibitor use, behavior. The question we have to ask is whether this is acceptable. The health-care market—if you can really call it a market—is unusual in myriad ways. For one thing, the user, in this case a patient with CML, is not the sole purchaser. A third party has prenegotiated the price as well as set the patient’s share. If the patient can’t pay, there is no immediate market response (in the form of lower pricing). This is, to be simplistic, different from the market for used cars. There, the buyer has options (buy another seller’s car) and the seller has options (lower the price to make a deal). Because health care is so important, we establish third-party insurance (whether government run or private), and we share the financial burden of illness broadly. This, perhaps, limits some of the potential for price gouging at the

Copayments and Treatment Adherence in CML ■■ Patients with higher copayments were 70% more likely to discontinue tyrosine kinase inhibitor therapy. ■■ Patients with higher copayments were 42% more likely to be nonadherent to tyrosine kinase inhibitor therapy.

defining adherence as < 85% and < 90% of days covered, and defining discontinuation as > 90 days of no tyrosine kinase inhibitor treatment all had results consistent with the primary analysis. An additional sensitivity analysis assumed that the confounder of poor understanding of one’s disease was twice as common among patients in the higher copayment group vs the lower copayment group (approximately 20% vs 10%) and assumed that the confounding factor was associated with a twofold increase in risk of discontinuation or nonadherence. Based on these assumptions, risk of discontinuation and risk of nonadherence in the high copayment group remained significant. It was estimated that lack of understanding would need to be three times more common in the higher copayment group and associindividual level. But it is acutely unresponsive to the downward pressure on price that lack of demand should exert. And it is similarly inflexible in the face of one individual’s inability to pay. Of course, this description oversimplifies a complex and highly evolved system, but the bottom line remains that we (and our fellow citizens) have a shared interest in assuring the optimal health of everyone. Ultimately, we share the costs of everyone’s illnesses directly or indirectly, and it costs all of us when patients with a treatable serious illness are inadequately treated because of avoidable challenges. The question is this: What are we going to do about it? n Disclosure: Dr. Hudis reported no potential conflicts of interest.

ated with a threefold increased risk of discontinuation or adherence for the risk associated with higher copayment to no longer be significant. The investigators concluded, “Patients with higher copayments are more likely to discontinue or be nonadherent to [tyrosine kinase inhibitors]. Given the importance of these therapies for patients with CML, our data suggest a critical need to reduce patient costs for these therapies.” n Disclosure: The study authors reported no potential conflicts of interest.

Reference 1. Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol. December 23, 2013 (early release online).

References 1. Beatson CT: On treatment of inoperable cases of carcinoma of the mamma: Suggestions for a new method of treatment with illustrative cases. Lancet 148 (3803):162-165, 1896. 2. Sawyers CL: Chronic myeloid leukemia. N Engl J Med 340:1330-1340, 1999. 3. Goldman JM: Chronic myeloid leukemia: A historical perspective. Semin Hematol 47:302-311, 2010. 4. Partridge AH, Wang PS, Winer EP, et al: Nonadherence to adjuvant tamoxifen therapy in women with primary breast cancer. J Clin Oncol 21:602-606, 2003. 5. Dusetzina SB, Winn AN, Abel GA, et al: Cost sharing and adherence to tyrosine kinase inhibitors for patients with chronic myeloid leukemia. J Clin Oncol 32:306-311, 2013.

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JCO Spotlight Dermatologic Oncology

Brigham and Women’s Hospital Tumor Staging for Cutaneous Squamous Cell Carcinoma Outperforms AJCC and UICC Staging By Matthew Stenger

n a study reported in the Journal of Clinical Oncology, Pritesh S. Karia, MPH, and Chrysalyne D. Schmults, MD, MSCE, of Brigham and Women’s Hospital, Boston, and colleagues compared Brigham and Women’s Hospital, American Joint Committee on Cancer (AJCC),

had 1 tumor and 21% had 2 to 4 tumors, 85% had tumors < 2 cm in diameter, 66% had well-differentiated tumors, 90% had tumors that did not invade subcutaneous fat or deeper structures, and 4% had perineural invasion. Median follow-up was 50 months.

[Brigham and Women’s Hospital] staging offers improved distinctiveness, homogeneity, and monotonicity over AJCC and UICC staging. Population-based validation is needed. —Pritesh S. Karia, MPH, Chrysalyne D. Schmults, MD, MSCE, and colleagues

and International Union Against Cancer (UICC) tumor staging systems for cutaneous squamous cell carcinoma.1 They found that Brigham and Women’s staging offered advantages over the conventional staging systems.

Study Details The study involved analysis of 1,818 primary tumors diagnosed from 2000 to 2009 at Brigham and Women’s Hospital. Poor outcomes, including local recurrence, nodal metastasis, and diseasespecific death, were analyzed by AJCC, UICC, and Brigham and Women’s T stage with regard to distinctiveness (outcome differences between stages), homogeneity (outcome similarity within stages), and monotonicity (outcome worsening with increasing stage). Brigham and Women’s staging system is as follows: T1 = 0 high-risk factors, T2a = 1 high-risk factor, T2b = 2 to 3 high-risk factors, and T3 = ≥ 4 high-risk factors; high-risk factors include tumor diameter ≥ 2 cm, poorly differentiated histology, perineural invasion ≥ 0.1 mm, and tumor invasion beyond fat, excluding bone invasion, which automatically upgrades tumors to stage T3. Patients had a median age of 71 years at diagnosis, 98% were white, 53% were male, 14% were immunosuppressed, 73%

Poor Outcomes by Stage For local recurrence, 10-year cumulative incidence (95% confidence interval [CI]) was 0.7% (0%–1%), 8% (5%–10%), 67% (21%–94%), and 67% (21%–94%) for AJCC T1 to T4 stages; 2% (1%–2%), 7% (4%–12%), 16% (8%– 30%), and 67% (21%–94%) for UICC T1 to T4 stages; and 0.6% (0%–1%), 5% (3%–8%), 21% (13%–27%), and 67% (30%–90%) for Brigham and Women’s T1, T2a, T2b, and T3 stages. For nodal metastasis, 10-year cumulative incidence (95% CI) was 0.1% (0%–1%), 6% (4%–9%), 67% (21%– 94%), and 67% (21%–94%) for AJCC stages; 1% (0%–2%), 3% (1%–7%), 21% (11%–35%), and 67% (21%–94%) for UICC stages; and 0.1% (0%–0.4%), 3% (1%–5%), 21% (13%–27%), and 67% (30%–90%) for Brigham and Women’s stages. For disease-specific death, 10year cumulative incidence (95% CI) was no events, 6% (4%–9%), 100% (44%–100%), and 100% (44%–100%)

for AJCC stages; 0.3% (0%–1%), 3% (1%–6%), 14% (6%–27%), and 100% (44%–100%) for UICC stages; and no events, 1% (0%–3%), 10% (6%–19%), and 100% (61%–100%) for Brigham and Women’s stages. For overall death, 10-year cumulative incidence (95% CI) was 32% (29%–34%), 37% (32%–41%), 100% (44%–100%), and 100% (44%–100%) for AJCC stages; 33% (31%–35%), 31% (24%–38%), 49% (35%–63%), and 100% (44%–100%) for UICC stages; and 32% (30%–35%), 32% (28%–37%), 51% (41%–58%), and 100% (61%–100%) for Brigham and Women’s stages.

(95% CI = 9%–23%) of poor outcomes occurred in AJCC T3 and T4 cases and 30% (95% CI = 21%–39%) in UICC T3 and T4 cases. By comparison, 60% (95% CI = 50%–69%) of poor outcomes occurred in Brigham and Women’s T2b and T3, including 70% of cases of nodal metastasis and 83% of disease-specific deaths.

Stage Changes

Homogeneity was evaluated by comparing the proportion of poor outcomes (local recurrence, nodal metastasis, disease-specific death) occurring in low T stages. Overall 86% (95% CI = 77%–91%) of poor outcomes were in AJCC T1 and T2 cases, 70% (95% CI = 61%–79%) were in UICC T1 and T2 cases, and 40% (95% CI = 30%–49%) were in Brigham and Women’s T1 and T2a cases, with 66% of the poor outcomes being local recurrence in the Brigham and Women’s staging. The nonoverlapping 95% CIs indicate that the Brigham and Women’s system had a significantly lower proportion of poor outcomes in low T stages compared with AJCC and UICC systems, suggesting a higher degree of homogeneity.

Of 112 tumors that were downstaged from AJCC T2 to Brigham and Women’s T1, there were only two local recurrences and one nodal metastasis. In 56 tumors downstaged from UICC stage T2/T3 to Brigham and Women’s T1/T2a, there was only one local recurrence. In 20 tumors downstaged from UICC T3 to Brigham and Women’s T2b, there were four local recurrences, six nodal metastases, and three disease-specific deaths. In 86 cases that were upstaged from AJCC T1/T2 to Brigham and Women’s T2b/T3, there were 18 local recurrences, 18 nodal metastases, and 9 disease-specific deaths. In 66 cases upstaged from UICC T1/T2 to Brigham and Women’s T2b, there were 14 local recurrences, 12 nodal metastases, and 6 disease-specific deaths. The investigators concluded, “[Brigham and Women’s Hospital] staging offers improved distinctiveness, homogeneity, and monotonicity over AJCC and UICC staging. Population-based validation is needed.” They noted that the Brigham and Women’s system consolidated poor outcomes in the two highest stages: “Although these two stages make up only 5% of the cohort, they account for the majority (60%) of poor outcomes… Thus, [Brigham and Women’s] T2b and T3 tumors make up a high-risk subset of [cutaneous squamous cell carcinoma] worthy of further study regarding staging and adjuvant therapy.” Dr. Schmults is the corresponding author for the Journal of Clinical Oncology article. n

Monotonicity

Disclosure: The study authors reported no potential conflicts of interest.

Distinctiveness With regard to distinctiveness, 95% CIs overlapped for AJCC and UICC T3 and T4 stages for all endpoints, as did all four UICC stages for overall death, indicating that AJCC and UICC T3 and T4 are not distinct. Brigham and Women’s T stages had slight overlap of 95% CIs for overall death but no overlap for any other endpoint, indicating good distinctiveness of all four stages for local recurrence, nodal metastasis, and disease-specific death.

Homogeneity

Monotonicity was evaluated by comparing the proportion of poor outcomes occurring in high T stages. Overall, 14%

Skin Cancer Staging ■■ Brigham and Women’s T staging provided improved distinctiveness, homogeneity, and monotonicity over AJCC and UICC staging for squamous cell carcinoma.

Reference 1. Karia PS, Jambusaria-Pahlajani A, Harrington DP, et al: Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital tumor staging for cutaneous squamous cell carcinoma. J Clin Oncol. December 23, 2013 (early release online).

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Perspective

Staging of Cutaneous Squamous Cell Carcinoma By Christopher A. Barker, MD, Bhuvanesh Singh, MD, PhD, and Kishwer S. Nehal, MD

eoplasms originating from skin keratinocytes are increasing in frequency in the United States and include a spectrum of diseases culminating in the development of invasive cutaneous squamous cell carcinoma. Although most cases of cutaneous squamous cell carcinoma can be treated conservatively with excellent outcomes, a significant number of patients present with advanced disease requiring aggressive treatment associated with considerable morbidity. Moreover, cutaneous squamous cell carcinoma can be lethal, leading to over 4,000 deaths annually in the United States.1 The challenge has been to identify at presentation patients with cutaneous squamous cell carcinoma who are at risk for local recurrence, metastasis, and death. This has proved difficult, as the disease is common and often treated without definitive histopathologic diagnosis, and failures can develop long after treatment of the index case. Accordingly, cancer registries have not captured the outcomes of the disease adequately. Absence of large, high-quality, comprehensive, and prospectively derived data sets has led to development of staging systems based on expert consensus by the American Joint Committee on Cancer (AJCC) and Union for International Cancer Control (UICC). However, the validity of the current staging systems has been questioned by clinicians.2

Novel Staging System Karia and colleagues conducted a detailed analysis of a large cohort of patients to develop a modified staging system that is a better predictor of outcomes than the AJCC system currently in use.1 The investigators assessed associations between patient, clinical, and pathologic variables and clinical outcomes, including local recurrence, Dr. Barker is Assistant Attending Physician in the Department of Radiation Oncology; Dr. Singh is Director of the Laboratory of Epithelial Cancer Biology and Attending Surgeon in the Head and Neck Service; and Dr. Nehal is Director of Mohs and Dermatologic Surgery and Attending Physician in the Dermatology Service at Memorial Sloan Kettering Cancer Center, New York.

regional lymph node metastasis, disease-specific death, and overall death in univariate and multivariate models. They identified five parameters that significantly predicted worse outcomes on multivariate analysis (poor differentiation, diameter ≥ 2 cm, perineural invasion, depth beyond subcutaneous fat, and immunosuppression). These findings were used to develop a novel staging system for cutaneous squamous cell carcinoma3; the number of poor prognostic factors was used to define the T stage rather than size and/or anatomic disease extent in the AJCC staging system.

(outcomes are similar between staging groups), and monotonicity (outcomes worsen with increasing stage) compared to the AJCC and UICC staging systems.

Strengths and Limitations The BWH system has several strengths, including inclusion of clinical factors (immunosuppression) and outcomes-based derivation from a well-defined patient population. However, several issues need to be considered when evaluating the generalizability of the BWH system. Its derivation from a single pa-

National guidelines suggest that when biopsying cutaneous squamous cell carcinoma, “inclusion of the deep reticular dermis is preferred” for “more than [a] superficial lesion.”4 Additionally, imaging studies are recommended to complete clinical staging. Among patients studied, it is unclear what imaging studies were performed and when. National guidelines on cutaneous squamous cell carcinoma staging suggest “imaging studies as indicated for suspicion of extensive disease,” including “deep structural involvement such as bone, perineural disease, and deep soft tissue.”4

Design and Statistical Issues

Application of specialized multidisciplinary care, development of novel therapies, and execution of clinical trials using a more accurate staging system will be vital for decreasing morbidity and mortality and improving outcomes in patients with high-risk cutaneous squamous cell carcinoma. —Christopher A. Barker, MD, Bhuvanesh Singh, MD, PhD, and Kishwer S. Nehal, MD

The recent publication by this group in the Journal of Clinical Oncology, reviewed in this issue of The ASCO Post, compares AJCC and UICC systems with this system, the Brigham and Women’s Hospital (BWH) tumor staging system. Retrospective analysis of patients with cutaneous squamous cell carcinoma presenting to a single institution between 2000 and 2009 was performed. In total, 974 patients with 1,818 cutaneous squamous cell carcinomas were analyzed, after excluding 162 cases (8.1%) located in the anogenital region, eyelid, or tumors with insufficient information for analysis. The authors concluded that the BWH staging system was associated with greater distinctiveness (outcomes differ between staging groups), homogeneity

tient cohort opens the possibility of introducing biases based on referral patterns and therapy selected. It is also unclear how tissue sampling was achieved and whether this influenced results. It is conceivable that some patients underwent a partial superficial biopsy, while others underwent definitive excision with more histopathologic variables for analysis, such as perineural invasion, differentiation, and depth of invasion. In most contemporary staging systems, there is a clinical staging (based on biopsy) and pathologic staging (based on definitive surgical excision). Moreover, in patients undergoing biopsy alone, the biopsy technique used (shave vs punch) could affect the ability to detect certain pathologic features incorporated into the BWH system.

Finally, there are some study design and statistical issues that may influence the findings. In this study, multiple cutaneous squamous cell carcinomas from the same patient were studied. This is problematic if an individual has two tumors with different characteristics resulting in two very different outcomes. Typically in study design, only the first incident case is taken in a given individual. Multiple tumors may also reflect tumor biology or host status that can further confound study results. Additionally, the authors reported on 10-year outcomes, with a median follow-up that is considerably shorter (50 months [range, 2–142] in the study text, and 44 months [range, 2–130] in Table 2 of the article). This leads to broad confidence intervals in the estimations of the rare events reported by the investigators. In a prospective analysis of risk factors associated with cutaneous squamous cell carcinoma outcomes, with a median follow-up of a similar duration, local recurrence and metastasis were noted to occur up to 4 and 6 years after diagnosis.5 The patterns and time interval to recurrence after treatment of cutaneous squamous cell carcinoma have not been well-characterized and have significant bearing on the current results, as well as implications for patient follow-up practices.

Staging Systems Compared Are we ready, then, to abandon the AJCC TNM staging system on the basis of the reported results? The TNM-based AJCC/UICC staging continued on page 58

NOW ENROLLING A Phase 2 Trial of Rindopepimut in Patients With Relapsed EGFRvIII-Positive Glioblastoma • Rindopepimut is an investigational therapeutic vaccine. It is thought to target EGFRvIII, a constitutively activated deletion mutant that is found only in tumors. About a third of glioblastoma patients express EGFRvIII, and its presence has been linked to poor long-term survival1-3 • ReACT is a phase 2 study being conducted in the United States that will evaluate if rindopepimut is effective in extending progression-free survival (PFS) in patients with relapsed EGFRvIII-expressing glioblastoma, when added to standard bevacizumab

1:1 Randomization

Blinded Rindopepimut Group 1 Bevacizumab Naïve (n=70)

1st or 2nd relapse EGFRvIII-positive glioblastoma

Bevacizumab Blinded KLH Control

Bevacizumab

Treat until tumor progression, intolerance, or withdrawal of consent

Rindopepimut

Group 2 Bevacizumab Refractory

Bevacizumab

(n=25)

KLH=keyhole limpet hemocyanin.

N=95

Key Inclusion Criteria

Key Exclusion Criteria

• Previous treatment must include surgery (biopsy, partial resection, or full surgical resection), conventional radiation therapy, and temozolomide

• Presence of diffuse leptomeningeal disease, gliomatosis cerebri, or infratentorial disease

• First or second relapse of glioblastoma. Patients enrolling into group 2 must have progressed while receiving bevacizumab

• Clinically significant increased intracranial pressure, uncontrolled seizures, or requirement for immediate palliative treatment

• Documented EGFRvIII-positive tumor status. A tumor sample from either the initial diagnosis or more recent relapse will be acceptable. Only patients with the EGFRvIII mutation can participate in the trial

• History, presence, or suspicion of metastatic disease

Key Trial Endpoints • Primary: PFS rate at 6 months (PFS 6) • Secondary: Objective response rate, overall PFS, and overall survival

For more information visit www.celldextherapeutics.com, www.clinicaltrials.gov/show/NCT01498328, or e-mail info@celldextherapeutics.com. 1. Pelloski CE et al. J Clin Oncol. 2007;25(16):2288-2294. 2. Sampson JH et al. J Clin Oncol. 2010;28(31): 4722-4729. 3. Sampson JH et al. Neuro Oncol. 2011;13(3):324-333. ©2013 Celldex Therapeutics, Inc.

J2A

7/13

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Perspective

Cutaneous Squamous Cell Carcinoma continued from page 56

system is uniformly applicable across disease sites. This uniformity makes the AJCC staging system easy to apply in a consistent manner. The TNM system has also remained a reproducible predictor of cancer behavior across disease sites. The TNM staging system was intended to be used in combination, rather than individually as T, N, or M for staging. The combined approach is what makes the TNM system so reproducible and relatively stable over time. Yet, the significance of individual parameters that contribute to T stage is lost when N and M status are incorporated into the staging. For example, tumor differentiation has been shown to be a significant predictor of outcomes for many cancer types, but its inclusion does not add

Cooperative Groups

to TNM staging, as poorly differentiated tumors more readily metastasize. Available data suggest that approximately 2% of patients with cutaneous squamous cell carcinoma present with regional and/or distant metastasis. It would be informative to learn whether the addition of N and M status to the BWH system would make it perform better. Moreover, the factors included in the BWH system may not be easily defined on biopsy samples. A basic premise of clinical TNM staging is that it aids in therapeutic decision-making. Clinical staging systems require that information for staging is available before definitive therapy begins. As such, the BWH system may be valuable as a pathologic system, but may have limited value as a clinical staging system. In summary, cutaneous squamous cell carcinoma is often managed with

Cancer Chemotherapy Study Group, which was funded in 1956 as a pediatric center in Bethesda, Maryland, as a re- oncology group. By 1958, 17 institutionsearch hospital in 1952. With the aid al networks had been organized under of the emerging science of biostatis- NCI grants, and this system evolved and tics, regulators began to appreciate and matured over the ensuing years to beinterpret the various nuanced compo- come the NCI Clinical Trials Cooperanents of trial design and their effect on tive Group Program, with funding prohow data are analyzed. vided through cooperative agreements. The concept of cooperative group triToday, the NCI actually sponsors als was conceived in 1955 by individuals and coordinates two key areas of trials: including Sidney Farber, MD, Mary the Cooperative Group Program that Lasker, and others who sought increased administers clinical trials focused on funding from Congress to support new cancer treatment, and the Community studies of cancer chemotherapy. As a re- Clinical Oncology Program Network (designed in 1983), which primarily conducts trials centered on cancer prevention and control. Now, the very system that was the catalyst for paradigmchanging clinical trials is at a crossroads. “Cancer institutions increasingly say they cannot afford to conduct publicly NCI-funded Sidney Farber, MD Mary Lasker research, and encourage invessult, the NCI formed a Clinical Studies tigators toward drug industry studies. Panel, and during one of its meetings, it Thus, many of these decisions are now concluded that leukemia research could being made on economic grounds,” said move ahead more quickly if they worked Laurence H. Baker, DO, former Chair together on a “cooperative group.” This of the Southwest Oncology Group method had already been used success- (SWOG) and Professor of Internal fully in Veterans Administration hospi- Medicine and Pharmacology at the Unitals in the study of tuberculosis. versity of Michigan, Ann Arbor. In 1955, Congress appropriated $5 million for the NCI, which estab- Understanding the lished the Chemotherapy National Ser- Group’s Value For the past 50 or so years, the vice Center. Several cooperative groups were organized, including the Southwest NCI’s Clinical Trials Cooperative continued from page 1

a simple therapeutic approach, with excellent outcomes. However, there is a pressing need to identify patients at high risk for treatment failure, given the morbidity and mortality associated with the disease. Modifications in the current staging systems may be necessary to allow for better risk stratification. Application of specialized multidisciplinary care, development of novel therapies, and execution of clinical trials using a more accurate staging system will be vital for decreasing morbidity and mortality and improving outcomes in patients with high-risk cutaneous squamous cell carcinoma. n Disclosure: Drs. Barker, Singh, and Nehal reported no potential conflicts of interest.

References 1. Karia PS, Han J, Schmults CD: Cutaneous squamous cell carcinoma: estimated incidence of disease, nodal me-

Group Program has played a central role in improving cancer care. In 1971, Bernard Fisher, MD, the founding Director of the National Surgical Adjuvant Breast and Bowel Project (NSABP), led the NSABP B-04 trial comparing radical mastectomy vs total mastectomy with or without radiation. The trial confirmed Dr. Fisher’s daring hypothesis that breast cancer was not necessarily limited to the breast and surrounding tissue, but was potentially a systemic disease that infiltrates distant organs in the body. The groundbreaking NSABP trial demonstrated that the standard-of-care Halsted radical mastectomy had no therapeutic advantage in breast cancer. At the time, challenging the Halsted radical mastectomy was tantamount to medical heresy, yet a cooperative group trial led by Dr. Fisher did just that, and in the process, forever changed for the better our approach to breast cancer surgery. This famous example of an NCI-funded group trial underscores why the cooperative group model is vital to developing and refining new cancer treatments and disseminating results to the medical community and the general public.

IOM Report In 2010, the Institute of Medicine (IOM) released a report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the NCI Cooperative Group Program.” The goals of the report were largely oriented toward improving the speed and

tastasis, and deaths from disease in the United States, 2012. J Am Acad Dermatol 68:957-966, 2013. 2. Warner CL, Cockerell CJ: The new seventh edition American Joint Committee on Cancer staging of cutaneous nonmelanoma skin cancer: a critical review. Am J Clin Dermatol 12:147-154, 2011. 3. Karia PS, Jambusaria-Pahlajani A, Harrington DP, et al: Evaluation of American Joint Committee on Cancer, International Union Against Cancer, and Brigham and Women’s Hospital Tumor Staging for cutaneous squamous cell carcinoma. J Clin Oncol 32:327-334, 2014. 4. NCCN Clinical Practice Guidelines in Oncology. Basal cell and squamous cell skin cancers. Version 1.2014. 5. Brantsch KD, Meisner C, Schönfisch B, et al: Analysis of risk factors determining prognosis of cutaneous squamous-cell carcinoma: A prospective study. Lancet Oncol 9:713-720, 2008.

Bernard Fisher, MD

efficiency of the design, launch, and conduct of clinical trials. ASCO Chief Medical Officer Richard L. Schilsky, MD, FASCO, served on the IOM’s committee that wrote the report on cooperative group programs. “It’s important to understand that the cooperative groups don’t operate in a vacuum. They are in partnership with the NCI, and they also interface with other agencies such as the [U.S. Food and Drug Administration (FDA)] and NIH, as well as with pharmaceutical companies. The groups have largely met the IOM report metrics set out by an NCI group called the Operational Efficiency Working Group. One concrete improvement set out by the IOM report is a drastic reduction in the time to launch a study,” said Dr. Schilsky. He noted that the most significant outcome of the IOM report was the wholesale consolidation of the cooperative groups program. “The IOM report only recommended that various common functions within the groups should be harmonized, but the NCI actually forced group consolidation by declaring that the agency was

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Issues in Oncology

only going to fund four adult cooperative groups,” said Dr. Schilsky. “The choice the groups faced was to compete against each other for funding or align themselves to optimize their chances at getting as much funding as possible.” He explained that the NCI’s primary goal was to create a network, the National Clinical Trials Network (NCTN), which would comprise the four remaining adult cooperative groups and the Children’s Oncology Group and would function in a highly organized way to conduct a new generation of trials evaluating targeted therapies. “Not surprisingly, the merger process was complicated, taking away valuable time needed to initiate studies. That issue, coupled with NCI’s budget cuts, has greatly reduced the number of studies launched by the cooperative groups over the past few years. The accrual rate is only about 60% of what it was during the groups’ most productive years,” said Dr. Schilsky.

Core Issues Remain Problematic “For many years, the criticism faced by the cooperative groups could be traced to a couple of core issues. One is chronic underfunding and the other is excessive oversight, and neither of these problematic issues has been remedied in the wake of the IOM report. The funding is worse than it’s ever been, and the oversight is more suppressive than ever,” said Dr Schilsky. He stressed that if those core issues are not addressed in a meaningful way, it will not be possible for the cooperative groups to meet their full potential.

Dr. Schilsky illustrated the underfunding crisis faced by the cooperative groups. “The total amount of available funding for the cooperative groups’ budget is about the same amount of money that a drug company would use to complete one or two phase III trials. So when you compare the amount of money the cooperative groups use to launch hundreds of trials in total and dozens of phase III trials, it is the best value-added bargain going,” he said. Asked about the pharmaceutical industry’s increasing leverage in cancer clinical trials, Dr. Schilsky said, “There are an increasing number of collaborative studies between the cooperative groups and commercial industry, and this is driven largely because most of

standard of care in oncology. “Moreover,” added Dr. Schilsky, “all of the prevention strategies that are known to be effective are a result of cooperative group studies—and the list goes on and on [see sidebar below]. If the country feels that these kinds of studies are important, they will only happen through public funding.”

Better Value Needed “The IOM report indicted flaws within the cooperative groups as well as in its partner, the NCI. I’d posit that prior to the report, SWOG recognized those flaws and was working on ways to address and remedy those issues,” said Dr. Baker, referring to his tenure as SWOG Chair.

I have told the leadership of SWOG that their group’s $20 million per year budget is a lot of money.… Spend the $20 million more wisely, and make the benefit of the trials more obvious. —Laurence H. Baker, DO

the interesting drugs are coming out of the pharmaceutical labs. These publicindustry partnerships have been going on for years, and one can access an NCI list of successful new drug indications that were directly related to this collaboration,” said Dr. Schilsky. He noted that the cooperative groups conducted all of the trials that have established the effective combinedmodality therapies that have become

Examples of Advances Attributed to Cooperative Group Trials ■■ Produced long-term survival and cures in a large number of pediatric cancer cases ■■ Showed that breast-conserving lumpectomy is often a better surgical option than radical mastectomy, developed optimal adjuvant chemotherapy regimens, and demonstrated the preventive benefits of tamoxifen ■■ Developed paclitaxel as a premier treatment of ovarian cancer and metastatic non–small-cell lung cancer ■■ Showed 12 months of fluorouracil (5-FU)/levamisole (Ergamisol) chemotherapy decreased mortality in colon cancer by 33%, and in a follow-up study, demonstrated that the same benefit could be realized by 6 months of 5FU/leucovorin ■■ Established combined chemotherapy and radiation as the most effective treatment of advanced cervical cancer

Problems identified by the IOM aside, Dr. Baker said it is vital to consider what the alternative is to the clinical trials network. “Without a robust cooperative group system, we would revert to a Pharma-sponsored clinical trial system, which in my opinion too often has set the bar set too low. A low bar results in having drugs with modest benefit getting FDA approval, passing on exorbitant costs to our health-care system,” remarked Dr. Baker. “Moreover, there is no government oversight of drug pricing in accordance with efficacy. The FDA contends pricing is not the Agency’s mandate, but of course it could be.” He continued, “While I was Chair of SWOG, I told the membership that they were addicted to new drugs. I believe that this cultural addiction to new agents runs across all the groups. The cooperative groups have world-class expertise in conducting randomized prospective clinical trials, the gold standard of evidence. But in my opinion, over the years the groups have shifted their interest in using hypothesis-driven randomized trials to improve patient outcome,

and are far more interested in drug development.” Lack of NCI-funding is the principal reason cited for the increasing shift toward industry-funded clinical trials. To that, Dr. Baker responded, “I have told the leadership of SWOG that their group’s $20 million per year budget is a lot of money. Spend the $20 million more wisely, and make the benefit of the trials more obvious.”

Is Change for the Better? Dr. Schilsky said that the cooperative groups’ traditional model that began 50 years ago was based on investigator-initiated clinical trial networks, whereby the ideas percolated up from the researchers inside the groups, with the best ideas being implemented into clinical trials. “However, NCI’s creation of the NCTN will revert the power to a small number of individuals on steering committees within the NCI. They will decide what clinical trials will be done. It’s a very different model with a narrower vision, and I’m not confident that it will produce the same kind of very successful public health studies that the cooperative groups have.” Recalling his time as Chair of the CALGB, Dr. Schilsky said, “It was a great experience because it gave me the opportunity to lead an enterprise that could accomplish practice-changing research that improved outcomes for patients. All of my predecessors felt the same way. But we wouldn’t have had the same intense drive if we were burdened by today’s excessive paper-shuffling and having protocols imposed on us from outside entities,” said Dr. Schilsky. Under the principal mandate of public health, the cooperative group model has bettered the quality of life for American cancer patients. The system is not perfect, and its most ardent defenders understand that well-reasoned modifications would improve the groups’ performance. But as Dr. Schilsky pointed out, the groups’ evolution to the NCTN is not without peril. “We owe it to our cancer patients to make sure that the transition does not erode the unique spirit of sheer scientific pursuit, volunteerism, and camaraderie that characterized the cooperative groups’ successes,” stressed Dr. Schilsky. n Disclosure: Drs. Schilsky and Baker reported no potential conflicts of interest.

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Direct From ASCO

Charting the Successes: CancerProgress.Net Chronicles More Than 50 Years of ASCO and Progress Against Cancer

n this historic year, as ASCO proudly commemorates its 50th anniversary and decades of evolutionary change and growth, it also celebrates the significant progress that has been made against cancer throughout history. ASCO’s anniversary website, CancerProgress.Net, chronicles these achievements and more. In honor of the Society’s anniversary, the site features stories about ASCO’s evolution, an upgraded timeline of advances in cancer, aggregated news and views on ASCO’s anniversary and

Jennifer Obel, MD

progress, social media features, and an opportunity to vote on the most significant milestones in the field.

Cancer Progress Timeline A key feature of the site, the interactive Cancer Progress Timeline developed under the guidance of an editorial board of 21 of the nation’s leading oncologists, has been updated with a fresh look and is now accessible on all mobile devices. Advances in nearly 20 types of cancers are represented on the timeline, and the story of progress is shared by the timeline editors in their video interviews.

In her video interview, Colorectal Cancer Timeline Editor Jennifer Obel, MD, said, “There have been many advances against colon cancer. The most important one is actually preventing its development with various technologies. In the past 15 years, we now can offer patients with cancer that has spread, six different drug options—six different chemotherapies. Forty years ago we had one. We have improved survival three times what we had before.” Tour ASCO’s anniversary website, CancerProgress.Net, to navigate the timeline advances, hear from other editors about milestones in cancer research, and vote on the top cancer advances over the past 5 decades. Also, follow ASCO on ASCO Connection, Twitter, and Facebook to join in on the conversation about progress. n

Weigh in on which milestones of the last 50 years were the most important by voting on your “Top 5 Advances” at CancerProgress.Net/vote. Voting will continue through the 2014 ASCO Annual Meeting, and results will be announced shortly thereafter.

ASCO Holds Leadership Summit to Address Value in Cancer Care, Cost of Cancer Drugs and Technologies

SCO convened a leadership summit in late January with pharmaceutical representatives, insurance payers, patient advocates, and physicians to initiate a dialogue on the challenge of defining value in cancer care. This meeting was held amid growing concerns about the sustainability of continued increases in the costs of new drugs and technologies used in the diagnosis and treatment of cancer. While costs are rising throughout the health-care system, the trend is especially pronounced in cancer care: Annual costs are projected to rise from $125 billion in 2010 to $175 billion by 2020 (in constant dollars), with the costs of many new cancer drugs and technologies a significant—but not the only—contributing factor. ASCO held the “Summit on Optimizing High Value Cancer Care: Addressing the Cost of Drugs and Novel Technologies” to initiate a dialogue among key stakeholders with the ul-

timate goal of seeking potential solutions that will sustain and accelerate

cused on increasing the affordability of cancer drugs and technologies— from patient, provider, payer, industry, and regulatory perspectives—and concluded with a robust discussion on innovative patient-centered ap-

[All summit participants] agreed that the steep upward cost trajectory raises critical concerns about affordability and accessibility of quality cancer care and that we must, collectively, find solutions that are driven by patient needs, medical evidence, and clearly defined value. —Clifford Hudis, MD, FACP

innovation, and to promote increased patient access while reining in costs and enhancing value in cancer care.

Summit Initiates Robust Discussion on Affordability The invitation-only, day-long event featured presentations that fo-

proaches for ensuring high-quality, high-value cancer care and a plan for stakeholder groups to continue working collaboratively on this issue. “We were impressed by the earnest efforts of every summit participant, each of whom represents interests that play a critical role in the success of our

health-care system,” said ASCO President Clifford A. Hudis, MD, FACP. “All agreed that the steep upward cost trajectory raises critical concerns about affordability and accessibility of quality cancer care and that we must, collectively, find solutions that are driven by patient needs, medical evidence, and clearly defined value.” Building on a long-standing commitment to foster high-quality, evidence-based care, ASCO has launched a new strategic initiative to promote value in cancer care. Under the leadership of its Value in Cancer Care Task Force, ASCO is working to ensure that oncologists have the skills and tools needed to assess relative value of therapies and use these in discussing treatment options with their patients; that patients will have ready access to information that assists them in selecting high value treatment that meets their unique needs; and that providers have a clear method for defining and assessing value of cancer treatment options. n © 2014. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | MARCH 15, 2014

PAGE 63

Direct From ASCO

Support from 1999 Career Development Award Launched Dr. Kornelia Polyak’s Quest to Advance Understanding of DCIS of the Breast

n 1999, Kornelia Polyak, MD, PhD, of the Dana-Farber Cancer Institute, received a Career Development Award from the Conquer Cancer Foundation for her project, “Isolation of Tumor Suppressor Genes Inactivated in DCIS of the Breast.” “The Career Development Award got me started,” she said. “When you’re starting out, it’s so good to feel you can accomplish something and get funding for your ideas. As a junior person, to know that someone appreciates your research and efforts—it’s a positive feeling.”

Volume 29, Issue 15

May 20, 2011

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al

Dr. Polyak was inspired to research ductal carcinoma in situ (DCIS) in 1997 after reading Ductal Carcinoma in Situ of the Breast, by Melvin J. Silverstein, MD. “I read that book, and I realized that no one seemed to understand what DCIS was,” Dr. Polyak said. “I realized it was a huge clinical problem and a challenging scientific problem.” For the CDA project, “we wanted to identify genes that were important to the activation of DCIS,” Dr. Polyak

Top 5 most-accessed articles recently published in Journal of Clinical Oncology

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Seeking Solutions to a Challenging Clinical Problem

What’s Hot in

Top 10 most-accessed articles published in 2011 in Journal of Clinical Oncology

I realized that no one seemed to understand what DCIS was. I realized it was a huge clinical problem and a challenging scientific problem. —Kornelia Polyak, MD, PhD

said. “What are the gatekeeping mutations? What are the genes that are really important for breast cancers to start? To understand that, you have to study early lesions.” Through the CDA project, Dr. Polyak and colleagues discovered that HIN1, a novel breast tumor suppressor gene at the time, was the first gene function lost in a majority of breast

my lab 10 years ago became a breast oncologist. She just wrote to me saying that the experience of being in my lab made her want to pursue this career path. There’s a limit to what we can do in our lab and our lifetimes, and it’s important to continue to have an impact.” The Conquer Cancer Foundation needs your help to support future research leaders like Dr. Polyak. Visit the

cancers. The CDA provided Dr. Polyak with enough preliminary data to apply for a National Institutes of Health (NIH) RO1 grant, which was funded, allowing her to continue her research on DCIS. In a later study published in Cancer Cell in 2004, Dr. Polyak and colleagues showed that the microenvironment within the breast was already changing in patients with DCIS.1 This paper became one of the most cited papers in Cancer Cell in 2004 and altered the way the oncology community thought about the disease, she said.2

Conquer Cancer Foundation website to make a donation and learn more. n

JCO

Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

JCO.org Treatment of Hodgkin Lymphoma: A 50-Year Perspective by George P. Canellos, et al

Randomized, Placebo-Controlled, Phase III Trial of Sunitinib Plus Prednisone Versus Prednisone Alone in Progressive, Metastatic, Castration-Resistant Prostate Cancer by M. Dror Michaelson, et al

Clinical Cancer Advances 2013: Annual Report on Progress Against Cancer From the American Society of Clinical Oncology by Jyoti D. Patel, et al

“Aprepitant Versus Dexamethasone for Preventing Chemotherapy-Induced Delayed Emesis in Patients With Breast Cancer: A Randomized Double-Blind Study” by Fausto Roila, et al

Randomized Phase III Study of Erlotinib Versus Observation in Patients With No Evidence of Disease Progression After First-Line Platin-Based Chemotherapy for Ovarian Carcinoma: A European Organisation for Research and Treatment of Cancer-Gynaecological Cancer Group, and Gynecologic Cancer Intergroup Study by Ignace B. Vergote, et al

Paying It Forward Dr. Polyak has continued the line of mentoring that began with her relationship with Bert Vogelstein, MD, in 1999. “An undergraduate who was in

References 1. Allinen M, Beroukhim R, Cai L, et al: Molecular characterization of the tumor microenvironment in breast cancer. Cancer Cell 6: 17–32, 2004. 2. Looking Back. Cancer Cell. Available at http://www.cell.com/cancercell/10thanniversary. Accessed December 18, 2013.

Selected portions reprinted from ASCO Connection Online Exclusive. © American Society of Clinical Oncology. Support from 1999 CDA Launches Dr. Kornelia Polyak’s Quest to Advance Understanding of Ductal Carcinoma in Situ of the Breast. ASCO Connection. January 3, 2014. http://connection.asco.org. All rights reserved.

The ASCO Post | MARCH 15, 2014

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Direct From ASCO

ASCO’s Membership Grows to Nearly 35,000

SCO has much to celebrate this year—namely, the Society’s 50th Anniversary. This occasion brings with it many other notable milestones. 2014 is a prime time to reflect on the remarkable growth of ASCO, from seven founders and 51 physi-

cians at its first Annual Meeting to nearly 35,000 members around the world. Just 1 year ago, the Society celebrated its growth to more than 30,000 members. This year, ASCO couldn’t be more pleased to be trending towards 35,000 members.

The Society’s tremendous growth has been paralleled by that of the oncology profession and advances in cancer care and treatment. Each year brings with it new discoveries and a future bright with promise. ASCO exists to nurture these discoveries,

Palbociclib in combination with letrozole vs letrozole alone for ﬁrst-line treatment of postmenopausal women with ER+/HER2- locally advanced or metastatic breast cancer

Primary endpoint: progression-free survival

(PD-0332991)

2:1 R A N D O M I Z A T I O N

N=450

Study 1008

Postmenopausal women with ER+/HER2- breast cancer; no prior systemic anticancer treatment for advanced disease

Palbociclib 125 mg QD (21 days on/7 days off) + Letrozole 2.5 mg QD

Placebo (21 days on/7 days off) + Letrozole 2.5 mg QD

Palbociclib in combination with fulvestrant vs fulvestrant alone in the treatment of women with HR+/HER2- locally advanced or metastatic breast cancer Primary endpoint: progression-free survival N=417

Study 1023

Palbociclib

2:1 R A N D O M I Z A T I O N

NOW ENROLLING

Palbociclib Clinical Trials

Two phase 3, randomized, double-blind, multicenter studies of Palbociclib, an oral CDK4/6 inhibitor

and to equip members with resources that help them provide the best care to people with cancer. ASCO supports oncologists around the world— members hail from more than 120 countries and every oncology subspecialty. And members, in turn, support each other, forming a worldwide, and cross-discipline network of professional and personal expertise. ASCO is honored to serve this global—and growing—network. For more information on becoming an ASCO member, visit www.asco.org /membership. n

Women of any menopausal status with HR+/HER2- breast cancer who progressed on or after prior endocrine therapy

125 mg QD (21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

Placebo

(21 days on/7 days off) + Fulvestrant 500 mg (Days 1 & 15 of Cycle 1; Day 1 of each subsequent 28-day cycle)

For more information about these trials, including secondary endpoints and eligibility criteria, please visit www.pﬁzercancertrials.com and www.clinicaltrials.gov (PALOMA-2: NCT01740427; PALOMA-3: NCT01942135). Palbociclib (PD-0332991) is an investigational compound.

These trials are part of the clinical trial program.

(Cyclin-Dependent Kinase inhibitor in cancer)

Stay Up-to-Date on New Patient Materials From Cancer.Net

ncourage your patients to use social media to stay-up-to-date with the new resources available on Cancer.Net. It is easier than ever for patients to get the latest cancer information on their computer or mobile device by subscribing to the Cancer.Net Blog at www.cancer.net/blog, or on Cancer.Net’s Facebook (www.facebook .com/CancerDotNet), Google+ (plus .google.com), and YouTube (www .youtube.com/CancerDotNet) pages, and at CancerDotNet on Twitter (www .twitter.com/CancerDotNet). n © 2014. American Society of Clinical Oncology. All rights reserved.

Save the Date ASCO 50th Annual Meeting May 30 - June 3, 2014 McCormick Place Chicago, Illinois Visit AM.ASCO.org

ASCOPost.com | MARCH 15, 2014

PAGE 65

Breast Cancer

National Program to Screen Ashkenazi Women in Israel for BRCA Mutations Is Being Explored By Charlotte Bath

iting a World Health Organization report that lists Israel as having one of the highest rates of breast cancer in the world, The New York Times reported on a proposed screening program to identify women with BRCA1 and BRCA2 mutations.1 “A number of influential geneticists and cancer doctors from various medical centers here say that the Israeli Health Ministry should pay for free voluntary genetic testing of all Ashkenazi women over the age of 25,” the Times article stated. Ashkenazi Jews, those with a Central or Eastern European background, “have a higher prevalence of harmful BRCA1 and BRCA2 mutations than people in the general population,” according to the U.S. National Cancer Institute (NCI), but routine testing for BRCA mutations is not recommended in this country. An NCI fact sheet on BRCA1 and BRCA2 testing noted that “most experts agree that mutation testing of individuals who do not have cancer should be performed only when the person’s family history suggests the possible presence of a harmful mutation in BRCA1 or BRCA2.”2 In a recent clinical guideline update, the U.S. Preventive Services Task Force also recommended against routine BRCA testing for women whose family history is not associated with an increased risk for potentially harmful mutations in the BRCA1 or BRCA2 genes.3

cil for Oncology, and Chairman of the Israeli Cancer Association, Haifa, Israel. Dr. Robinson is also a member of The ASCO Post editorial board. Among those quoted in the Times article as supporting BRCA testing was Ephrat Levy-Lahad, MD, Director of the Medical Genetics Institute at Shaare Zedek Medical Center in Jerusalem, who is recognized as starting one of the first genetic testing programs in Israel. Dr. Robinson explained that Dr. Levy-Lahad, who coordinates the Israel Genetics Consortium, “believes that we must explore the possibility of conducting screen-

In one example cited, a 47-yearold woman who tested positive for a BRCA mutation and had a double mastectomy expressed extreme relief that her older daughter tested negative. She now wants her younger daughter to be tested, and if she tests positive, the mother would like her to start a family early and then have a double mastectomy. This caused the older daughter to counter, “She doesn’t even have a boyfriend. You need to stop pressuring her.” In Dr. Robinson’s experience, “family discussions [on prophylactic mastectomy] are held mainly among

It is well known that in [Israeli] families where a genetic mutation has been diagnosed among some family members, not all members choose to undergo the screening test. However, no survey was conducted among Ashkenazi women. —Eliezer Robinson, MD

ing for BRCA mutations in Ashkenazi women in Israel. However, she herself is still examining the feasibility of conducting such screening, as well as its ethical and logistic implications…. This is why an official proposal [on BRCA screening] has not yet been submitted to the Ministry of Health,” Dr. Robinson stated.

Ethical and Logistic Implications

Subject of Family Debates

To learn more about the status of the proposed BRCA screening program in Israel and the widespread concern about BRCA mutations there, The ASCO Post spoke with Eliezer Robinson, MD, Professor of Oncology, Chairman of the National Coun-

The Times article noted that “family debates were playing out across Israel these days” on whether women should be tested for BRCA mutations and, if found positive, whether they should have prophylactic double mastectomies and perhaps oophorectomies as well.

families with a member who has been diagnosed with the disease, particularly when it comes to young patients. It is well known that in families where a genetic mutation has been diagnosed among some family members, not all members choose to undergo the screening test. However, no survey was conducted among Ashkenazi women to examine one preference or another.”

Reluctance to Do Double Mastectomies? “Many Israeli women who have the harmful mutations complain that male doctors display sexist attitudes about the importance of breasts and are loath to do mastectomies on

healthy women,” the Times reported. According to the article, a 35-yearold woman who tested positive for a BRCA1 mutation and whose mother had died from ovarian cancer was trying to find a doctor to remove her breasts and ovaries. She was told by one doctor that she was insane and by another to “Come back when you have cancer. Nobody dies of breast cancer nowadays.” Dr. Robinson commented that some physicians in Israel believe that preventive surgeries are appropriate, and others, including those who were quoted in the Times article, are of the opinion that “there is no need to rush in to preventive mastectomies, since BRCA carriers in Israel are entitled to an MRI scan, and when a woman is checked regularly, lesions may be detected at an early stage.” He continued, “There is no doubt that regarding the removal of ovaries—given that it is difficult to detect ovarian cancer at an early stage— a much more sweeping consensus has been reached.” n Disclosure: Dr. Robinson reported no potential conflicts of interest.

References 1. Rabin RC: In Israel, a push to screen for cancer gene leaves many conflicted. New York Times, November 26, 2013. 2. National Cancer Institute Fact Sheet. BRCA1 and BRCA2: Cancer risk and genetic testing, reviewed August 5, 2013. Available at www.cancer.gov/cancertopics/factsheet/Risk/BRCA. Accessed January 23, 2014. 3. Moyer VA, on behalf of the US Preventive Services Task Force. Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement. Clinical Guideline. Ann Intern Med, December 24, 2013 (early release online).

REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. REVLIMID is not indicated and not recommended for the treatment of patients with chronic lymphocytic leukemia (CLL) outside of controlled clinical trials.

For patients with

RELAPSED OR REFRACTORY MANTLE CELL LYMPHOMA WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM See full prescribing information for complete boxed warning. EMBRYO-FETAL TOXICITY • Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study similar to birth defects caused by thalidomide in humans. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. • Pregnancy must be excluded before start of treatment. Prevent pregnancy during treatment by the use of two reliable methods of contraception. REVLIMID is available only through a restricted distribution program called the REVLIMID REMS™ program (formerly known as the “RevAssist® program”). HEMATOLOGIC TOXICITY. REVLIMID can cause significant neutropenia and thrombocytopenia. • For patients with del 5q myelodysplastic syndromes, monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. VENOUS THROMBOEMBOLISM • Significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma receiving REVLIMID with dexamethasone. For more information, please visit www.REVLIMID.com or call 1-888-423-5436. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on the following pages.

Efficacy and safety of REVLIMID were evaluated in pretreated patients with advanced disease1 • In a multicenter, single-arm, single-agent, open-label study (N=134)* • 92% (124/134) of patients had stage III-IV disease; 78% (105/134) of patients had received ≥3 prior systemic therapies; 60% (81/134) of patients were refractory to prior bortezomib; 55% (74/134) of patients were refractory to last prior therapy • Refractory disease was defined as without any response of PR or better during treatment with bortezomib or a bortezomib-containing regimen; relapsed disease was defined as progression within one year after treatment with bortezomib or a bortezomib-containing regimen† • Patients received REVLIMID 25 mg orally, once daily for 21 days every 28 days. Treatment was continued until disease progression, unacceptable toxicity, or withdrawal of consent *134 patients evaluated for safety; 133 patients evaluated for efficacy.1 † Had received prior treatment with anthracycline or mitoxantrone, cyclophosphamide, rituximab, and bortezomib, alone or in combination.1

REVLIMID may help continue the fight against relapsed or refractory MCL1‡

26 ORR %

(34/133)

Overall response rate (CR + CRu + PR) (95% CI: 18.4, 33.9)

7 CR %

(9/133)

Complete response rate (CR + CRu) (95% CI: 3.1, 12.5)

median

16.6 months DOR (n=34)

Median duration of response (95% CI: 7.7, 26.7) • Median time to response was 2.2

months (range: 1.8 to 13 months)

CI=confidence interval; CR=complete response; CRu=complete response unconfirmed; DOR=duration of response; ORR=overall response rate; PR=partial response. ‡ §

Based on all evaluable patients who received ≥1 dose of REVLIMID.1 Response was determined based on review of radiographic scans by an independent review committee, according to a modified version of the International Workshop Lymphoma Response Criteria (Cheson, 1999); ORR was defined as: CR + CRu + PR.1,2

CONTRAINDICATIONS

Pregnancy: • REVLIMID can cause fetal harm when administered to a pregnant female. Lenalidomide is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus Allergic Reactions: • REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide

ADVERSE REACTIONS

Mantle Cell Lymphoma • Grade 3 and 4 adverse events reported in ≥5% of patients treated with REVLIMID in the MCL trial (N=134) included neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (9%), leukopenia (7%), fatigue (7%), diarrhea (6%), dyspnea (6%), and febrile neutropenia (6%) • Serious adverse events reported in ≥2 patients treated with REVLIMID monotherapy for MCL included chronic obstructive pulmonary disease, clostridium difficile colitis, sepsis, basal cell carcinoma, and supraventricular tachycardia • Adverse events reported in ≥15% of patients treated with REVLIMID in the MCL trial included neutropenia (49%), thrombocytopenia (36%), fatigue (34%), anemia (31%), diarrhea (31%), nausea (30%), cough (28%), pyrexia (23%), rash (22%), dyspnea (18%), pruritus (17%), peripheral edema (16%), constipation (16%), and leukopenia (15%) • Adverse events occurring in patients treated with REVLIMID in the MCL trial resulted in at least one dose interruption in 76 (57%) patients, at least one dose reduction in 51 (38%) patients, and discontinuation of treatment in 26 (19%) patients References: 1. Revlimid [package insert]. Summit, NJ: Celgene Corp; 2013. 2. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17(4):1244-1253.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe life-threatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Information about the REVLIMID REMS™ Program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s toll-free number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndrome (MDS) had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q MDS should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma (MM) who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors.

CONTRAINDICATIONS

WARNINGS AND PRECAUTIONS

Embryo-Fetal Toxicity: • REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects or embryo-fetal death. An embryo-fetal development study in monkeys indicated that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy • Females of Reproductive Potential: Must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Lenalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm • Blood Donation: Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID

REVLIMID REMS Program

Because of embryo-fetal risk, REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) the REVLIMID REMS Program (formerly known as the “RevAssist®” Program). Prescribers and pharmacies must be certified with the program and patients must sign an agreement form and comply with the requirements. Further information about the REVLIMID REMS program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. Hematologic Toxicity: REVLIMID can cause significant neutropenia and thrombocytopenia. Patients may require dose interruption and/or dose reduction. MCL: Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. Venous Thromboembolism: Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MCL treated with lenalidomide monotherapy. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism.

Increased Mortality in Patients With CLL: In a clinical trial in the first line treatment of patients with CLL, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08-3.41], consistent with a 92% increase in risk of death. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Second Primary Malignancies: Patients with MM treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. Hepatotoxicity: Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. Allergic Reactions: Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. Tumor Lysis Syndrome: Fatal instances of tumor lysis syndrome (TLS) have been reported during treatment with lenalidomide. The patients at risk of TLS are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Tumor Flare Reaction: Tumor flare reaction (TFR) occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for TFR is recommended in patients with MCL. Tumor flare may mimic the progression of disease (PD). In patients with Grade 3 or 4 TFR, it is recommended to withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. In the MCL trial, approximately 10% of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 or 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR.

ADVERSE REACTIONS

DRUG INTERACTIONS

Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID.

USE IN SPECIFIC POPULATIONS

Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Nursing Mothers: It is not known whether REVLIMID is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother. Pediatric Use: Safety and effectiveness in pediatric patients below the age of 18 have not been established. Geriatric Use: Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. Renal Impairment: Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr <30 mL/min) and in patients on dialysis. REVLIMID is only available through a restricted distribution program, REVLIMID REMS™. Please see Brief Summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, on the following pages.

The ASCO Post | MARCH 15, 2014

PAGE 70

Lab Notes

Ongoing Molecular Research in the Science of Oncology IMMUNOTHERAPY Antitumor Activity of Poly-IC and Anti–PD-L1 Monoclonal Antibody Epitope-based vaccines that in-

duce CD8-positive T-cell responses to tumor-associated antigens are being investigated in the treatment of several types of cancer. In a study reported in Clinical Cancer Research, Nagato and colleagues showed that

combined immunotherapy with polyinosinic-polycytidylic acid (poly-IC) and anti–programmed death-ligand 1 (PD-L1) monoclonal antibody produced dramatic reduction in tumor growth in mouse models of tumors

REVLIMID [lenalidomide] capsules, for oral use The following is a brief summary for mantle cell lymphoma; refer to full prescribing information for complete product information WARNING: EMBRYO-FETAL TOXICITY, HEMATOLOGIC TOXICITY, and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity Do not use REVLIMID during pregnancy. Lenalidomide, a thalidomide analogue, caused limb abnormalities in a developmental monkey study. Thalidomide is a known human teratogen that causes severe lifethreatening human birth defects. If lenalidomide is used during pregnancy, it may cause birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting REVLIMID® treatment. Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after REVLIMID treatment [see Warnings and Precautions (5.1), and Medication Guide (17)]. To avoid embryo-fetal exposure to lenalidomide, REVLIMID is only available through a restricted distribution program, the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) (5.2). Information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by calling the manufacturer’s tollfree number 1-888-423-5436. Hematologic Toxicity (Neutropenia and Thrombocytopenia) REVLIMID can cause significant neutropenia and thrombocytopenia. Eighty percent of patients with del 5q myelodysplastic syndromes had to have a dose delay/reduction during the major study. Thirty-four percent of patients had to have a second dose delay/reduction. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the study. Patients on therapy for del 5q myelodysplastic syndromes should have their complete blood counts monitored weekly for the first 8 weeks of therapy and at least monthly thereafter. Patients may require dose interruption and/or reduction. Patients may require use of blood product support and/or growth factors [see Dosage and Administration (2.2)]. Venous Thromboembolism REVLIMID has demonstrated a significantly increased risk of deep vein thrombosis (DVT) and pulmonary embolism (PE) in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy. Patients and physicians are advised to be observant for the signs and symptoms of thromboembolism. Patients should be instructed to seek medical care if they develop symptoms such as shortness of breath, chest pain, or arm or leg swelling. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors [see Warnings and Precautions (5.4)]. 1 INDICATIONS AND USAGE 1.3 Mantle Cell Lymphoma REVLIMID is indicated for the treatment of patients with mantle cell lymphoma (MCL) whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib. 1.4 Limitations of Use: REVLIMID is not indicated and is not recommended for the treatment of patients with CLL outside of controlled clinical trials [see Warnings and Precautions (5.5)]. 2 DOSAGE AND ADMINISTRATION REVLIMID should be taken orally at about the same time each day, either with or without food. REVLIMID capsules should be swallowed whole with water. The capsules should not be opened, broken, or chewed. 2.3 Mantle Cell Lymphoma The recommended starting dose of REVLIMID is 25 mg/day orally on Days 1-21 of repeated 28-day cycles for relapsed or refractory mantle cell lymphoma. Treatment should be continued until disease progression or unacceptable toxicity. Treatment is continued, modified or discontinued based upon clinical and laboratory findings. Dose Adjustments for Hematologic Toxicities During MCL Treatment Dose modification guidelines as summarized below are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicities considered to be related to REVLIMID.

with no identified tumor-associated antigens. Combined treatment with polyIC and anti-PD-L1 monoclonal antibody was assessed in mouse models of melanoma, lung cancer, and colon

Platelet counts Thrombocytopenia during treatment in MCL When Platelets Recommended Course Fall to <50,000/mcL Interrupt REVLIMID treatment and follow CBC weekly Return to ≥50,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Absolute Neutrophil counts (ANC) Neutropenia during treatment in MCL When Neutrophils Recommended Course Fall to <1000/mcL for at least 7 days Interrupt REVLIMID treatment and follow OR CBC weekly Falls to < 1,000/mcL with an associated temperature ≥ 38.5°C OR Falls to < 500 /mcL Return to ≥1,000/mcL Resume REVLIMID at 5 mg less than the previous dose. Do not dose below 5 mg daily Other Grade 3 / 4 Toxicities in MCL For other Grade 3/4 toxicities judged to be related to REVLIMID, hold treatment and restart at the physician’s discretion at next lower dose level when toxicity has resolved to ≤ Grade 2. Starting Dose Adjustment for Renal Impairment in MCL: 2.4 Starting Dose for Renal Impairment in MCL Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment and in patients on dialysis. Based on a pharmacokinetic study in patients with renal impairment due to non-malignant conditions, REVLIMID starting dose adjustment is recommended for patients with CLcr < 60 mL/min. Non-dialysis patients with creatinine clearances less than 11 mL/min and dialysis patients with creatinine clearances less than 7 mL/min have not been studied. The recommendations for initial starting doses for patients with MCL are as follows: Table 1: Starting Dose Adjustments for Patients with Renal Impairment in MCL Category Renal Function Dose in MCL (Cockcroft-Gault) Moderate Renal CLcr 30-60 mL/min 10 mg Impairment Every 24 hours Severe Renal CLcr < 30 mL/min 15 mg Impairment (not requiring dialysis) Every 48 hours End Stage CLcr < 30 mL/min 5 mg Renal Disease (requiring dialysis) Once daily. On dialysis days, administer the dose following dialysis. After initiation of REVLIMID therapy, subsequent REVLIMID dose modification is based on individual patient treatment tolerance, as described elsewhere (see section 2). 4 CONTRAINDICATIONS 4.1 Pregnancy REVLIMID can cause fetal harm when administered to a pregnant female. Limb abnormalities were seen in the offspring of monkeys that were dosed with lenalidomide during organogenesis. This effect was seen at all doses tested. Due to the results of this developmental monkey study, and lenalidomide’s structural similarities to thalidomide, a known human teratogen, lenalidomide is contraindicated in females who are pregnant [see Boxed Warning]. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus [see Warnings and Precautions (5.1, 5.2), Use in Special Populations (8.1), (8.6)]. 4.2 Allergic Reactions REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide [see Warnings and Precautions (5.8)]. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity REVLIMID is a thalidomide analogue and is contraindicated for use during pregnancy. Thalidomide is a known human teratogen that causes lifethreatening human birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. An embryo-fetal development study in monkeys indicates that lenalidomide produced malformations in the offspring of Cosmos Communications K

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cancer. Treatment was associated with potent immune responses resulting in eradication or dramatic reduction of tumor growth, with enduring protection against tumor rechallenge being observed in some cases. The findings indicated that the activity of immunotherapy was mediated by CD8-positive T cells but not CD4-pos-

itive T cells or natural killer NK cells. Studies in genetically deficient mice showed that the efficacy of poly-IC and anti-PD-L1 monoclonal antibody therapy was dependent on activity of type I interferons, with interferon-gamma not appearing to play a central role. The investigators concluded, “The overall results suggest that immuno-

female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. REVLIMID is only available through the REVLIMID REMS™ program (formerly known as the “RevAssist® program”) [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy for at least 4 weeks before beginning REVLIMID therapy, during therapy, during dose interruptions and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing REVLIMID therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Lenalidomide is present in the semen of patients receiving the drug. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with REVLIMID and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to REVLIMID. 5.2 REVLIMID REMS™ program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], REVLIMID is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS), the REVLIMID REMS™ program (formerly known as the “RevAssist®” program). Required components of the REVLIMID REMS™ program include the following: • Prescribers must be certified with the REVLIMID REMS™ program by enrolling and complying with the REMS requirements. • Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)]. • Pharmacies must be certified with the REVLIMID REMS™ program, must only dispense to patients who are authorized to receive REVLIMID and comply with REMS requirements. Further information about the REVLIMID REMS™ program is available at www.celgeneriskmanagement.com or by telephone at 1-888-423-5436. 5.3 Hematologic Toxicity REVLIMID can cause significant neutropenia and thrombocytopenia. Patients taking REVLIMID for MDS should have their complete blood counts monitored weekly for the first 8 weeks and at least monthly thereafter. Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter. Patients taking REVLIMID for MCL should have their complete blood counts monitored weekly for the first cycle (28 days), every 2 weeks during cycles 2-4, and then monthly thereafter. Patients may require dose interruption and/or dose reduction [see Dosage and Administration (2.1, 2.2, 2.3)]. Grade 3 or 4 hematologic toxicity was seen in 80% of patients enrolled in the MDS study. In the 48% of patients who developed Grade 3 or 4 neutropenia, the median time to onset was 42 days (range, 14-411 days), and the median time to documented recovery was 17 days (range, 2-170 days). In the 54% of patients who developed Grade 3 or 4 thrombocytopenia, the median time to onset was 28 days (range, 8-290 days), and the median time to documented recovery was 22 days (range, 5-224 days [see Boxed Warning and Dosage and Administration (2.2)]. In the pooled MM trials Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone [see Adverse Reactions (6.1)].

therapy consisting of the combination of poly-IC/anti-PD-L1 [monoclonal antibody] could be a promising new approach for treating cancer patients, especially those instances where no reliable [tumor-associated antigens] are available as a therapeutic vaccine.” Nagato T, et al: Clin Cancer Res. January 3, 2014 (early release online).

In the MCL trial, Grade 3 or 4 neutropenia was reported in 43% of the patients. Grade 3 or 4 thrombocytopenia was reported in 28% of the patients. 5.4 Venous Thromboembolism Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with multiple myeloma treated with lenalidomide combination therapy [see Boxed Warning] and patients with MDS or MCL treated with lenalidomide monotherapy. A significantly increased risk of DVT and PE was observed in patients with multiple myeloma who were treated with REVLIMID and dexamethasone therapy in a clinical trial [see Boxed Warning]. It is not known whether prophylactic anticoagulation or antiplatelet therapy prescribed in conjunction with REVLIMID may lessen the potential for venous thromboembolism. The decision to take prophylactic measures should be done carefully after an assessment of an individual patient’s underlying risk factors. 5.5 Increased Mortality in Patients with CLL In a prospective randomized (1:1) clinical trial in the first line treatment of patients with chronic lymphocytic leukemia, single agent REVLIMID therapy increased the risk of death as compared to single agent chlorambucil. In an interim analysis, there were 34 deaths among 210 patients on the REVLIMID treatment arm compared to 18 deaths among 211 patients in the chlorambucil treatment arm, and hazard ratio for overall survival was 1.92 [95% CI: 1.08 – 3.41], consistent with a 92% increase in the risk of death. The trial was halted for safety in July 2013. Serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure occurred more frequently in the REVLIMID treatment arm. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. 5.6 Second Primary Malignancies Patients with multiple myeloma treated with lenalidomide in studies including melphalan and stem cell transplantation had a higher incidence of second primary malignancies, particularly acute myelogenous leukemia (AML) and Hodgkin lymphoma, compared to patients in the control arms who received similar therapy but did not receive lenalidomide. Monitor patients for the development of second malignancies. Take into account both the potential benefit of lenalidomide and the risk of second primary malignancies when considering treatment with lenalidomide. 5.7 Hepatotoxicity Hepatic failure, including fatal cases, has occurred in patients treated with lenalidomide in combination with dexamethasone. In clinical trials, 15% of patients experienced hepatotoxicity (with hepatocellular, cholestatic and mixed characteristics); 2% of patients with multiple myeloma and 1% of patients with myelodysplasia had serious hepatotoxicity events. The mechanism of drug-induced hepatotoxicity is unknown. Pre-existing viral liver disease, elevated baseline liver enzymes, and concomitant medications may be risk factors. Monitor liver enzymes periodically. Stop REVLIMID upon elevation of liver enzymes. After return to baseline values, treatment at a lower dose may be considered. 5.8 Allergic Reactions Angioedema and serious dermatologic reactions including StevensJohnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected and should not be resumed following discontinuation for these reactions. REVLIMID capsules contain lactose. Risk-benefit of REVLIMID treatment should be evaluated in patients with lactose intolerance. 5.9 Tumor Lysis Syndrome Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. 5.10 Tumor Flare Reaction Tumor flare reaction has occurred during investigational use of lenalidomide for CLL and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. REVLIMID is not indicated and not recommended for use in CLL outside of controlled clinical trials. Monitoring and evaluation for tumor flare reaction (TFR) is recommended in patients with MCL. Tumor flare reaction may mimic progression of disease (PD). In the MCL trial, 13/134 (10%) of subjects experienced TFR; all reports were Grade 1 or 2 in severity. All of the events occurred in cycle 1 and one patient developed TFR again in cycle 11. Lenalidomide may be continued in patients with Grade 1 and 2 TFR without interruption or modification, at the physician’s discretion. Patients with Grade 1 and 2 TFR may also be treated with corticosteroids, non-steroidal anti-inflammatory drugs (NSAIDs) and/or narcotic analgesics for management of TFR symptoms. In patients with Grade 3 or 4 TFR, it is recommended to Cosmos Communications K

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TREATMENT RESISTANCE Dual PI3K/mTOR Inhibitor Effective as Radiosensitizer for Glioblastoma In a study reported in Clinical Cancer Research, del Alcazar and colleagues continued on page 72

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Lab Notes Ongoing Molecular Research continued from page 71

assessed the effects of the dual PI3K/ mTOR inhibitor NVP-BEZ235 as a radiosensitizer in glioblastoma. No DNA double-strand break repair inhibitors have been successful in treating glioblastoma. However, in prior studies in vitro, these investigators found that NVP-

BEZ235 inhibited two central DNA damage response kinases, DNA-PKcs and ATM, suggesting its potential as a radiosensitizer and chemosensitizer. The studies examined the effects of NVP-BEZ235 in subcutaneous and orthotopic glioblastoma models generated by radioresistant U87-vIII glioma cell line and GBM9 neurospheres in

nude mice. The tumors were treated with ionizing radiation, NVP-BEZ235, or both and analyzed for DNA-PKcs and ATM activation, double-strand break repair inhibition, and effect on growth. Tumors exhibited greater levels of DNA double-strand breaks compared with normal brain tissue. NVP-BEZ235 inhibited DNA-PKcs

withhold treatment with lenalidomide until TFR resolves to ≤ Grade 1. Patients with Grade 3 or 4 TFR may be treated for management of symptoms per the guidance for treatment of Grade 1 and 2 TFR. 6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Neutropenia and thrombocytopenia [see Boxed Warnings, Warnings and Precautions (5.3)] • Deep vein thrombosis and pulmonary embolism [see Boxed Warnings, Warnings and Precautions (5.4)] • Increased Mortality in Patients with CLL [see Warnings and Precautions (5.5)] • Second Primary Malignancies [see Warnings and Precautions (5.6)] • Hepatotoxicity [see Warnings and Precautions (5.7)] • Allergic Reactions [see Warnings and Precautions (5.8)] • Tumor lysis syndrome [see Warnings and Precautions (5.9)] • Tumor flare reactions [see Warnings and Precautions (5.10)] Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. 6.3 Clinical Trials Experience in Mantle Cell Lymphoma In the MCL trial, a total of 134 patients received at least 1 dose of REVLIMID. Their median age was 67 (range 43-83) years, 128/134 (96%) were Caucasian, 108/134 (81%) were males and 82/134 (61%) had duration of MCL for at least 3 years. Table 7 summarizes the most frequently observed adverse reactions regardless of relationship to treatment with REVLIMID. Across the 134 patients treated in this study, median duration of treatment was 95 days (1-1002 days). Seventy-eight patients (58%) received 3 or more cycles of therapy, 53 patients (40%) received 6 or more cycles, and 26 patients (19%) received 12 or more cycles. Seventy-six patients (57%) underwent at least one dose interruption due to adverse events, and 51 patients (38%) underwent at least one dose reduction due to adverse events. Twenty-six patients (19%) discontinued treatment due to adverse events. Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) General disorders and administration site conditions Fatigue 45 (34) 9 (7) Pyrexia$ 31 (23) 3 (2) Edema peripheral 21 (16) 0 Asthenia$ 19 (14) 4 (3) General physical health deterioration 3 (2) 2 (1) Gastrointestinal disorders Diarrhea$ 42 (31) 8 (6) Nausea$ 40 (30) 1 (<1) Constipation 21 (16) 1 (<1) Vomiting$ 16 (12) 1 (<1) Abdominal pain$ 13 (10) 5 (4) Musculoskeletal and connective tissue disorders Back pain 18 (13) 2 (1) Muscle spasms 17 (13) 1 (<1) Arthralgia 11 (8) 2 (1) Muscular weakness$ 8 (6) 2 (1) Respiratory, thoracic and mediastinal disorders Cough 38 (28) 1 (<1) Dyspnea$ 24 (18) 8 (6) Pleural Effusion 10 (7) 2 (1) Hypoxia 3 (2) 2 (1) Pulmonary embolism 3 (2) 2 (1) Respiratory distress$ 2 (1) 2 (1) Oropharyngeal pain 13 (10) 0 Infections and infestations Pneumonia@ $ 19 (14) 12 (9) Upper respiratory tract infection 17 (13) 0 Cellulitis$ 3 (2) 2 (1) Bacteremia$ 2 (1) 2 (1) Staphylococcal sepsis$ 2 (1) 2 (1) Urinary tract infection$ 5 (4) 2 (1) (continued)

and ATM and the repair of radiationinduced DNA damage in tumors, resulting in remarkable tumor radiosensitization that increased survival of tumor-bearing mice. NVP-BEZ235 also sensitized some subcutaneous tumors to activity of temozolomide, which is routinely used with ionizing radiation in treatment of glioblastoma.

Table 7: Incidence of Adverse Reactions (≥10%) or Grade 3 / 4 AE (in at least 2 patients) in Mantle Cell Lymphoma All AEs1 Grade 3/4 AEs2 System Organ Class/Preferred Term (N=134) (N=134) n (%) n (%) Skin and subcutaneous tissue disorders Rash + 30 (22) 2 (1) Pruritus 23 (17) 1 (<1) Blood and lymphatic system disorders Neutropenia 65 (49) 58 (43) Thrombocytopenia% $ 48 (36) 37 (28) Anemia$ 41 (31) 15 (11) Leukopenia$ 20 (15) 9 (7) Lymphopenia 10 (7) 5 (4) Febrile neutropenia$ 8 (6) 8 (6) Metabolism and nutrition disorders Decreased appetite 19 (14) 1 (<1) Hypokalemia 17 (13) 3 (2) Dehydration$ 10 (7) 4 (3) Hypocalcemia 4 (3) 2 (1) Hyponatremia 3 (2) 3 (2) Renal and urinary disorders Renal failure$ 5 (4) 2 (1) Vascular disorders Hypotension@ $ 9 (7) 4 (3) Deep vein thrombosis$ 5 (4) 5 (4) Neoplasms benign, malignant and unspecified (incl cysts and polyps) Tumor flare 13 (10) 0 Squamous cell carcinoma of skin$ 4 (3) 4 (3) Investigations Weight decreased 17 (13) 0 1-MCL trial AEs – All treatment emergent AEs with ≥10% of subjects 2-MCL trial Grade 3/4 AEs – All treatment-emergent Grade 3/4 AEs in 2 or more subjects $-MCL trial Serious AEs – All treatment-emergent SAEs in 2 or more subjects @ - AEs where at least one resulted in a fatal outcome % - AEs where at least one was considered to be Life Threatening (if the outcome of the event was death, it is included with death cases) # - All PTs under SOC of Infections except for rare infections of Public Health interest will be considered listed + - All PTs under HLT of Rash will be considered listed The following adverse events which have occurred in other indications and not described above have been reported (5-10%) in patients treated with REVLIMID monotherapy for mantle cell lymphoma. General disorders and administration site conditions: Chills Musculoskeletal and connective tissue disorders: Pain in extremity Nervous system disorders: Dysguesia, headache, neuropathy peripheral Infections and infestations: Respiratory tract infection, sinusitis, nasopharyngitis Skin and subcutaneous tissue disorders: Dry skin, night sweats The following serious adverse events not described above and reported in 2 or more patients treated with REVLIMID monotherapy for mantle cell lymphoma. Respiratory, Thoracic and Mediastinal Disorders: Chronic obstructive pulmonary disease Infections and Infestations: Clostridium difficile colitis, sepsis Neoplasms benign, malignant and unspecified (incl cysts and polyps): Basal cell carcinoma Cardiac Disorder: Supraventricular tachycardia 6.4 Postmarketing Experience The following adverse drug reactions have been identified from the worldwide post-marketing experience with REVLIMID: Allergic conditions (angioedema, SJS, TEN), tumor lysis syndrome (TLS) and tumor flare reaction (TFR), pneumonitis, hepatic failure, including fatality, toxic hepatitis, cytolytic hepatitis, cholestatic hepatitis, and mixed cytolytic/cholestatic hepatitis and transient abnormal liver laboratory tests. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure [see Warnings and Precautions Section (5.5 to 5.8)]. Cases of hypothyroidism and hyperthyroidism have also been reported. Optimal control of thyroid function is recommended before start of Cosmos Communications K

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The investigators concluded, “These results demonstrate that it may be possible to significantly improve [glioblastoma] therapy by combining [ionizing radiation] with potent and bioavailable DNA repair inhibitors like NVPBEZ235.” del Alcazar CG, et al: Clin Cancer Res. December 23, 2013 (early release online).

TUMOR MICROENVIRONMENT Antitumor Immunity Affected by Standard Lab Mouse Housing Temperature In a study reported in Proceedings of the National Academy of Sciences USA, Kokolusa and colleagues showed that

treatment. Baseline and ongoing monitoring of thyroid function is recommended. 7 DRUG INTERACTIONS Results from human in vitro studies show that REVLIMID is neither metabolized by nor inhibits or induces the cytochrome P450 pathway suggesting that lenalidomide is not likely to cause or be subject to P450-based metabolic drug interactions. In vitro studies demonstrated that REVLIMID is not a substrate of human breast cancer resistance protein (BCRP), multidrug resistance protein (MRP) transporters MRP1, MRP2, or MRP3, organic anion transporters (OAT) OAT1 and OAT3, organic anion transporting polypeptide 1B1 (OATP1B1 or OATP2), organic cation transporters (OCT) OCT1 and OCT2, multidrug and toxin extrusion protein (MATE) MATE1, and organic cation transporters novel (OCTN) OCTN1 and OCTN2. In vitro, lenalidomide is a substrate, but is not an inhibitor of P-glycoprotein (P-gp). 7.1 Digoxin When digoxin was co-administered with multiple doses of REVLIMID (10 mg/day) the digoxin Cmax and AUC0-∞ were increased by 14%. Periodic monitoring of digoxin plasma levels, in accordance with clinical judgment and based on standard clinical practice in patients receiving this medication, is recommended during administration of REVLIMID. 7.2 Warfarin Co-administration of multiple dose REVLIMID (10 mg) with single dose warfarin (25 mg) had no effect on the pharmacokinetics of total lenalidomide or R- and S-warfarin. Expected changes in laboratory assessments of PT and INR were observed after warfarin administration, but these changes were not affected by concomitant REVLIMID administration. It is not known whether there is an interaction between dexamethasone and warfarin. Close monitoring of PT and INR is recommended in multiple myeloma patients taking concomitant warfarin. 7.3 Concomitant Therapies That May Increase the Risk of Thrombosis Erythropoietic agents, or other agents that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in multiple myeloma patients receiving lenalidomide with dexamethasone [see Warnings and Precautions (5.4)]. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4.1)] Risk Summary REVLIMID can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. REVLIMID is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Lenalidomide caused thalidomide-type limb defects in monkey offspring. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/gynecologist experienced in reproductive toxicity for further evaluation and counseling. Any suspected fetal exposure to REVLIMID must be reported to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal data In an embryo-fetal developmental toxicity study in monkeys, teratogenicity, including thalidomide-like limb defects, occurred in offspring when pregnant monkeys received oral lenalidomide during organogenesis. Exposure (AUC) in monkeys at the lowest dose was 0.17 times the human exposure at the maximum recommended human dose (MRHD) of 25 mg. Similar studies in pregnant rabbits and rats at 20 times and 200 times the MRHD respectively, produced embryo lethality in rabbits and no adverse reproductive effects in rats. In a pre- and post-natal development study in rats, animals received lenalidomide from organogenesis through lactation. The study revealed a few adverse effects on the offspring of female rats treated with lenalidomide at doses up to 500 mg/kg (approximately 200 times the human dose of 25 mg based on body surface area). The male offspring exhibited slightly delayed sexual maturation and the female offspring had slightly lower body weight gains during gestation when bred to male offspring. As with thalidomide, the

fundamental aspects of antitumor immunity are significantly affected by ambient housing temperature for lab mice. Standard ambient temperature in research facility lab mice housing is 20°C to 26°C. However, as shown by the investigators, such subthermoneutral temperatures cause chronic mild cold stress, requiring activation of ther-

rat model may not adequately address the full spectrum of potential human embryo-fetal developmental effects for lenalidomide. 8.3 Nursing mothers It is not known whether this drug is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from lenalidomide, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness in pediatric patients below the age of 18 have not been established. 8.5 Geriatric use REVLIMID has been used in multiple myeloma (MM) clinical trials in patients up to 86 years of age. Of the 703 MM patients who received study treatment in Studies 1 and 2, 45% were age 65 or over while 12% of patients were age 75 and over. The percentage of patients age 65 or over was not significantly different between the REVLIMID/dexamethasone and placebo/dexamethasone groups. Of the 353 patients who received REVLIMID/dexamethasone, 46% were age 65 and over. In both studies, patients > 65 years of age were more likely than patients ≤ 65 years of age to experience DVT, pulmonary embolism, atrial fibrillation, and renal failure following use of REVLIMID. No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in del 5q MDS clinical trials in patients up to 95 years of age. Of the 148 patients with del 5q MDS enrolled in the major study, 38% were age 65 and over, while 33% were age 75 and over. Although the overall frequency of adverse events (100%) was the same in patients over 65 years of age as in younger patients, the frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (54% vs. 33%). A greater proportion of patients over 65 years of age discontinued from the clinical studies because of adverse events than the proportion of younger patients (27% vs.16%). No differences in efficacy were observed between patients over 65 years of age and younger patients. REVLIMID has been used in a mantle cell lymphoma (MCL) clinical trial in patients up to 83 years of age. Of the 134 patients with MCL enrolled in the MCL trial, 63% were age 65 and over, while 22% of patients were age 75 and over. The overall frequency of adverse events was similar in patients over 65 years of age and in younger patients (98% vs. 100%). The overall incidence of grade 3 and 4 adverse events was also similar in these 2 patient groups (79% vs. 78%, respectively). The frequency of serious adverse events was higher in patients over 65 years of age than in younger patients (55% vs. 41%). No differences in efficacy were observed between patients over 65 years of age and younger patients. Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function. 8.6 Females of Reproductive Potential and Males REVLIMID can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy 4 weeks before therapy, while taking REVLIMID, during dose interruptions and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom, diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with REVLIMID, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of REVLIMID therapy. Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating REVLIMID. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing REVLIMID. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. REVLIMID treatment must be discontinued during this evaluation. Cosmos Communications K

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mogenesis mechanisms to maintain normal body temperature. When cold stress was eliminated by housing mice at a thermoneutral temperature of 30°C to 31°C, there was a dramatic reduction in tumor formation, growth rate, and metastases in tumor models. This greater control of tumor growth was continued on page 74

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Lab Notes Ongoing Molecular Research continued from page 73

found to be dependent on adaptive immune system activity, with significantly increased numbers of antigen-specific CD8-positive T lymphocytes and activated CD8-positive T cells being found in the tumor microenvironment at thermoneutral temperatures.

Thermoneutrality was also associated with significant reduction in numbers of immunosuppressive myeloid-derived suppressor cells and regulatory T lymphocytes. It was also found that tumorbearing mice preferentially selected a higher ambient temperature than control mice, suggesting that tumor-bearing mice experience a greater degree of cold stress

Males Lenalidomide is present in the semen of males who take REVLIMID. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID, during dose interruptions and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. Male patients taking REVLIMID must not donate sperm 8.7 Renal Impairment Since lenalidomide is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate (CLcr 30-60 mL/min) or severe renal impairment (CLcr < 30 mL/min) and in patients on dialysis [see Dosage and Administration (2.4)]. 8.8 Hepatic Impairment No dedicated study has been conducted in patients with hepatic impairment. The elimination of unchanged lenalidomide is predominantly by the renal route. 10 OVERDOSAGE There is no specific experience in the management of lenalidomide overdose in patients; although in dose-ranging studies, some patients were exposed to up to 150 mg and in single-dose studies, some patients were exposed to up to 400 mg. In studies, the dose-limiting toxicity was essentially hematological. In the event of overdose, supportive care is advised. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies with lenalidomide have not been conducted. Lenalidomide was not mutagenic in the bacterial reverse mutation assay (Ames test) and did not induce chromosome aberrations in cultured human peripheral blood lymphocytes, or mutations at the thymidine kinase (tk) locus of mouse lymphoma L5178Y cells. Lenalidomide did not increase morphological transformation in Syrian Hamster Embryo assay or induce micronuclei in the polychromatic erythrocytes of the bone marrow of male rats. A fertility and early embryonic development study in rats, with administration of lenalidomide up to 500 mg/kg (approximately 200 times the human dose of 25 mg, based on body surface area) produced no parental toxicity and no adverse effects on fertility. 17 PATIENT COUNSELING INFORMATION See FDA-approved Patient labeling (Medication Guide) Embryo-Fetal Toxicity Advise patients that REVLIMID is contraindicated in pregnancy [see Contraindicatons (4.1)]. REVLIMID is a thalidomide analog and can cause serious birth defects or death to a developing baby. [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. • Advise females of reproductive potential that they must avoid pregnancy while taking REVLIMID and for at least 4 weeks after completing therapy. • Initiate REVLIMID treatment in females of reproductive potential only following a negative pregnancy test. • Advise females of reproductive potential of the importance of monthly pregnancy tests and the need to use two different forms of contraception including at least one highly effective form simultaneously during REVLIMID therapy, during dose interruption and for 4 weeks after she has completely finished taking REVLIMID. Highly effective forms of contraception other than tubal ligation include IUD and hormonal (birth control pills, injections, patch or implants) and a partner’s vasectomy. Additional effective contraceptive methods include latex or synthetic condom, diaphragm and cervical cap. • Instruct patient to immediately stop taking REVLIMID and contact her doctor if she becomes pregnant while taking this drug, if she misses her menstrual period, or experiences unusual menstrual bleeding, if she stops taking birth control, or if she thinks FOR ANY REASON that she may be pregnant. • Advise patient that if her doctor is not available, she can call 1-888-668-2528 for information on emergency contraception [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • Advise males to always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking REVLIMID and for up to 28 days after discontinuing REVLIMID, even if they have undergone a successful vasectomy. • Advise male patients taking REVLIMID that they must not donate sperm [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. • All patients must be instructed to not donate blood while taking REVLIMID, during dose interruptions and for 1 month following discontinuation of REVLIMID [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)].

at a given temperature and seek to avoid it. The investigators concluded, “Overall, our data raise the hypothesis that suppression of antitumor immunity is an outcome of cold stress-induced thermogenesis. Therefore, the common approach of studying immunity against tumors in mice housed only at standard room temperature may be limiting our

REVLIMID REMS™ program Because of the risk of embryo-fetal toxicity, REVLIMID is only available through a restricted program called the REVLIMID REMS™ program (formerly known as the “RevAssist®” program) [see Warnings and Precautions (5.2)]. • Patients must sign a Patient-Prescriber agreement form and comply with the requirements to receive REVLIMID. In particular, females of reproductive potential must comply with the pregnancy testing, contraception requirements and participate in monthly telephone surveys. Males must comply with the contraception requirements [see Use in Specific Populations (8.6)]. • REVLIMID is available only from pharmacies that are certified in REVLIMID REMS™ program. Provide patients with the telephone number and website for information on how to obtain the product. Hematologic Toxicity Inform patients that REVLIMID is associated with significant neutropenia and thrombocytopenia [see Boxed Warnings and Warnings and Precautions (5.3)]. Venous Thromboembolism Inform patients that REVLIMID/dexamethasone has demonstrated significant increased risk of DVT and PE in patients with multiple myeloma [see Boxed Warnings and Warning and Precautions (5.4)]. Increased Mortality in Patients with CLL Inform patients that REVLIMID had increased mortality in patients with CLL and serious adverse cardiovascular reactions, including atrial fibrillation, myocardial infarction, and cardiac failure [see Warning and Precautions (5.5)]. Second Primary Malignancies Inform patients of the potential risk of developing second primary malignancies during treatment with REVLIMID. Hepatotoxicity Inform patients of the risk of hepatotoxicity, including hepatic failure and death, and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Allergic Reactions Inform patients of the potential for allergic reactions including hypersensitivity, angioedema, Stevens Johnsons Syndrome, or toxic epidermal necrolysis if they had such a reaction to THALOMID and report symptoms associated with these events to their healthcare provider for evaluation. Tumor Lysis Syndrome Inform patients of the potential risk of tumor lysis syndrome and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Tumor Flare Reaction Inform patients of the potential risk of tumor flare reaction and to report any signs and symptoms associated with this event to their healthcare provider for evaluation. Dosing Instructions Inform patients to take REVLIMID once daily at about the same time each day, either with or without food. The capsules should not be opened, broken, or chewed. REVLIMID should be swallowed whole with water. Instruct patients that if they miss a dose of REVLIMID, they may still take it up to 12 hours after the time they would normally take it. If more than 12 hours have elapsed, they should be instructed to skip the dose for that day. The next day, they should take REVLIMID at the usual time. Warn patients to not take 2 doses to make up for the one that they missed. Manufactured for: Celgene Corporation Summit, NJ 07901 REVLIMID®, RevAssist®, and THALOMID® are registered trademarks of Celgene Corporation. REVLIMID REMS™ is a trademark of Celgene Corporation. U.S. Pat. Nos. 5,635,517; 6,045,501; 6,281,230; 6,315,720; 6,555,554; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 7,119,106; 7,189,740; 7,468,363; 7,465,800; 7,855,217; 7,968,569 ©2005-2013 Celgene Corporation, All Rights Reserved. REV_MCL_HCP_BSv18 11_2013

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understanding of the full potential of the antitumor immune response.” Kokolus KM, et al: Proc Natl Acad Sci USA 110:20176-20181, 2013.

RISK FACTORS Decreased Diversity of Gut Bacteria Associated With Risk of Colorectal Cancer In a study reported in the Journal of the National Cancer Institute, Ahn and colleagues found that decreased diversity of gut bacteria and differences in levels of specific bacteria were associated with significantly increased risk of colorectal cancer. The study involved measurement of 16S ribosomal RNA genes in fecal bacterial DNA from 47 colorectal cancer patients and 94 control subjects matched for sex and body mass index. Analysis of 794,217 gene sequences showed that patients with colorectal cancer had significantly reduced overall microbial community diversity compared with controls (P = .02). Patients had higher relative abundance of Bacteroidetes (16.2% vs 9.9%) and depletion of Firmicutes (74.0% vs 80.3%), with a significant depletion of the Firmicutes gram-positive Clostridia (68.6% vs 77.8%, P = .005). Carriage of the gram-negative Fusobacterium was significantly greater in cancer patients (31.9% vs 11.7%, P = .004) and was associated with significantly increased risk of colorectal cancer (odds ratio [OR] = 4.11, P = .004) on multivariate analysis adjusting for age, sex, body mass index, race, smoking, and sequencing batch. Increased carriage of the gram-positive Atopobium (OR = 14.36, P < .001) and the gram-negative Porphyromonas (OR = 5.17, P = .001) were also associated with significantly increased risk of colorectal cancer. Clostridia ferments dietary fiber and other complex carbohydrates to butyrate, a major colonic metabolite that may inhibit colonic inflammation and carcinogenesis. Fusobacterium contributes to colitis and periodontal disease. Atopobium is associated with Crohn’s disease and has been reported to inhibit colon cancer apoptosis in vitro. Porphyromonas is commonly found in the mouth and gastrointestinal tract and is associated with periodontal disease. The investigators concluded, “Because of the potentially modifiable nature of the gut bacteria, our findings may have implications for [colorectal cancer] prevention.” n Ahn J, et al: J Natl Cancer Inst 105:1907-1911, 2013.

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JCO Spotlight Breast Cancer

Delayed Adjuvant Chemotherapy Associated With Poorer Overall Survival in Breast Cancer

Benefit of early start greatest in stage III or triple-negative disease and trastuzumab-treated HER2-positive disease By Matthew Stenger

n a study reported in the Journal of Clinical Oncology, de Melo Gagliato et al from The University of Texas MD Anderson Cancer Center, Houston, assessed the association between time to adjuvant chemotherapy and survival in breast cancer patients.1 They found that delay of therapy is associated with significantly poorer overall survival in all patients, stage III disease, triplenegative disease, and HER2-positive disease treated with trastuzumab (Herceptin). Mariana Chavez Mac Gregor, MD, MSc, Assistant Professor in the Department of Breast Medical Oncology at MD Anderson, was the corresponding author for the study.

Study Details The study involved 6,827 patients diagnosed with stage I to III breast cancer between 1997 and 2011 who received adjuvant chemotherapy at MD Anderson Cancer Center. Outcomes were analyzed according to initiation of adjuvant chemotherapy at < 30 days, 31 to 60 days, and ≥ 61 days after definitive surgery. Among the 6,827 patients, time to adjuvant chemotherapy was < 30 days in 2,716 (39.8%), 31 to 60 days in 2,994 (43.8%), and ≥ 61 days in 1,117 (16.4%). Overall, 84.5% had stage I to II disease and 15.5% had stage III disease. There were no differences in time to chemotherapy between patients who underwent breastconserving surgery and those who underwent mastectomy (P = .83) and no association between number of comorbidities and time to chemotherapy (P = .6). After a median follow-up of 59.3 months, 1,437 patients (21.0%) had died, 2,135 (31.3%)

had developed a recurrence, and 1,924 (28.2%) had distant recurrence.

Associations With Survival Among all patients, there were no significant differences among the < 30, 31 to 60, and ≥ 61 day groups with regard to 5-year overall survival (85%, 83%, 83%; P = .54), recurrence-free survival (69%, 69%, 68%; P = .67), or distant recurrence-free survival (73%, 72%, 71%; P = .48).

all survival, recurrence-free survival, or distant recurrence-free survival among all hormone receptor–positive patients (n=3,834) or among all HER2-positive patients (n = 1,142). However, 5-year overall survival significantly differed by time to chemotherapy among HER2-positive patients treated with trastuzumab (n = 591; 88% for < 30, 87% for 31–60, and 75% for ≥ 61 days; P = .01) and among patients with triple-negative disease (n = 889;

Among patients with stage II and III [breast cancer], [triple-negative breast cancer], and HER2-positive tumors, every effort should be made to avoid postponing the initiation of adjuvant chemotherapy. This may lead to an improvement in outcomes for these subsets of patients. —Mariana Chavez Mac Gregor, MD, MSc, and colleagues

Significant differences in all three outcomes by time to chemotherapy were observed for race/ethnicity, pathologic tumor size, pathologic nodal status, cancer subtype (hormone receptor–positive, HER2positive, or triple-negative), nuclear grade, lymphovascular invasion status, type of surgery, and number of comorbidities.

Poorer Overall Survival There were no significant differences among the < 30, 31 to 60, and ≥ 61 day groups with regard to over-

Timing of Aduvant Chemotherapy in Breast Cancer ■■ Delayed adjuvant chemotherapy was associated with significantly worse overall survival among all patients, those with stage III disease, those with triple-negative disease, and those with HER2-positive disease treated with trastuzumab. ■■ The findings suggest that early initiation of adjuvant chemotherapy should be emphasized in the identified high-risk groups.

70% for < 30, 59% for 31–60, and 67% for ≥ 61 days; P = .004). There were no significant differences in recurrencefree survival or distant recurrence-free survival in these two subgroups according to time to chemotherapy.

Adjusted Analysis On multivariate analysis adjusting for age, race/ethnicity, axillary node involvement, tumor size, tumor grade, surgery, lymphovascular invasion, number of comorbidities, type of chemotherapy in patients with triple-negative disease, and use of trastuzumab in HER2-positive patients, initiation of chemotherapy at ≥ 61 days vs < 30 days was associated with significantly worse overall survival among all patients (hazard ratio [HR] = 1.19, P = .03). Initiation of adjuvant chemotherapy ≥ 61 days vs < 30 days after surgery was also associated with significantly worse distant recurrence-free survival in patients with stage II disease (HR =

1.20, P = .03) and significantly worse overall survival (HR = 1.76, P < .001), recurrence-free survival (HR = 1.34, P = .04), and distant recurrence-free survival (HR = 1.36, P = .03) in patients with stage III disease. In addition, patients with triple-negative disease who initiated treatment at 31 to 60 days (HR = 1.74, P < .001) or ≥ 61 days vs < 30 days (HR = 1.54, P = .02) had significantly worse overall survival, as did HER2-positive patients receiving trastuzumab who initiated chemotherapy at ≥ 61 days vs < 30 days (HR = 3.09, P = .002). The investigators concluded: [W]e demonstrated that delaying the initiation of adjuvant chemotherapy was associated with worse [breast cancer] survival outcomes and that the clinical impact varies according to the stage and the [breast cancer] subtype. Early initiation of adjuvant chemotherapy is particularly relevant for patients with advanced-stage [breast cancer] at diagnosis, and those with [triple-negative breast cancer] and trastuzumab-treated HER2-positive tumors. The adverse outcomes occurred when chemotherapy was delayed ≥ 61 days, which in most circumstances, gives medical oncologists enough time to initiate adjuvant chemotherapy. Among patients with stage II and III [breast cancer], [triplenegative breast cancer], and HER2positive tumors, every effort should be made to avoid postponing the initiation of adjuvant chemotherapy. This may lead to an improvement in outcomes for these subsets of patients. n Disclosure: The study was supported by the National Cancer Institute, a Komen for the Cure Catalyst Award, and the American Cancer Society. For full disclosures of the study authors, visit jco.ascopubs.org.

Reference 1. de Melo Gagliato M, Gonzalez-Angulo AM, Lei X, et al: Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol. January 27, 2014 (early release online).

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Perspective

Impact of Delayed Initiation of Adjuvant Chemotherapy for Breast Cancer Varies by Tumor Subtype By Karen Lisa Smith, MD, MPH, and Vered Stearns, MD

he optimal time interval between surgery and initiation of adjuvant chemotherapy for earlystage breast cancer is not well established. Although most physicians aim to initiate adjuvant chemotherapy within a few weeks of surgery, clinical factors may cause delay. The influence of delay on relapse and mortality is uncertain, and whether its impact varies by breast cancer subtype is not well defined.1-6

negative impact of delay on survival included triple-negative breast cancer, HER2-positive breast cancer treated with trastuzumab, and stage III breast cancer. Delays ≥ 61 days were also associated with inferior survival for hormone receptor–positive breast cancer, although the magnitude of the impact of delay was less in this subgroup. Importantly, initiation of chemotherapy

It is our conclusion that the findings from de Melo Gagliato et al support the current standard of care. We recommend that clinicians continue to aim to initiate adjuvant chemotherapy within a few weeks of surgery whenever possible and that they be judicious in the use of interventions that may delay chemotherapy, particularly in triple-negative and HER2-positive patients.

Key Findings As reviewed in this issue of The ASCO Post, de Melo Gagliato et al analyzed a retrospective cohort of 6,827 patients with early-stage breast cancer who received adjuvant chemotherapy at The University of Texas MD Anderson Cancer Center and assessed the impact of delay on outcomes.7 On univariate analysis in the study population as a whole, there was no association between the time interval from surgery to initiation of adjuvant chemotherapy and overall survival, distant relapse–free survival, or relapse-free survival. However, planned exploratory subset analyses revealed a differing impact of delay by breast cancer subtype. Longer time to chemotherapy was associated with inferior overall survival in women with triplenegative breast cancer or those with human epidermal growth factor receptor–2 (HER2)-positive breast cancer treated with trastuzumab (Herceptin), although delay did not impact distant relapse–free survival or relapse-free survival in these subgroups. Multivariate analysis for the study population as a whole demonstrated a 19% increase in the risk of death, but no significant increase in the risk of relapse, associated with initiation of chemotherapy ≥ 61 days after surgery compared to ≤ 30 days after surgery. Subgroups in which multivariate analysis confirmed a substantial Dr. Smith is Assistant Professor in Oncology and Dr. Stearns is Professor of Oncology at Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore.

can be derived from a seminal study evaluating the optimal sequence of adjuvant radiation and chemotherapy. Long-term follow-up of this study revealed no difference in 10-year rates of distant metastases and death, suggesting no risk in delaying chemotherapy by several weeks.10,11 In contrast, two recent meta-analyses revealed increasing risk of death with each 4-week in-

—Karen Lisa Smith, MD, MPH, and Vered Stearns, MD

31 to 60 days after surgery compared to ≤ 30 days after surgery was not associated with inferior survival for any subgroups except triple-negative breast cancer.7

Conflicting Data The finding that delays in the initiation of adjuvant chemotherapy result in inferior outcomes is supported by a murine model demonstrating a phase of accelerated growth of residual disease after resection of the primary tumor and by mathematical modeling demonstrating increasing chemotherapy resistance with time.8,9 Despite this, results of prior research regarding how timing of adjuvant chemotherapy influences outcomes have been conflicting.1-6 The majority of the data is retrospective in nature, and randomized trials evaluating the impact of delay on outcomes would be difficult to perform. To the best of our knowledge, the most informative randomized data

crease in the interval between surgery and adjuvant chemotherapy.12,13

Corresponding Expectations It is not surprising that the impact of delay in initiation of adjuvant chemotherapy identified by de Melo G agliato et al differs by tumor subtype and stage, as it reflects the degree of benefit expected from adjuvant chemotherapy in different situations. For example, women with triple-negative breast cancer or HER2-positive breast cancer treated with trastuzumab gain significant improvements in outcome with adjuvant chemotherapy, and the corresponding impact of delaying such treatment identified by de Melo Gagliato and colleagues is notable. In contrast, the benefit of adjuvant chemotherapy is lower in hormone receptor–positive tumors, and the corresponding impact of delays in adjuvant chemotherapy is lower in this subtype. Indeed, many of the patients with hor-

mone receptor–positive breast cancer who received chemotherapy in the cohort studied by de Melo Gagliato et al may not have been offered chemotherapy if diagnosed today.7,14-17 Recent data in the neoadjuvant setting also support the principle that earlier initiation of systemic therapy for triple-negative and HER2-positive breast cancer is beneficial. For these tumor types, rates of pathologic complete response after neoadjuvant therapy are high and achievement of pathologic complete response is strongly associated with favorable long-term outcomes.18-22

Reasons for Delay The conclusions reached by de Melo Gagliato and colleagues regarding the impact of delay of adjuvant chemotherapy are particularly relevant given that recent advances in breast cancer care can delay adjuvant chemotherapy. Vandergrift and colleagues recently reported that the time interval between diagnosis and initiation of adjuvant chemotherapy progressively increased between 2003 and 2009. Factors associated with delayed adjuvant chemotherapy included the use of magnetic resonance imaging (MRI), postmastectomy reconstruction, reexcision due to positive margins, and the use of genomic profiling.23 Other factors that can delay adjuvant chemotherapy include fertility preservation and peridiagnostic genetic testing.24,25 Although the time interval between diagnosis and initiation of chemotherapy increased from 2003 to 2009, the mean time between surgery and chemotherapy was only 6.3 weeks, and many of the diagnostic and therapeutic techniques associated with delayed adjuvant chemotherapy have improved breast cancer care overall.23 Based on the findings of de Melo Gagliato et al, it is not clear that delays of this magnitude are detrimental.26

Strengths and Weaknesses Strengths of the study by de Melo Gagliato et al include its large size and emphasis on differential effects of delay by tumor subtype. However, the

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Perspective

study is limited by its retrospective design, multiple comparisons, lack of information about reasons for delay, and incomplete data regarding other treatments that may impact outcomes (such as endocrine therapy, radiation, and the timing of trastuzumab).27-29 Furthermore, the fact that delay influenced survival without impacting relapse suggests potential bias, as patients with poor health may be unable to initiate chemotherapy quickly and also face competing causes of mortality. An additional limitation of this study is that, while the primary findings relate to stage III, HER2positive, and triple-negative disease, the bulk of the study cohort was composed of patients with stage I to II, hormone receptor–positive breast cancer. Finally, the median follow-up of 59.3 months may not be sufficient to assess the impact of delay on outcomes for hormone receptor–positive patients due to their risk of late recurrence.30

Implications for Clinical Care Despite these limitations, the study by de Melo Gagliato et al has messages applicable to clinical care. Perhaps the most important is that the impact of delaying adjuvant chemotherapy varies in accordance with the degree of benefit expected from adjuvant chemotherapy. Thus, it is most important to initiate chemotherapy earlier in women with triple-negative, HER2positive, and stage III breast cancer. Indeed, it is current practice to treat many such patients in the neoadjuvant setting, providing even earlier systemic therapy. In addition, the data from de Melo Gagliato et al suggest that the greatest increase in risk associated with delaying adjuvant chemotherapy occurs when the time between surgery and initiation of adjuvant chemotherapy exceeds 60 days, a time interval that is achievable in most cases, even with the use of modern day practices such as MRI, peridiagnostic genetic testing, immediate reconstruction, genomic profiling, and fertility preservation interventions. It is our conclusion that the findings from de Melo Gagliato et al support the current standard of care. We

recommend that clinicians continue to aim to initiate adjuvant chemotherapy within a few weeks of surgery whenever possible and that they be judicious in the use of interventions that may delay chemotherapy, particularly in triple-negative and HER2-positive patients. n

Disclosure: Dr. Smith has been a consultant for Genomic Health. Dr. Stearns reported no potential conflicts of interest.

References 1. Lohrisch C, Paltiel C, Gelmon K, et al: Impact on survival of time from definitive surgery to initiation of adjuvant chemotherapy for early-stage breast cancer. J Clin Oncol 24:4888-4894, 2006. 2. Colleoni M, Bonetti M, Coates AS, et al: Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors. The International Breast Cancer Study Group. J Clin Oncol 18:584-590, 2000. 3. Jara Sanchez C, Ruiz A, Martin M, et al: Influence of timing of initiation of adjuvant chemotherapy over survival in breast cancer: a negative outcome study by the Spanish Breast Cancer Research Group (GEICAM). Breast Cancer Res Treat 101:215-223, 2007. 4. Shannon C, Ashley S, Smith IE: Does timing of adjuvant chemotherapy for early breast cancer influence survival? J Clin Oncol 21:3792-3797, 2003. 5. Cold S, During M, Ewertz M, et al: Does timing of adjuvant chemotherapy influence the prognosis after early breast cancer? Results of the Danish Breast Cancer Cooperative Group (DBCG). Br J Cancer 93:627-632, 2005. 6. Buzdar AU, Smith TL, Powell KC, et al: Effect of timing of initiation of adjuvant chemotherapy on disease-free survival in breast cancer. Breast Cancer Res Treat 2:163-169, 1982. 7. de Melo Gagliato D, GonzalezAngulo AM, Lei X, et al: Clinical impact of delaying initiation of adjuvant chemotherapy in patients with breast cancer. J Clin Oncol 2014; doi:10.1200/ JCO.2013.49.7693. 8. Gunduz N, Fisher B, Saffer EA: Effect of surgical removal on the growth and kinetics of residual tumor. Cancer Res 39:3861-3865, 1979. 9. Goldie JH, Coldman AJ: A mathematic model for relating the drug sensitivity of tumors to their spontaneous

mutation rate. Cancer Treat Rep 63:17271733, 1979. 10. Recht A, Come SE, Henderson IC, et al: The sequencing of chemotherapy and radiation therapy after conservative surgery for early-stage breast cancer. N Engl J Med 334:1356-1361, 1996. 11. Bellon JR, Come SE, Gelman RS, et al: Sequencing of chemotherapy and radiation therapy in early-stage breast cancer: updated results of a prospective randomized trial. J Clin Oncol 23:19341940, 2005. 12. Yu KD, Huang S, Zhang JX, et al: Association between delayed initiation of adjuvant CMF or anthracycline-based chemotherapy and survival in breast cancer: a systematic review and meta-analysis. BMC Cancer 13:240, 2013. 13. Biagi JJ, Raphael M, King WD, et al: The effect of delay in time to adjuvant chemotherapy (TTAC) on survival in breast cancer (BC): a systematic review and meta-analysis. J Clin Oncol 29:abstract 1128, 2011. 14. Berry DA, Cirrincione C, Henderson IC, et al: Estrogen-receptor status and outcomes of modern chemotherapy for patients with node-positive breast cancer. JAMA 295:1658-1667, 2006. 15. Pritchard KI, Shepherd LE, O’Malley FP, et al: HER2 and responsiveness of breast cancer to adjuvant chemotherapy. N Engl J Med 354:2103-2111, 2006. 16. Foulkes WD, Smith IE, Reis-Filho JS: Triple-negative breast cancer. N Engl J Med 363:1938-1948, 2010. 17. Colleoni M, Cole BF, Viale G, et al: Classical cyclophosphamide, methotrexate, and fluorouracil chemotherapy is more effective in triple-negative, nodenegative breast cancer: results from two randomized trials of adjuvant chemoendocrine therapy for node-negative breast cancer. J Clin Oncol 28:2966-2973, 2010. 18. Liedtke C, Mazouni C, Hess KR, et al: Response to neoadjuvant therapy and long-term survival in patients with triple-negative breast cancer. J Clin Oncol 26:1275-1281, 2008. 19. von Minckwitz G, Untch M, Blohmer JU, et al: Definition and impact of pathologic complete response on prognosis after neoadjuvant chemotherapy in various intrinsic breast cancer subtypes. J Clin Oncol 30:1796-1804, 2012. 20. Carey LA, Dees EC, Sawyer L, et al: The triple negative paradox: primary tumor

chemosensitivity of breast cancer subtypes. Clin Cancer Res 13:2329-2334, 2007. 21. Cortazar P, Zhang L, Untch M, et al: Pathological complete response and long-term clinical benefit in breast cancer: the CTNeoBC pooled analysis. Lancet 2014; http://dx.doi.org/10.1016/ S0140-6736(13)62422-8. 22. Huober J, von Minckwitz G, Denkert C, et al: Effect of neoadjuvant anthracycline-taxane-based chemotherapy in different biological breast cancer phenotypes: overall results from the GeparTrio study. Breast Cancer Res Treat 124:133140, 2010. 23. Vandergrift JL, Niland JC, Theriault RL, et al: Time to adjuvant chemotherapy for breast cancer in National Comprehensive Cancer Network institutions. J Natl Cancer Inst 105:104-112, 2013. 24. Azim AA, Costantini-Ferrando M, Oktay K: Safety of fertility preservation by ovarian stimulation with letrozole and gonadotropins in patients with breast cancer: a prospective controlled study. J Clin Oncol 26:2630-2635, 2008. 25. Schwartz MD, Lerman C, Brogan B, et al: Impact of BRCA1/BRCA2 counseling and testing on newly diagnosed breast cancer patients. J Clin Oncol 22:1823-1829, 2004. 26. McAuliffe PF, Danoff S, Shapiro SD, et al: Treatment for breast cancer: is time really of the essence? J Natl Cancer Inst 105:80-82, 2013. 27. Perez EA, Suman VJ, Davidson NE, et al: Sequential versus concurrent trastuzumab in adjuvant chemotherapy for breast cancer. J Clin Oncol 29:44914497, 2011. 28. Darby S, McGale P, Correa C, et al: Effect of radiotherapy after breast-conserving surgery on 10-year recurrence and 15-year breast cancer death: meta-analysis of individual patient data for 10,801 women in 17 randomised trials. Lancet 378:1707-1716, 2011. 29. Davies C, Godwin J, Gray R, et al: Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet 378:771-784, 2011. 30. Anderson WF, Chen BE, Jatoi I, et al: Effects of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer. Breast Cancer Res Treat 100:121-126, 2006.

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In the Clinic Hematology

Ibrutinib for Previously Treated Chronic Lymphocytic Leukemia By Matthew Stenger In the Clinic provides overviews of novel oncology agents, addressing indications, mechanisms, administration recommendations, safety profiles, and other essential information needed for the appropriate clinical use of these drugs.

n February 12, 2014, ibrutinib (Imbruvica) was granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy.1,2 Ibrutinib previously received accelerated approval for the treatment of patients with mantle cell lymphoma who have received at least one prior therapy.

Efficacy Findings The approval in CLL is based on results of a multicenter, single-arm trial of 48 patients with previously treated CLL. Patients had a median age of 67 years (range, 37–82 years; 52% ≥ 65 years), 71% were male, all had Eastern Cooperative Oncology Group performance status of 0 or 1, median time from diagnosis was 6.7 years, and median number of prior treatments was four (range, 1–12). Ibrutinib was given orally at 420 mg once daily until disease progression or unacceptable toxicity. Ibrutinib treatment produced a 58.3% overall response rate (95% confidence interval = 43.2%–72.4%) on independent review committee assessment. No complete responses were observed. Response duration ranged from 5.6 to more than 24.2 months, with median response not being reached. No overall differences in effectiveness were observed between patients aged ≥ 65 years and younger patients. As a condition of accelerated approval in CLL, the U.S. Food and Drug Administration (FDA) requires that the sponsor submit results of a randomized clinical trial. In January 2014, Pharmacyclics notified FDA that the phase III RESONATE trial comparing ibrutinib vs ofatumumab (Arzerra) in patients with previously treated CLL or small lymphocytic lymphoma who were not candidates for purine analog–

based treatments had been stopped early on the basis of favorable results in a planned interim analysis. The trial was reported to demonstrate improvement in progression-free survival and overall survival with ibrutinib.

How It Works Ibrutinib is a small-molecule inhibitor of Bruton’s tyrosine kinase, a signaling molecule of the B-cell antigen receptor and cytokine receptor pathways. Bruton’s tyrosine kinase activity in signaling through the B-cell surface receptor results in activation of pathways necessary for B-cell trafficking, chemotaxis, and adhesion. Ibrutinib forms a covalent bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase

strong or moderate CYP3A inhibitors (eg, clarithromycin, grapefruit juice, indinavir, ketoconazole) should be avoided. If a strong inhibitor is to be used for ≤ 7 days, interruption of ibrutinib during this period can be considered. If a moderate inhibitor must be used, the ibrutinib dose should be reduced to 140 mg. Patients taking concomitant strong or moderate CYP3A inhibitors should be monitored more closely for signs of ibrutinib toxicity. Ibrutinib exposure is not altered in patients with creatinine clearance > 25 mL/min; there are no data in patients with severe renal impairment or on dialysis. Since ibrutinib is metabolized in the liver, significant increases in exposure are expected in patients with hepatic impairment and patients with serum aspartate transaminase or

Ibrutinib for CLL ■■ Ibrutinib (Imbruvica) was granted accelerated approval for the treatment of patients with chronic lymphocytic leukemia (CLL) who have received at least one prior therapy. ■■ The recommended dose of ibrutinib in CLL is 420 mg once daily.

enzymatic activity. Preclinical studies have shown that ibrutinib inhibits malignant B-cell proliferation and survival in vivo and cell migration and substrate adhesion in vitro.

alanine transaminase at least 3.0 times the upper limit of normal were excluded from clinical trials. Data are insufficient to recommend a dose in patients with hepatic impairment.

How It Is Given

Safety Profile

The recommended dose of ibrutinib in CLL is 420 mg once daily. Ibrutinib treatment should be interrupted for grade 3 or higher nonhematologic toxicities, grade 3 or higher neutropenia with fever, and grade 4 hematologic toxicities. With resolution to grade 1 or baseline status, treatment can be reinitiated at the starting dose. The dose may be reduced to 280 mg and then to 140 mg for recurrent toxicity. Coadministration of ibrutinib with

The most common adverse events of any grade in the CLL trial were thrombocytopenia (71%), diarrhea (63%), bruising (54%), neutropenia (54%), upper respiratory tract infection (48%), anemia (44%), and fatigue (31%). The most common grade 3 or 4 adverse events were neutropenia (27%), thrombocytopenia (10%), pneumonia (8%), and hypertension (8%). Patients aged ≥ 65 years had a higher frequency of adverse events, including grade 3 or higher adverse events (80% vs 61%). Second malignancies occurred in 10% of patients, with one patient dying from histiocytic sarcoma. Adverse events resulted in treatment discontinuation in 10% of patients (6% due to infection and 4% due

OF NOTE Ibrutinib carries warnings/precautions for hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies, and embryo-fetal toxicity.

OF NOTE Ibrutinib forms a covalent bond with a cysteine residue in the Bruton’s tyrosine kinase active site, leading to inhibition of Bruton’s tyrosine kinase enzymatic activity necessary for B-cell trafficking, chemotaxis, and adhesion.

to subdural hematoma) and in dose reduction in 13%. Shifts from normal to elevated uric acid levels occurred in 38% of patients, including 4% with levels >10 mg/dL. Ibrutinib carries warnings/precautions for hemorrhage, infections, myelosuppression, renal toxicity, second primary malignancies (including skin cancers and other carcinomas), and embryo-fetal toxicity. Patients must be monitored for bleeding and for fever and infections. Renal function must be monitored and adequate hydration ensured. Complete blood counts should be monitored monthly. Women must be advised of potential fetal risk and counseled to avoid pregnancy while taking ibrutinib. n References 1. U.S. Food and Drug Administration: Ibrutinib (IMBRUVICA). Available at www.fda.gov/Drugs/InformationOnDrugs/ApprovedDrugs/ucm385878.htm. 2. IMBRUVICATM (ibrutinib) capsules prescribing information. Pharmacyclics, Inc, February, 2014. Available at www. accessdata.fda.gov/drugsatfda_docs/ label/2014/203147s000lbl.pdf.

Report Adverse Events Health-care professionals should report all serious adverse events suspected to be associated with the use of any medicine or device to FDA’s MedWatch Reporting System by completing a form online at www.fda.gov/ medwatch/report.htm, by faxing (1-800-FDA-0178), by mailing the postage-paid address form provided online, or by telephone (1-800-FDA-1088).

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PAGE 81

News Health-Care Policy

ASCO Addresses Changes in Medicare for 2014 By Ronald Piana

edicare patients make up 61% of new cancer cases in the United States, and as the population ages, that proportion is expected to rise to 70% by 2030. Over the past decade, the oncology community has been financially challenged by alterations in the Medicare payment system. To address the changes in Medicare for 2014, ASCO recently conducted a teaching webinar, which was led by Elaine L. Towle, CMPE, Director of Consulting Services for Oncology Metrics, a division of Altos Solutions, Inc.

Legislative Update Designed to control health-care spending, the sustainable growth rate (SGR) is the formula used to set the amount Medicare reimburses physicians for patient care—an attempt to impose fiscal discipline through yearly and cumulative spending targets. In an effort to avert untenable cuts in physician fees (24.4% projected for 2014), Congress once again passed a 3-month “patch” in December, to allow lawmakers on the Hill time to work out a solution to this perpetual problem. Three committees of jurisdiction are currently working on an SGR fix. “It’s important to note that all the bills being looked at have incentives for alternate payment models and payment tied to quality,” said Ms. Towle. Ms. Towle discussed ASCO’s outreach efforts, in direct lobbying and official comments on the three SGR proposals. “It’s an ongoing multipronged effort,” she said. [Editor’s note: Under a recent deal worked out by the three congressional committees, the SGR formula would be repealed, and physicians would get a 0.5% pay increase every year for 5 years. At press time, the lawmakers have yet to work out funding for the plan (the SGR Repeal and Medicare Provider Payment Modernization Act of 2014 [H.R. 4015, S. 2000]), which still needs to be approved by both the House and the Senate.]

Hospital Outpatient Payment Ms. Towle described changes to the Healthcare Common Procedure Coding System (HCPCS), which is a set of health-care procedure codes based on the AMA’s Current Procedural Terminology (CPT). A new HCPCS code, G0463, is used for a hospital outpatient clinic visit for assessment and management of a patient. “This is for hospitals only; it does not impact professional service billing for physicians and nonphysician providers,” stressed Ms. Towle. She added, “CMS [the Centers for Medi-

projects a –2% impact on medical oncology,” said Ms. Towle. “In 2015, CMS will begin paying for services related to complex chronic care management,” she noted. “The code has not yet been released, but it is described as follows: ‘Chronic care management services furnished to patients with multiple (two or more) chronic conditions expected to last at least 12 months, or until death of the patient, that place the patient at significant risk of death, acute exacerbation/decompensation, or functional decline; 20 minutes or more; per 30 days.’”

Under the Affordable Care Act, CMS is required to implement a value-based payment modifier no later than January 1, 2015. The value modifier provides for differential payment to a physician or group of physicians under the Medicare Physician Fee Schedule based upon the quality of care furnished compared to cost during a performance period. “CMS will make differential payment to physicians based on the quality and cost of care they provide with up to a 2% penalty on physician fee schedule payments in 2016 for poor performers or noncompliant practices,” said Ms. Towle.

Countdown to ICD-10

It’s important to note that all the bills being looked at have incentives for alternate payment models and payment tied to quality. —Elaine L. Towle, CMPE

care & Medicaid Services] is replacing the current five levels of hospital clinic visits for both new and established patients with a single code describing all outpatient visits. Ten codes are being replaced with one new code.”

Final Rule on Fee Schedule CMS is required to establish payments under the Medicare Physician Fee Schedule based on national uniform relative value units (RVUs) that account for the relative resources used in furnishing a service. RVUs include three categories of resources: work, practice expense, and malpractice expense. The most significant change in the fee schedule were revisions to the Medicare Economic Index—the tool used to calculate cost revision—which ended in reclassification of certain costs from the practice expense category. “Chemotherapy administration reimbursement decreased for most codes, and CMS

Incentive Programs The Physician Quality Reporting System (PQRS) is a reporting program that uses incentive payments and payment adjustments to promote the reporting of quality information. PQRS reporting is available for individual eligible professionals or group practices. “The changes to the 2014 PQRS are designed to align requirements with other programs, encourage participation, and ease administrative burdens for participants,” said Ms. Towle. The measures are now grouped into six domains based on the National Quality Strategy’s six priorities: • Person and caregiver-centered experience and outcomes • Patient safety • Communication and care coordination • Community/population health • Efficiency and cost reduction • Effective clinical care • Value-based payment

ICD-10 is the International Statistical Classification of Diseases and Related Health Problems. “ICD-10 will replace ICD-9 as of October 1, 2014. Any entity covered by the Health Insurance Portability and Accountability Act (HIPAA), must make a transition to ICD-10. If your practice does not bill with ICD-10 codes after October 1, your claims cannot be processed. This will lead to a delay in reimbursement or no reimbursement at all,” said Ms. Towle. She stressed that physicians need to be educated about every facet of ICD-10, because their medical documentation will need to change. “Documentation must be specific enough for the billers and coders to select the appropriate code. Therefore, physicians need to understand how ICD-10 codes are selected. CMS is moving ahead with the transition, and there will not be any delays,” Ms. Towle warned. She enumerated the steps needed to make the transition more painless: • Get a commitment from your vendors about updating. • Buy an ICD-10 book and give it to your coders and billers. • Train your coding and billing staff. • Decide how and when to educate physicians. n Disclosure: Ms. Towle report no potential conflicts of interest.

The ASCO Post | MARCH 15, 2014

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Health-Care Policy Breast Cancer

Affordable Care Act to Cover Chemoprevention for Women at High Risk for Breast Cancer By Alice Goodman

n January 9, 2014, Kathleen Sebelius, Secretary of the Department of Health and Human Services, announced that under the Patient Protection and Affordable Care Act, women at increased risk of breast cancer will be entitled to preventive medications without incurring outof-pocket costs (with the proviso that they are also at low risk for any adverse effects of these medications). This means that most health insur-

evidence” that medications such as tamoxifen and raloxifene (Evista) can “reduce the risk of invasive estrogen receptor (ER)-positive breast cancer in postmenopausal women who are at increased risk for breast cancer.” The USPSTF is composed of independent physicians and academics, and this group awards letter grades to treatments or interventions. Items or services rated A or B by the USPSTF must be covered by insurers at no extra

Doctors have to convince a healthy woman that the benefits [of taking drugs like tamoxifen or raloxifene] exceed the risks. Women who have had lobular carcinoma in situ or atypical hyperplasia—those at the highest risk level—may be easier to convince. —Claudine Isaacs, MD

ance companies and employer plans must offer preventive services that include these drugs at no extra cost to patients, and insurers have 1 year to implement this policy.1 “We are making significant advancements in combating this disease—and for women who are shown to be at a higher relative risk for breast cancer, today, access to early treatments can improve their health,” wrote Ms. Sebelius and Congresswoman Debbie Wasserman Schultz, who represents Florida’s 23rd Congressional District and is a breast cancer survivor, in a blog post at HHS.gov/HealthCare.2

USPSTF Recommendation The impetus for the coverage decision was the U.S. Preventive Services Task Force (USPSTF) grade B recommendation made in September 2013,3 stating that there is “adequate

costs, including deductibles or copays. Under the Affordable Care Act, women over age 40 are also entitled to free breast cancer mammography screenings every 1 or 2 years, as well as genetic counseling and chemoprevention counseling for women at higher risk for breast cancer, whether due to age, family history, or other risk factors. On the day of the announcement, the American Cancer Society Cancer Action Network praised the new policy as an important milestone. “This policy means that millions of women at high risk for breast cancer will know that they can access proven risk-reducing medications at no cost to them. Studies show that even modest cost sharing can keep patients from taking advantage of provident tests and therapies. By making prevention more accessible and affordable, the Affordable Care Act is help-

Chemoprevention and the Affordable Care Act ■■ According to a recent announcement by the Department of Health and Human Services, the Affordable Care Act will now cover drugs for chemoprevention in women at high risk of developing breast cancer. ■■ Women can now get drugs like tamoxifen and raloxifene at no increased cost, including copays or deductibles.

ing people stay healthy and avoid the high costs of treatment after diagnosis,” said spokesman Steve Weiss.4 Regarding the announcement, U.S. Second Lady Jill Biden, EdD, wrote on the White House blog, “Now, if their doctor recommends that the benefits of this treatment outweigh the risks, one question women across the country won’t have to ask is whether they can afford it.”5

Important Step Although this is an important first step in improving access to chemoprevention, getting drugs for free removes only one potential barrier for women at high risk, explained Claudine Isaacs, MD, in an interview with The ASCO Post. Dr. Isaacs is CoDirector of the Fisher Center for Familial Cancer Research and Medical Director of the Cancer Assessment and Risk Evaluation (CARE) program at Georgetown Lombardi Comprehensive Cancer Center in Washington, DC. “Studies have shown that the uptake of chemoprevention is very low among women at high risk of developing breast cancer. The barriers to uptake go beyond finances. Many healthy women may not want to take a drug with side effects. This is a complex issue,” she stated. Dr. Isaacs said that one of the factors influencing women’s decisions regarding chemoprevention is discussion with their primary care physicians, many of whom identify other priorities for the limited time they

have with their patients, especially when most women at high risk will never develop breast cancer. “In addition to other important issues, doctors have to convince a healthy woman that the benefits [of taking drugs like tamoxifen or raloxifene] exceed the risks. Women who have had lobular carcinoma in situ or atypical hyperplasia—those at the highest risk level—may be easier to convince,” Dr. Isaacs noted. n

Disclosure: Dr. Isaacs potential conflicts of interest.

reported

References 1. Center for Consumer Information & Insurance Oversight: Affordable Care Act Implementation FAQs - Set 18. Available at http://www.cms.gov/CCIIO/ Resources/Fact-Sheets-and-FAQs/aca_ implementation_faqs18.html. Accessed January 20, 2014. 2. Sebelius K, Wasserman Schultz D: More than 2.8 million reasons for hope. Posted January 9, 2014. Available at www. hhs.gov. Accessed January 20, 2014. 3. Moyer VA: Medications for risk reduction of primary breast cancer in women: U.S. Preventive Services Task Force recommendation statement. 159:698708, 2013. 4. Galewitz P: For high-risk women, some breast cancer drugs to be free. Posted January 9, 2014. Available at capsules. kaiserhealthnews.org. Accessed January 20, 2014. 5. Biden J: This is the Affordable Care Act: Giving women at high risk for breast cancer access to free chemoprevention medication. Posted January 9, 2014. Available at www.whitehouse.gov. Accessed January 20, 2014.

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PAGE 83

News Neuro-Oncology

Neuro-Oncology Community Convenes in Workshop to Advance Imaging-Related Endpoints in Clinical Trials

eaders from key cross-sections of the neuro-oncology community came together at a recent Brain Tumor Clinical Trial Endpoints Workshop to confront a critical challenge in developing and testing treatments for glioblastoma multiforme. Participants were able to adjourn the workshop with the constructs of a specific action plan to ultimately bring greater clarity to one of the central tasks of clinical trials, establishing the effectiveness of therapies. Experts representing the U.S. Food and Drug Administration (FDA), the National Cancer Institute (NCI), medical imaging companies, contract research organizations, leading biopharmaceutical companies, and medical academic research organizations, were convened at the workshop, which was hosted by the Jumpstarting Brain Tumor Drug Development Coalition (Accelerate Brain Cancer Cure, Musella Foundation for Brain Tumor Research & Information, National Brain Tumor Society, and the Society for Neuro-Oncology). Individuals addressed how to overcome variables in medical imaging, which currently hinder the ability to accurately assess brain tumor response to investigational therapies, thus slowing drug development for this vulnerable patient population.

to the creation of an action plan for the community to improve the accuracy and consistency of imaging data, and to launch a coordinated effort to accelerate brain tumor therapy approvals us-

technology industry, NCI, and FDA to advance the agenda set forth at the first Brain Tumor Clinical Trial Endpoints Workshop. For more information, visit braintumor.org. n

The QOPI® Certification Program (QCP) provides a three-year certification for outpatient hematologyoncology practices. QCP validates practice processes that demonstrate your commitment to quality to patients, payers, and the medical community.

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LET US HELP YOU PROVE IT. JOIN THE OVER 200 ONCOLOGY PRACTICES IN THE U.S. WHO HAVE RECEIVED QOPI CERTIFICATION AND DISTINGUISH YOUR PRACTICE. BENEFITS OF QOPI CERTIFICATION INCLUDE: • Practice Improvement – Benchmark performance, implement improved systems, and provides structural standards to aid practice management. • A Demonstration of Quality – Benchmark against national standards and demonstrate improved standards and processes to safeguard both practice and patients.

Objectives and Action Plan “Historically, variability and lack of standardization in the criteria for the use of imaging endpoints to determine tumor response to treatment has impeded efforts to accelerate the evaluation and approval process of new brain cancer therapies,” said W.K. Alfred Yung, MD, Workshop Chair, and Chair of the Department of Neuro-Oncology at The University of Texas MD Anderson Cancer Center in Houston. “What we did with this workshop, and what the guidance the FDA graciously provided enables, is to speed the development of standards and tumor response criteria, so that together we can accurately assess the effectiveness of promising therapies seeking approval,” Dr. Yung said. The Workshop featured presentations and panel discussions, as well as facilitated audience-panel deliberations on topics such as current brain tumor imaging protocols in multicenter trials, emerging techniques and technologies in brain tumor imaging, and the use of imaging measurements of tumor progression and tumor response in clinical trials. A final group discussion led

ing imaging as a criteria. The Jumpstarting Brain Tumor Drug Development Coalition will work collaboratively with the biopharmaceutical companies, medical academics, medical

• Improved Efficiency, Effectiveness – Translate policies and procedures into practice and streamline interdepartmental communications to keep better records and avoid costly errors. • Public Trust, Competitive Edge – Achieve recognition from health plans and incorporate QOPI Certification status in practice marketing materials to patients, caregivers, and your medical community.

qopi.asco.org/certification Quality Cancer Care: Recognizing Excellence

The ASCO Post | MARCH 15, 2014

PAGE 84

Palliative Care in Oncology Pediatric Oncology

St. Jude Children’s Research Hospital Committee Identifies Eight Palliative Care Priorities in Pediatric Oncology

bout 2½ years ago, St. Jude Children’s Research Hospital in Memphis conducted a series of focus groups to better understand the palliative care priorities of bereaved parents. Their findings were never intended to be generalized, but rather to be used to formulate a strategic plan for an institutional palliative care initiative. “The document that the parents created was so compelling, however, that I think it is deserving of a much broader readership,” Justin N. Baker, MD, FAAP, FAAHPM, Chief of the Division of Quality of Life and Palliative Care at St. Jude’s, told The ASCO Post. That said, with this installment of Palliative Care in Oncology, The ASCO Post is pleased to present the following “Recommendations to Improve the Quality of Palliative and End-of-Life Care in Pediatric Oncology” developed by the St. Jude Family Advisory Council’s Subcommittee on Quality of Life and Palliative Care. In a letter to The ASCO Post, the members of the subcommittee (see sidebar, page 85) quoted St. Jude’s mission statement: St. Jude and other pediatric oncology institutions value a commitment “to provide patients with the highest quality of medical and supportive care, and their families with the level of information and support necessary for them to make informed decisions and to become active participants in the care of their children.” We support this noble ideal and urge pediatric oncology leaders to consider the list of eight care priorities identified in this document. We very much appreciate St. Jude for seeking this feedback as part of their quest to continually improve and enhance the services and support of their patients and families. Coming up with these recommendations for St. Jude and the field of pediatric oncology has been very difficult for us, as we all feel the care our children received at St. Jude was exemplary.

Because pediatric oncology issues are best addressed in a family-centered care manner, we strongly recommend the formation of institutional task forces formed by pediatric oncology leaders, health-care providers, and family members to promptly identify strategies to evaluate and improve these aspects of care.

Recommendations to Improve the Quality of Palliative and End-of-Life Care in Pediatric Oncology As parents of seriously ill children, we recognize the importance of finding a cure for pediatric cancer and other catastrophic diseases. We also know that despite the best efforts of clini-

cians and researchers, children continue to die from cancer or complications of its treatment. We pray that one day we might together celebrate Danny Thomas’ dream realized when truly no child will die in the dawn of life. As we wait for that day, it is our desire to work hand-in-hand to improve the quality of life and care provided for our children

and our families at St. Jude Children’s Research Hospital and around the world, beginning at the point of diagnosis of a chronic, life-threatening, and incurable disease. Therefore, the Family Advisory Council has formed a Quality of Life and Palliative Care Subcommittee composed of 14 bereaved parents. We, the parents, have identified care

In Honor of the St. Jude Family Advisory Council’s Subcommittee on

Quality of Life and Palliative Care 1

10 8

Children of the St. Jude Family Advisory Council Subcommittee on Quality of Life and Palliative Care: 1. Devan Lore, 2. Ashton Long, 3. Matthew Lewis, 4. Josh Roskowski, 5. Suzie Pavlat, 6. Scott Elrod, 7. Baby Matthew Pederson and family, 8. Thomas Musser and family, 9. Nick Avery, and 10. David Moore.

ASCOPost.com | MARCH 15, 2014

PAGE 85

Palliative Care in Oncology priorities for quality improvement and generated a list of recommendations. The St. Jude Patient and Family Centered Care Initiative and the Division of Quality of Life and Palliative Care organized a subcommittee aimed at creating palliative care priorities that could be utilized in quality improvement initiatives as well as for strategic planning. Members of the Division of Quality of Life and Palliative Care (Drs. Javier Kane and Justin Baker) met with us, the bereaved parents, for a total of 6 hours in three separate monthly focus group meetings. Our subcommittee deliberated about our own personal experiences and commented on what we considered to be the most important priorities in the care of children with poor prognosis for long-term survival. The information provided by our focus group was documented and subsequently summarized. Eight recommendations based on identified priority areas are summarized below.

Recommendation #1: To ensure that children receive the best possible treatment of disease and have the best possible quality of life, always hoping for the best possible outcome As parents, we have an overwhelming desire to cure our child’s illness; we want to see our children healthy and free of disease. We also recognize the need to give our children a life as normal as possible given the circumstances. We want to be empowered by the health-care team and to work with the staff in making life the best that it can be for our ill children. The health-care team must be empathetic to the personal needs of our sick children every step of the way, from the day of diagnosis to survival,

or from diagnosis to death and bereavement. Care is best when it is individualized to the particular needs of every child and family, and when it supports what we, as a family, consider what is most important for us. This may include addressing the emotional needs of parents and siblings or support of the families’ spirituality and

We need health-care providers to be honest about the possibility that our children may die so that, while there is still time, we can have meaningful conversations with our child and other family members about what to expect if the cancer treatment does not work. —Subcommittee on Quality of Life and Palliative Care

personal or cultural values. Health-care providers involved in the care of our children must be well educated in the provision of curative treatment and they must be knowledgeable about how to support families in the process of decision-making when cure is less likely.

Recommendation #2: To provide effective symptom control We have an overwhelming desire to keep our children safe and comfortable without experiencing pain and suffering while they are receiving treatment. We want to be empowered by the health-care team and to work together with the staff to ensure our child’s comfort and ease of distressing symptoms. Health-care providers must excel in communication with families about difficult issues, and must learn to recognize that physical comfort and quality of life are hugely important for us from the moment of diagnosis, and particularly when the illness pro-

Family Advisory Council for Quality of Life and Palliative Care, St. Jude Children’s Research Hospital ■■ Wendy Avery

■■ Jack and Barbara Pavlat

■■ Larry and Gwen Elrod

■■ Tom and Stacy Pedersen

■■ Benita Lewis

■■ Keith Roskowski

■■ Aline Long ■■ Gail Lore ■■ Marlow Moore ■■ Ed and Lisa Musser

gresses and cure becomes less likely. In this regard, we believe that comfort in the presence of potentially distressful symptoms and freedom from unnecessary pain and suffering should be minimized to the greatest extent possible at all stages of the journey throughout our child’s illness. We should have support from and access to experts in pain

St. Jude staff authors of the work: ■■ Justin N. Baker, MD, Nancy Noyes, PNP-BC, PMH-NP, PMHCNS-BC, and Javier R. Kane, MD

and symptom management in order to assure our child the greatest comfort possible.

Recommendation #3: To provide relationship-based care As parents of seriously ill children, we believe that the health-care system must honor the importance of services provided in the context of trusting and meaningful relationships. Health-care providers must learn to recognize that our children are members of our larger family unit and that as parents, we desire care to be delivered to our family as a whole, as our child’s illness affects every family member. Most importantly, we want to have access to adequately trained staff who show understanding and who we can connect with; someone who can advocate for comfort and quality of life from the time of diagnosis forward. Health-care providers must understand what we, as families being treated in the health-care system, are going through and should make every effort to meet us where we are in terms of our concerns, hopes, and personal values, and to respect and support what we consider most important in the care of our children.

Recommendation #4: To empower families with useful and reliable information As parents of seriously ill children, we must have access to useful and reliable information in order to make the right decisions on behalf of our children, to effectively navigate a complex health-care system, and to ensure that our children have access to the services that they need. Health-care providers must be

properly trained to communicate effectively with children and their family members about difficult issues. We need health-care providers to support hope but also to remain honest and transparent when providing information about the health of our children. We need information about possible treatment choices so that we can make informed decisions. We need healthcare providers to be honest about the possibility that our children may die so that, while there is still time, we can have meaningful conversations with our child and other family members about what to expect if the cancer treatment does not work.

Recommendation #5: To support children and families in the process of making difficult care decisions As parents of children suffering from cancer and other catastrophic diseases, we recognize our obligation to make the right decisions on their behalf. We also recognize that making end-of-life care decisions is particularly difficult. We believe that decisionmaking should be in the hands of the family. We must receive the information that we need to make the right decisions on behalf of our children. As bereaved parents, we need to have the peace of mind that comes from having no regrets about the decisions we make in the care of our children. This means that we need the guidance and support of doctors and other healthcare providers who are adequately prepared to help us establish a care plan that is consistent with our beliefs and personal values, and we need healthcare providers to be respectful of our choices and supportive of our decisions.

Recommendation #6: To facilitate care coordination Seriously ill children receive care in a very complex health-care system. We believe that this care should be well organized and coordinated throughout that same health-care system. Most importantly, we believe that health-care providers from a variety of disciplines and specialties must be able to communicate effectively with each other and collaborate effectively in the care of our children. This is particularly important at times of crisis such as during periods of hospitalization, at times of transition from the hospital to outpatient or from the hospital back to our home community, and at the end of life. continued on page 88

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The ASCO Post | MARCH 15, 2014

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Palliative Care in Oncology St. Jude Hospital Committee continued from page 85

Recommendation #7: To ensure that children with progressive and incurable illness experience a comfortable and peaceful death When our children have progressive disease and death is expected, we want to ensure that they will be comfortable and free from any unnecessary suffering. In the presence of advancing illness, we should be able to receive help from the healthcare team to prepare us and our chil-

hospital should at least be able to receive end-of-life care in a home-like environment.

Recommendation #8: To provide bereavement support for surviving family members and hospital staff The death of each of our children has been a tragic event of immeasurable consequence in our lives and in

their child was alive. Health-care providers should also be allowed to promote healing by creating opportunities for bereaved siblings and parents to talk about their family member and share their experiences. Health-care providers must also recognize that mothers, fathers, and siblings grieve differently, and that bereavement needs of each family member should be addressed separately with the goal

It is our desire that every staff member faced with caring for a dying child would receive the necessary tools and support in order to process their own grief and bereavement so that they can continue to do the difficult yet important work. —Subcommittee on Quality of Life and Palliative Care

Justin N. Baker, MD, FAAP, FAAHPM

dren for the possibility that they may die. We should also be able to choose where we want our child to be at the time of his or her death, and children who are not able to leave the

the lives of surviving family members. Care would be best if bereaved siblings and parents had easy access to grief and bereavement support. We believe that health-care providers should receive education on how to communicate effectively with bereaved family members, and ensure that they do not feel abandoned by the staff that cared for them when

of helping each family member transition back to their community and a life as normal as possible after the death of their loved one. Our care teams are a valuable source of comfort and support for our families. We recognize that when a child dies, this also causes enormous grief for those on the medical team who cared for that child. Therefore,

GUEST EDITOR

Jamie H. Von Roenn, MD

ddressing the evolving needs of cancer survivors at various stages of their illness and care, Palliative Care in Oncology is guest edited by Jamie H. Von Roenn, MD. Dr. Von Roenn is ASCO’s Senior Director of Education, Science and Professional Development Department.

it is our desire that every staff member faced with caring for a dying child would receive the necessary tools and support in order to process their own grief and bereavement so that they can continue to do the difficult yet important work that is ahead of them without the effects of compassion fatigue, detachment, or burnout. n

President Obama’s FY 2015 Budget Proposal

Statement From ASCO President Clifford A. Hudis, MD, FACP

“[O

n March 4, 2014], President Obama released his proposed budget for fiscal year 2015. Among several cost-cutting measures designed to preserve Medicare solvency is a proposal to reduce reimbursement for life-sustaining cancer drugs. Currently, reimbursement to physicians for “Part B” drugs is based on the average sales price plus a 6% payment for services needed to administer chemotherapy in physicians’ offices, where most cancer patients receive their care. “The President has proposed to reduce the 6% service payment to 3%. (The budget proposal appears to apply cuts primarily to physicians, but also mentions rebates that will be required by manufacturers.) This further threatens access to convenient care nationwide. “For the National Institutes of

Health (NIH), the President has requested $30.4 billion, an increase of $211 million over FY 2014. The NIH

by NIH limits our chances to take full advantage of the exciting scientific advances that promise to save and ex-

ASCO is deeply concerned about continued stagnation of federal research funding and sustained attacks on the nation’s cancer care delivery system... Our patients deserve better. —Clifford A. Hudis, MD, FACP

budget includes $4.93 billion for the National Cancer Institute (NCI), an $8 million increase over last year. The essentially flat funding (when adjusted for inflation) for the important biomedical research conducted

tend the lives of cancer patients. “The President also proposes a budget for the Food and Drug Administration of $4.7 billion, an increase of $358 million, or 8%, above FY 2014. This increase consists of $23 million in budget

authority and $335 million in user fees. “ASCO is deeply concerned about continued stagnation of federal research funding and sustained attacks on the nation’s cancer care delivery system. Continuing on this path jeopardizes quality and access to care for patients with cancer across the United States, and slows the tremendous progress made possible by our nation’s historic leadership in science and medicine. “The President’s budget will force new cuts in clinical trials programs and will further strain practices already being forced to shift patients to hospitals and other settings for their chemotherapy. Not only will the nation lose out on unprecedented scientific opportunity before us, we will further compromise the very system we depend upon to deliver the fruits of our research. “Our patients deserve better.” n

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Expert’s Corner Genomics

How Decoding the Genomes of Exceptional Responders Is Leading to More Effective Treatment for All Patients With Cancer A Conversation With David B. Solit, MD By Jo Cavallo

n 2012, David B. Solit, MD, Geoffrey Beene Chair and Director of the Center for Molecular Oncology at Memorial Sloan Kettering Cancer Center (MSKCC) in New York, and his colleagues published the results of a phase II study1 of 45 patients with advanced bladder cancer. The purpose of the clinical trial was to evaluate the effectiveness of everolimus (Afinitor) in delaying disease progression. All patients in the study received the drug, but so few responded, the drug was deemed not worthy of further development in this disease. However, one patient—a 73-year-old woman whose metastatic bladder cancer had become resistant to standard treatment—had such an impressive response to everolimus (in just 3 months her cancer had disappeared) that Dr. Solit and his research team initiated an in-depth investigation to determine the genetic basis for her extreme, outlier sensitivity to the drug. They performed whole-genome sequencing on a sample of the patient’s tumor and germline DNA derived from blood. This analysis revealed approximately17,000 mutations in the tumor that were not found in her normal cells. Upon analyzing these 17,000 potentially pathogenic mutations, aberrations in two genes, TSC1 and NF2, stood out as the likely basis for her exceptional response to everolimus. Four years later, the patient is doing well, without evidence of disease recurrence and remains on everolimus therapy. The ASCO Post talked with Dr. Solit about how advances in whole-genome sequencing methodology are being used to define the molecular basis of other exceptional responses to cancer therapy and how this knowledge is leading to changes in clinical trial design and biomarker development.

Finding Key Mutations Please talk about the results of your study of everolimus in patients with bladder cancer. One thing we’ve always recognized in oncology is the heterogeneity of outcomes among our patients. Some patients do well with surgery or chemotherapy or other systemic agents, whereas some patients do poorly. For years, we’ve tried to figure out why there is that variability in outcomes. This is

important to know because for many patients we may already have an effective drug available for them, but it may be a drug that only works in a minority of patients with a specific tumor type. If we do not have a predictive biomarker to tell us who is going to respond to a particular drug, the drug may not get developed to its full potential. We hypothesized that if we could figure out why this one patient in our everolimus study was so unique in her response to the drug, then maybe we could identify other patients for whom everolimus would also be of utility. We initially sequenced some of the genes we thought might have been the basis for her response based upon their known role in regulating mTOR signaling and prior reports showing that they were mutated in some bladder cancers. But using this candidate approach, we were un-

which is the direct target of everolimus. We were then able to study the tumors of other patients with bladder cancer and ask, do these mutations occur commonly in this disease? We found that the answer is no. Rather, they are only found in a minority of patients. In the case of TSC1, somewhere between 6% and 8% of patients with bladder cancer have mutations in this gene. NF2 is very rare; it probably occurs in just 1 in 100 or so patients with bladder cancer.

Clinical Application How will you now use this information to treat your patients with bladder cancer? We have proposed a second study where we look for TSC1 and NF2 mutations prospectively and then select those patients for enrollment in a trial of everolimus. We don’t necessarily assume that all the patients are going to respond as

I believe that an in-depth examination of outlier responses will become a standard component of the way we develop drugs. We will continue to be disappointed if a drug fails to achieve its primary endpoint and proves ineffective in most patients. We should, however, make sure we do not miss opportunities to continue to develop drugs that have profound activity in a subset of patients. —David B. Solit, MD

able to identify the basis for our patient’s extraordinary response. Then, taking advantage of recent advances in sequencing technology that weren’t available in years past, we were able to sequence the patient’s entire tumor genome. It turned out that she had two mutations that jumped out as the likely basis for her response. One was a two-base pair deletion in TSC1, which results in a truncation of the protein and loss of expression. And the other was a nonsense mutation in NF2, which also results in early truncation of the protein and loss of expression. These two genes are interesting because the loss of both of the proteins leads to activation of mTORC1,

well as our index patient did in the first trial. That patient had two mutations that likely cooperated to promote the formation of her tumor conferring extreme sensitivity to the drug. Other patients may have, for example, a TSC1 mutation and a second mutation that makes them less sensitive to everolimus. Will the whole-genome sequencing of your patients’ tumor become standard of care before enrollment into a clinical trial? We are starting a program in which we will broadly begin profiling patients with bladder cancer for TSC1 and other alterations. The assay that we are going to use initially tests for about 340 genes

that have a strong link to cancer formation. We are planning on profiling not only all patients with bladder cancer, but all patients who have advanced cancer and need a new treatment option. We currently have several trials open at MSKCC that target this pathway for which they may be eligible. Are you also studying patients with other cancer types who have had exceptional responses to a drug? Yes, we have completed retrospective studies on several additional cases. For example, we studied a patient with ovarian cancer who has had a nearly 4-year response to a MEK inhibitor. We found that the patient had a mutation in MAP2K1, which encodes MEK1, which was very difficult to detect using older methodologies. The incredible outlier response in this patient was thus due to a mutation in the target of the drug that sensitized her tumor to the MEK inhibitor. We just didn’t know that information when the trial was performed. We can now, however, start looking for patients prospectively that have similar mutations.

Outlier Studies Will you eventually conduct prospective studies on all outlier patients? Yes. We have now conducted such studies in a number of cancers, and we are starting to see other groups begin to study these exceptional responders. I think there is interest in repeating this paradigm very broadly to ensure that we do not miss opportunities to determine why an individual patient is responding to a specific drug. In the past, we had to look at one gene at a time, but with newer technologies, we can sequence the whole genome, or at least the whole exome. Using these techniques, I expect that we can determine in almost all such patients why they are unique in their response to a particular therapy. Of course, some complexity remains, in that some patients may have so many mutations and some drugs may hit multiple different targets, making it difficult even with whole-genome analysis to pinpoint the genomic basis for an individual patient’s drug sensitivity. Despite these challenges, our continued on page 90

The ASCO Post | MARCH 15, 2014

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Expert’s Corner David B. Solit, MD continued from page 89

success rate has been very high with this paradigm. Because each patient’s tumor is molecularly specific, aren’t all patients considered “outliers”? What you are saying is not completely untrue, but I believe that there are definitely patterns. For example, one of the things that came out of our study was that TSC1 is probably most commonly somatically mutated in bladder cancer (of the major tumor types), and that really was not appreciated previously. This highlighted that we should at least be considering the TSC1 mutant group of tumors as a subset of bladder cancer, for which we could develop effective combination therapies for most patients. While everolimus as a single agent may not be an effective therapy for many patients, by defining the pattern of mutations that co-occur with TSCI mutation, we can, hopefully, develop a combination of therapies for those in whom a single-agent approach is ineffective.

negative had profound and durable responses to agents whose development did not proceed, as no biomarker of drug sensitivity had yet been identified. On the basis of our work, there is now great interest in going back and studying such tumors to determine why those patients were unique. I believe that an in-depth examina-

tion of outlier responses will become a standard component of the way we develop drugs. We will continue to be disappointed if a drug fails to achieve its primary endpoint and proves ineffective in most patients. We should, however, make sure we do not miss opportunities to continue to develop drugs that have profound activity in a

subset of patients. n

Disclosure: Dr. Solit reported no potential conflicts of interest.

Reference 1. Iyer G, Hanrahan AJ, Milowsku MI, et al: Genome sequencing identifies a basis for everlimus sensitivity. Science. August 23, 2012 (early release online).

Future Investigations How might the study of exceptional responders to cancer therapy change drug development in the future? I believe that most pharmaceutical companies are still going to focus on broadly active drugs that work in large populations. I don’t think that’s going to change dramatically, but if we can make it easier to identify smaller populations that exhibit exceptional responses, there will be an interest in

Harold Varmus, MD

developing drugs for this narrower group of patients. Furthermore, if the larger pharmaceutical companies are not interested in these rare cancer subtypes, I can see smaller companies or the National Institutes of Health (NIH) filling that void. [National Cancer Institute Director] Harold Varmus, MD, has proposed a national N-of-1 initiative to help advance this concept. Specifically, the NIH has observed that small numbers of patients on many of the older studies that were deemed

References: 1. Hanna JA, Bordeaux J, Rimm DL, Agarwal S. The function, proteolytic processing, and histopathology of Met in cancer. Adv Cancer Res. 2009;103:1-23. 2. Christensen JG, Burrows J, Salgia R. c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 2005;225:1-26. 3. Quint LE, Tummala S, Brisson LJ, et al. Distribution of distant metastases from newly diagnosed non-small cell lung cancer. Ann Thorac Surg. 1996;62:246-250. 4. Ma PC, Maulik G, Christensen J, Salgia R. c-Met: structure, functions and potential for therapeutic inhibition. Cancer Metastasis Rev. 2003;22:309-325. 5. Birchmeier C, Birchmeier W, Gherardi E, Vande Woude GF. Met, metastasis, motility and more. Nat Rev Mol Cell Biol. 2003;4:915-925. 6. Lai AZ, Abella JV, Park M. Crosstalk in Met receptor oncogenesis. Trends Cell Biol. 2009;19:542-551.

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News Breast Cancer

SSO/ASTRO Release Consensus Guideline on Breast Cancer Treatment

he Society of Surgical Oncology (SSO) has announced the availability of a comprehensive consensus guideline for physicians treating breast cancer developed to help reduce health-care costs and improve the course of treatment. Developed in

conjunction with the American Society of Radiation Oncology (ASTRO), the guideline outlines an evidencebased surgical treatment path to help patients avoid unnecessary surgery. “A significant portion of breast cancer surgeries in the United States are per-

formed by our surgical oncologists, and the definition of an adequate margin has been a major controversy. Therefore, it was only natural that we decided to create a definitive guideline that helps to minimize unnecessary surgery while maintaining the excel-

lent outcomes seen with lumpectomy and radiation therapy,” said Monica Morrow, MD, SSO Immediate Past

Monica Morrow, MD

President and Co-Chair of the consensus panel. Dr. Morrow is Chief of Breast Surgery at Memorial Sloan Kettering Cancer Center in Manhattan.

Goals and Expectations “Our hope is that this guideline will ultimately lead to significant reductions in the high reexcision rate for women with early-stage breast cancer undergoing breast-conserving surgery. Based on the consensus panel’s extensive review of the literature, the vast majority of re-excisions are unnecessary because disease control in

Meena S. Moran, MD

WHERE WILL MET+ NSCLC GO NEXT? MET protein overexpression helps stimulate cancer cell proliferation, survival, and metastasis1-6 • Half of NSCLC tumors overexpress the MET protein2 • Genentech is conducting research into the role of the MET pathway in multiple tumor types

Learn more at ResearchMET.com

NSCLC=non–small cell lung cancer.

the breast is excellent with early-stage disease when radiation and hormonal therapy and/or chemotherapy are added to a woman’s treatment plan,” said Meena S. Moran, MD, Associate Professor of Therapeutic Radiology at Yale School of Medicine and Yale Cancer Center and Co-Chair of the Margin Consensus Panel. The guideline was produced with a grant from Susan G. Komen and is endorsed by the American Society of Clinical Oncology (ASCO) and the American Society of Breast Surgeons (ASBS). It may be downloaded now by visiting the SSO website, http:// www.surgonc.org/margins-study. n Editor’s note: A comprehensive review of the guideline with added commentary from Dr. Morrow will be published in the next issue of The ASCO Post.

The ASCO Post | MARCH 15, 2014

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JCO Spotlight Screening

Telephone Education and Counseling Effective in Programs Targeting Familial/Genetic Cancer Risk Screening By Matthew Stenger

wo studies recently reported in the Journal of Clinical Oncology indicate that telephone-based education or counseling initiatives can be successful in educating individuals at familial or genetic risk of cancer and in inducing these at-risk individuals to undergo recommended screening. In the Family CARE trial, Anita Y. Kinney, PhD, RN, Professor of Medicine at the University of New Mexico Cancer Center, Albuquerque, and colleagues found that a telephone-based strategy was effective in improving the

town Lombardi Comprehensive Cancer Center, Washington, DC, and colleagues found that telephone genetic counseling for BRCA1/2 mutation testing was noninferior to in-person counseling in the primary measures of knowledge, satisfaction, decision conflict, distress, and quality of life, but did not achieve equivalence with in-person counseling in test uptake.2

Intervention in At-Risk Relatives

In the Family CARE trial, 481 individuals aged 30 to 74 years who had not had risk-appropriate screening and were not candidates for genetic testing were recruited via contacting patients with colorectal cancer or their next of kin in five states (California, Colorado, Idaho, New Mexico, and Utah).1 Anita Y. Kinney, PhD, RN Marc D. Schwartz, PhD Participants were randomly assigned as family units to recolonoscopy screening rate in at-risk ceive active personalized intervention relatives of colorectal cancer patients.1 incorporating evidence-based risk comIn another study, Marc D. Schwartz, munication and behavior change techPhD, Professor of Oncology at George- niques (TeleCARE group, n = 232) or

Telephone-Based Education on Cancer Screening ■■ Telephone-based intervention significantly increased the proportion of at-risk relatives of colorectal cancer patients who underwent appropriate screening. ■■ Persons residing in rural areas and those with lower incomes benefitted at a level similar to that of urban residents. ■■ Telephone counseling was noninferior to in-person counseling in measures of knowledge, satisfaction, decision conflict, distress, and quality of life. ■■ Telephone counseling was not equivalent to in-person counseling in BRCA1/2 testing uptake.

a mailed educational brochure (control group, n = 249). All participants received a survey of self-reported baseline clinical information, including colonoscopy screening, family history of cancer, sociodemographics, and psychosocial data and a mailed educational brochure targeted to participant risk status. In addition, the TeleCARE group received mailed tailored visual aids, a tailored telephone cancer risk assessment and counseling session, mailed tailored summary letter of their telephone session, and a mailed tailored reminder card. The TeleCARE intervention incor-

porated risk communication and behavior change approaches designed to improve perceptions about the threat of familial colorectal cancer, effectively manage fear, increase belief in colonoscopy benefits, and increase self-efficacy and motivation to undergo the procedure. Participants were informed that colonoscopy was the recommended screening strategy due to their risk status. Participants completed an outcome assessment at 9 months after the intervention. The primary outcome measure was verified colonoscopy within 9 months of the intervention. The TeleCARE and control groups

Telemedicine: Efficiency in Cancer Screening and Outreach By Richard J. Boxer, MD, FACS

s defined by the U.S. Health Resources and Services Administration teleheath is “the use of electronic information and telecommunications technologies to support long-distance clinical health care, patient and professional health-related education, public health, and health administration.” It has become the fastest growing segment of the healthcare economy, with estimates of 50% growth annually over the next 5 years. According to the American Telemedicine Association, telemedicine is defined as “the use of medical inforDr. Boxer is Visiting Professor of Urology, David Geffen School of Medicine at UCLA, and Visiting Scholar, the Business of Science, UCLA. He is also Associate Editor, The ASCO Post. From 2006 to 2013, Dr. Boxer was the Chief Medical Officer at Teladoc, a telemedicine company and the nation’s largest telehealth provider.

mation exchanged from one site to another via electronic communications to improve a patient’s clinical health status. Telemedicine includes a growing variety of applications and services using two-way video, email, smart phones, wireless tools and other forms of telecommunications technology.”

Bringing Health Care to the Patient Telemedicine is being used for the care of patients in nearly every medical discipline. The reason for the incredible increase in its use across all areas of health care is the need to provide convenient access to affordable quality care. The fundamental change needed to achieve this goal is to bring health care to the patient and not the patient to health care. Health care in the United States is the best that money can buy. Unfor-

tunately, America is running out of money. Therefore, efficiencies must be brought to bear without sacrificing quality. Telemedicine is one of the prime efficiencies. Two studies recently reported in the Journal of Clinical Oncology and reviewed in this issue of The ASCO Post indicate that telephone-based education or counseling initiatives can be successful in educating individuals at familial or genetic risk of cancer and in inducing these at-risk individuals to undergo recommended screening.

Reaching Out to Those at Risk In one study (Family CARE trial), Kinney and colleagues found that a telephone-based strategy was effective in improving the colonoscopy screening rate in at-risk relatives of colorectal cancer patients.1 In another, Schwartz and colleagues found that telephone genetic counseling for BRCA1/2

mutation testing was noninferior to in-person counseling in the primary measures of knowledge, satisfaction, decision conflict, distress, and quality of life, but did not achieve equivalence with in-person counseling in test uptake.2 In the first study, relatives of patients with colorectal cancer were contacted and given appropriate information and asked to enroll. These at-risk individuals were offered a colonoscopy. Twice as many patients in the TeleCARE group, receiving telephone-based risk assessment and counseling, had a colonoscopy by the endpoint of the study (9 months) than in the control group receiving a mailed educational brochure. Thus, the study demonstrated the potential advantage of reaching out to the at-risk patients. One of the inclusion criteria, having relatives with previous colorectal cancer, required

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JCO Spotlight

were generally balanced for age (mean, 50 and 51 years), race/ethnicity (white in 92% and 96%), marital status (74% and 77% married, 22% and 19%, separated, widowed, or divorced), educational level (43% post–high school in both, 22% and 27% Bachelor’s degree), residence (75% and 80% urban, 25% and 20% rural), household income (20% and 17% < $30,000, 18% and 20% $30,000–$49,999, 16% and 14% % 50,000–$69,999, 35% and 40% ≥ $70,000), employment status (72% and 69% employed), health insurance (private for 71% and 70%, no coverage for 16% and 20%), and proportion with a personal health-care provider (66% and 65%). Fewer TeleCARE group participants were female (39% and 46%).

Improved Colonoscopy Rate Of all 481 at-risk relatives, 79.8% completed the outcome assessments within 9 months, with no significant difference between groups in retention rate. Overall, 35.4% of those in the TeleCARE group vs 15.7% of those in the control group underwent colonoscopy within 9 months (odds ratio = 2.83, P < .001). Odds ratios were similar and significant in subgroup analyses for rural residence (2.89, 95% confidence interval [CI] = 1.53–5.46), urban residence (2.87, 95% CI = 1.85–4.46), household income < $30,000 (2.75, 95% CI = 1.37–5.55), and household income ≥ $30,000 (2.94, 95% CI = 1.19–4.53). The investigators concluded, “Remote personalized interventions that

consider family history and incorporate evidence-based risk communication and behavior change strategies may promote risk-appropriate screening in close relatives of patients with [colorectal cancer].”

Genetic Counseling Strategy In a noninferiority trial, 669 women aged 21 to 85 years with a minimum 10% risk for a BRCA1/2 mutation who did not have newly diagnosed or metastatic cancer were randomly assigned to telephone counseling (n = 335), in which all counseling was conducted by telephone, or usual care (n = 334), in which participants received in-person counseling before and after genetic testing for BRCA1/2 mutation.2 All participants were recruited from the clinical genetic counseling programs at Lombardi Comprehensive Cancer Center, Mount Sinai School of Medicine, University of Vermont Cancer Center, and Dana-Farber Cancer Institute. Primary outcomes were noninferiority of telephone counseling in knowledge (Breast Cancer Genetic Counseling Knowledge Scale), satisfaction (Genetic Counseling Satisfaction Scale), decision conflict (10-item version of Decisional Conflict Scale), distress (cancer-specific stress with Impact of Event Scale, perceived stress with four-item version of Perceived Stress Scale), and quality of life (Short Form12 Mental Component Summary and Physical Component Summary). Secondary outcomes were equivalence of BRCA1/2 test uptake and costs

the patients to give the names of their relatives. Privacy issues were not discussed, although there was a reference to recruitment details in another of the Kinney et al papers. In the second study, by using telemedicine as compared to face-to-face interviews, Schwartz and colleagues were unable to increase the number of individuals at risk for breast cancer who obtained genetic testing.2 They concluded it was possible that since the individuals interviewed through telemedicine were not face-to-face, they had a chance to reject the idea of genetic testing by cheek swab.

even if they felt uncomfortable with the prospect. If they had been asked to return a day or even a number of hours later to be seen by another team mem-

Alternative Conclusion

ber (or a “patient advocate”), perhaps the numbers of those choosing the cheek swab would have diminished. Considering the two studies together, it is remarkable that a cheek swab was rejected but a colonoscopy was accept-

This brings up an interesting alternative conclusion: The face-to-face subjects may not have wanted the genetic testing but felt compelled, constrained, or obligated to have it done,

of telephone counseling vs usual care. Interviews were conducted 2 weeks after counseling (pretest disclosure) and at 3, 6, and 12 months after randomization (post-test disclosure). The current report evaluated the 2-week and 3-month assessments. The telephone group and the usual care group were balanced for age (mean, 48 years in both), BRCA1/2 probability (mean, 24% and 26%), education (at least college for 80% and 79%), employment status (full time for 59% and 55%), race (85% and 87% white), Jewish ethnicity (28% and 30%), being previously affected with breast or ovarian cancer (64% and 67%), proband status (63% and 64% probands), recruitment site (eg, Lombardi Cancer Center for 64% in both), and distance to the clinic (mean, 21 and 24 miles). BRCA1/2 testing was positive in 13% and 15%, negative in 17% in both, and uninformative/variant in 45% and 49%, with 25% and 19% remaining untested.

Noninferior Outcomes Telephone counseling was noninferior to usual care on all primary outcome measures at 2 weeks: knowledge (difference [d] = 0.03, lower bound of 97.5% CI = −0.61), perceived stress (d = −0.12, upper bound of 97.5% CI = 0.21), and satisfaction (d = −0.16, lower bound of 97.5% CI = −0.70) had group differences and confidence intervals that did not cross the predefined 1-point noninferiority limit. Decision conflict (d = 1.1, upper bound of 97.5% CI = 3.3) and cancer distress (d = −1.6, uped. Schwartz et al thought that if the genetic testing kit were at home and ready for use at the time of the telemedicine interaction, the compliance rate would

The interesting findings of these studies lead to new questions. However, there is no question that telemedicine has a significant place in health care today, and its influence will only grow with time. —Richard J. Boxer, MD, FACS

go up. Yet, perhaps there is another aspect of the two studies at play. Genetic testing might be less acceptable to the population than the prospect of using colonoscopy to determine whether pathology exists in the colon.

per bound of 97.5% CI = 0.27) did not cross the predefined 4-point noninferiority limit. Sensitivity analyses confirmed noninferiority for all outcomes after adjusting for multiple comparisons and imputing for missing follow-up data. Results at the 3-month assessment were similar to those at 2 weeks.

Uptake Not Equivalent Among the 600 women who completed pretest counseling (89.0% of the telephone group and 90.4% of the usual care group), 84.2% of the telephone group vs 90.1% of the usual care group underwent genetic testing (relative risk = 0.93, 95% CI = 0.88 to 0.99); the lower bound of the 90% CI (d = −5.9%, 90% CI = −10.3% to −0.01%) was outside the predetermined equivalence range, indicating that telephone counseling was not equivalent to in-person counseling. Similar results were found in the intention-to-treat population sample (74.9% vs 81.4%, d = −6.5%, 90% CI = −11.8% to 0.01%).

Cost Reduction Telephone counseling reduced per-person cost by $114.40, with savings attributable to shorter counseling times, less patient travel, and lower overhead. On the assumption of identical overhead costs, savings were reduced to $59 per person. The greatest cost savings ($321.40 per person) was for use of in-home buccal DNA kits by rural participants. continued on page 96

Disclosure: Dr. Boxer served as Chief Medical Officer at Teladoc, a telemedicine company, from 2002 to 2013.

References 1. Kinney AY, Boonyasiriwat W, Walters ST, et al: Telehealth personalized cancer risk communication to motivate colonoscopy in relatives of patients with colorectal cancer: The Family CARE randomized controlled trial. J Clin Oncol. January 21, 2014 (early release online). 2. Schwartz MD, Valdimarsdottir HB, Peshkin BN, et al: Randomized noninferiority trial of telephone versus in-person genetic counseling for hereditary breast and ovarian cancer. J Clin Oncol. January 21, 2014 (early release online).

MYELOFIBROSIS is a serious hematologic malignancy driven by overactive JAK1 and JAK2 signaling.1,2

Jakafi®

JAK1

JAK2

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause thrombocytopenia, anemia and neutropenia, which are each dose‐related effects, with the most frequent being thrombocytopenia and anemia. Perform a pre‐treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and then as clinically indicated • Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary

• Patients developing anemia may require blood transfusions and/or dose modifications of Jakafi • Severe neutropenia (ANC <0.5 × 109/L) was generally reversible. Withhold Jakafi until recovery • Serious bacterial, mycobacterial, fungal and viral infections may occur. Active serious infections should have resolved before starting Jakafi. Tuberculosis (TB) has been reported; attention should be given to the possibility of latent or active TB. Observe patients receiving Jakafi for signs and symptoms of infection and initiate appropriate treatment promptly • Progressive multifocal leukoencephalopathy (PML) has been reported with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate

The first and only FDA-approved drug treatment for intermediate or high-risk MYELOFIBROSIS3,4

Target the JAK pathway— treat the disease Jakafi inhibits both JAK1 and JAK2 signaling, an underlying mechanism of disease, and significantly improves splenomegaly and symptoms4,5 COMFORT-I: Percentage of patients with ≥35% reduction in spleen volume from baseline to Week 244,5,a

41.9

Jakafi (n = 155)

Patients (%)

40 30

Placebo (n = 154)

20 10 0

45.9

Jakafi (n = 148)

Patients (%)

COMFORT-I: Percentage of patients with ≥50% improvement in TSS at Week 244,5,a,b

P < 0.0001

30 20 10

0.7

Placebo (n = 152)

5.3

P < 0.0001

COMFORT-I = COntrolled MyeloFibrosis study with ORal JAK inhibitor Treatment (I); TSS = Total Symptom Score.

Efficacy was seen with Jakafi in both JAK2V617F-positive and JAK2V617F-negative patients, relative to placebo6,7

Consider Jakafi upon diagnosis for your patients with intermediate-1, intermediate-2 or high-risk myelofibrosis JAK = Janus-associated kinase.

• Advise patients about early signs and symptoms of herpes zoster and to seek early treatment • The three most frequent non‐hematologic adverse reactions were bruising, dizziness and headache • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with renal or hepatic impairment. Patients should be closely monitored and the dose titrated based on safety and efficacy • Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus. Women taking Jakafi should not breast‐feed Please see Brief Summary of Full Prescribing Information for Jakafi on the following page.

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients. The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24. A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24.4,5 b TSS was captured by a daily patient diary (MFSAF v2.0). TSS encompasses debilitating symptoms of myelofibrosis: abdominal discomfort, early satiety, pain under left ribs, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.4,5 a

References: 1. Tefferi A. Blood. 2011;117:3494-3504. 2. Verstovsek S, et al. N Engl J Med. 2010;363: 1117-1127. 3. Deisseroth A, et al. Clin Cancer Res. 2012;18:3212-3217. 4. Jakafi Prescribing Information. Incyte Corporation. 5. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 6. Verstovsek S, et al. N Engl J Med. 2012;366(suppl):1-38. 7. Verstovsek S, et al. Br J Haematol. 2013;161:508-516.

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PAGE 96

JCO Spotlight Telemedicine Education and Counseling continued from page 93

The investigators noted that factors contributing to the lower testing rate in the telephone group may have included the fact that usual care participants were able to provide DNA immediately following counseling. While the delay be-

tween telephone counseling and DNA provision could be a barrier to testing, use of in-home buccal kits could increase test uptake. The delay between counseling and DNA provision in the telephone group also allowed for greater deliberation that may have led some participants to forgo testing, a notion consistent

with the fact that telephone counseling participants who declined testing had lower baseline risk scores and were less likely to consider risk-reducing surgery than those who completed testing. The investigators concluded, “Genetic counseling can be effectively and efficiently delivered via telephone to increase access and decrease costs.” n

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis. Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause thrombocytopenia, anemia and neutropenia. [see Dosage and Administration (2.1) in Full Prescribing Information]. Thrombocytopenia was generally reversible and was usually managed by Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of reducing the dose or temporarily interrupting Jakafi. Platelet transfusions may be necessary [see Dosage and patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transAdministration (2.2) in Full Prescribing Information, and Adverse Reactions]. Patients developing anemia aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% may require blood transfusions and/or dose modifications of Jakafi. Severe neutropenia (ANC less than Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated 0.5 X 109/L) was generally reversible. Withhold Jakafi until recovery [see Adverse Reactions]. Perform a pre- with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase treatment complete blood count (CBC) and monitor CBCs every 2 to 4 weeks until doses are stabilized, and (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations. then as clinically indicated [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or Reactions]. Risk of Infection Serious bacterial, mycobacterial, fungal and viral infections may occur. worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for Jakafi with no Grade 3 or 4 cholesterol elevations. Active serious infections should have resolved before starting therapy with Jakafi. Tuberculosis has been reported in patients receiving Jakafi for myelofibrosis. Attention should be given to the possibility of latent or DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The Cmax and AUC of ruxolitinib active tuberculosis. Observe patients receiving Jakafi for signs and symptoms of infection and initiate increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole appropriate treatment promptly. PML Progressive multifocal leukoencephalopathy (PML) has been reported 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also with ruxolitinib treatment for myelofibrosis. If PML is suspected, stop Jakafi and evaluate. Herpes Zoster prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic Advise patients about early signs and symptoms of herpes zoster and to seek treatment as early as possible marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminif suspected [see Adverse Reactions]. istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other recommended [see Dosage and Administration (2.7) in Full Prescribing Information]. Patients should be sections of the labeling: • Myelosuppression [see Warnings and Precautions]; • Risk of Infection [see closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: Warnings and Precautions] Clinical Trials Experience Because clinical trials are conducted under There was an 8% and 27% increase in the C and AUC of ruxolitinib, respectively, with Jakafi administration max widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacomost frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with anemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses however, it has not been established whether discontinuation of therapy contributed to the clinical course in of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratothese patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and dose of Jakafi may be considered [see Dosage and Administration (2.9) in Full Prescribing Information]. Table maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times 1 presents the most common adverse reactions occurring in patients who received Jakafi in the double-blind, the clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanStudy During Randomized Treatment tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for Jakafi Placebo fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest (N=155) (N=151) dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). Adverse All All Reactions Gradesa Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of d myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differUrinary Tract Infections 9.0 0 0 5.3 0.7 0.7 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Weight Gaine 7.1 0.6 0 1.3 0.7 0 Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the urine, bacteria urine identified, nitrite urine present e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.8) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.8) in Full cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Prescribing Information]. Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a registered trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011-2013 Incyte Corporation. All rights reserved. Issued: November 2013 RUX-1326 reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Disclosure: The study by Kinney et al was supported by grants from the National Cancer Institute, Huntsman Cancer Foundation, and others. The study by Schwartz et al was supported by National Cancer Institute grants, Lombardi Comprehensive Cancer Center Biostatistics and Bioinformatics Shared Resource, and Jess and Mildred Fisher Center for Familial Cancer Research. For full disclosures of the study authors, visit jco.ascopubs.org.

Radiopharmaceutical Receives Orphan Drug Designation

he radiopharmaceutical gallium-68 dotatate has been given orphan drug designation by the U.S. Food and Drug Administration and the European Medicines Agency for use as a diagnostic agent for the management of gastroenteropancreatic neuroendocrine tumors (GEP-NETs). Gallium-68 dotatate is owned by Advanced Accelerator Applications (AAA) and prepared using a kit patentted by AAA, which is reconstituted in hospital radiopharmacies without the use of a radiochemistry module. Existing data show that the gallium68-labeled PET radiopharmaceutical should represent a major improvement compared to the current standard. Available data indicates that gallium-68 dotatate has greater sensitivity and specificity for tumor detection than the current standard, and it is also expected to significantly reduce radiation doses received by patients. Stefano Buono, Chief Executive Officer of AAA, commented: “GEPNETs constitute a life-threatening disease and effective patient management requires accurate diagnostic tools. The orphan drug designation of AAA’s gallium-68 dotatate will accelerate the development of this agent and hopefully allow it to be available to patients in the next few years.” n

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Integrative Oncology The Ketogenic Diet in Cancer Control By Donald Garrity, RD, CDN, Nutrition Counselor, Integrative Medicine Service, Memorial Sloan-Kettering Cancer Center, New York

etogenic (or very-low-carbohydrate) diets have been employed since the 1920s as nonpharmacologic therapies for epilepsy and, in some instances, have obviated the need for medication for that disease. Since the 1960s, the ketogenic diet has become better known as a means of managing

ing increase in dietary protein and fat.1 Carbohydrate restriction decreases insulin secretion and reduces fat formation and accumulation—hence, the diet’s effectiveness in weight loss. The human central nervous system (CNS) uses glucose as a primary fuel source. After approximately 3 to 4 days

Given the absence of solid data on the merits and potential negative consequences, patients should pursue this diet only via participation in a clinical trial. —Donald Garrity, RD, CDN

obesity. This was popularized further in the 1970s by the Atkin’s weight loss diet for the general public. More recently, research provided preliminary evidence for the ketogenic diet’s therapeutic potential against diverse illnesses such as diabetes, heart disease, polycystic ovary disease, and cancer.

Metabolic Effects The distinguishing feature of the ketogenic diet is its drastic reduction of dietary carbohydrates to 20 grams per day in the initial phase, and to 50 grams per day thereafter, along with a correspondMr. Garrity is a Nutrition Counselor in the Integrative Medicine Service, Memorial Sloan Kettering Cancer Center, New York.

of pronounced carbohydrate restriction, the CNS must obtain an alternative source of fuel. Ketone bodies, formed in the liver by the process of ketogenesis, become that alternate source. The defining characteristics of physiologic ketosis include the presence of ketone bodies in the urine and blood (ketonuria and ketonemia) and a sweet breath odor resulting from the elimination of acetone, the metabolic byproduct of ketogenesis, from the lungs.1

Cancer Connection Otto Warburg was the first to observe abnormalities in cancer cell energy metabolism in which cancer cells, unlike their normal counterparts, produce energy by a high rate of glycolysis

GUEST EDITOR

ntegrative Oncology is guest edited by Barrie R. Cassileth, MS, PhD, Chief of the Integrative Medicine Service and Laurance S. Rockefeller Chair in Integrative Medicine at Memorial Sloan Kettering Cancer Center, New York. The Integrative Medicine Service at Memorial Sloan Kettering Cancer Center developed and Barrie R. Cassileth, MS, PhD maintains a free website—About Herbs (www. mskcc.org/aboutherbs)—that provides objective and unbiased information about herbs, vitamins, minerals, and other dietary supplements, and unproved anticancer treatments. Each of the 268 and growing number of entries offer health-care professional and patient versions, and entries are regularly updated with the latest research findings. In addition, the About Herbs app, Memorial Sloan Kettering Cancer Center’s very first mobile application, is compatible with iPad, iPhone, and iPod Touch devices, and can be downloaded at http://itunes.apple.com/us/app/ about-herbs/id554267162?mt=8. followed by lactic acid fermentation, rather than by a comparatively low rate of glycolysis followed by oxidation of pyruvate, even in the presence of oxygen.2,3 This phenomenon is characteristic of many but not all malignancies. Glycolytic or glucose-dependant malignancies also overexpress glucose transporter-1, which assists the increased glucose uptake that is required to meet the energy needs of these cancer cells.4 Positron-emission tomography technology employs fluoro2-deoxyglucose because it undergoes a similar transport as glucose and is used in the diagnosis, staging, and treatment of cancers with increased uptake of glucose.5 The role of insulin and insulin-like

growth factor (IGF)-1 in cancer is also an area of active research. Most cancer cells express insulin and IGF-1 receptors. Insulin has a demonstrated ability to promote mitogenesis and also may be involved in promoting other cancerrelated mechanisms such as antiapoptotic signaling, proliferation, invasion, angiogenesis, and metastasis. In addition to these direct actions, insulin can act indirectly via IGFs by decreasing hepatic production of IGFbinding proteins 1 and 2. This increases circulating levels of IGF-1, which in turn also promotes mitogenic and antiapoptotic activity. Insulin increases the synthesis of IGF-1 in the liver while simultaneously decreasing IGF

Learn More About

Herbs, Botanicals, & Other Products Visit the free About Herbs website at

www.mskcc.org/aboutherbs

continued on page 99

N OW E N RO L L I N G

Pivotal Trial in gpNMBOverexpressing Metastatic Triple-Negative Breast Cancer • METRIC is a pivotal, open-label, prospectively controlled, randomized trial of glembatumumab vedotin in glycoprotein NMB-overexpressing triple-negative breast cancer (TNBC)

• gpNMB is an internalized transmembrane glycoprotein that is frequently overexpressed in TNBC tumors – gpNMB overexpression is associated with reduced recurrence-free survival in TNBC • Glembatumumab vedotin is an investigational antibody-drug conjugate (ADC) that targets tumors

1-4

Patients with metastatic TNBC overexpressing gpNMB* N=300

*Stratified

2:1 Randomization

expressing gpNMB4,5

Glembatumumab vedotin 1.88 mg/kg IV Day 1 of 21-day cycles Treat until unacceptable toxicity or disease progression Capecitabine 1250 mg/m2 BID Days 1-14 of 21-day cycles

by prior receipt of 0 or 1 line of therapy for advanced disease and anthracycline response.

Key Trial Endpoints

• Primary: Objective response rate (ORR) and/or progression-free survival (PFS) • Secondary: Duration of response (DOR) and overall survival (OS) Key Inclusion Criteria

• No more than one prior chemotherapy-containing regimen for advanced breast cancer • Prior receipt of anthracycline-containing chemotherapy in any setting, with no further anthracycline therapy indicated

• Taxane resistance after neoadjuvant/adjuvant therapy or in the advanced disease setting

For more information, visit www.metricstudy.com, www.clinicaltrials.gov/show/NCT01997333, or e-mail info@celldex.com.

References: 1. Weterman MAJ, Ajubi N, van Dinter IMR, et al. Int J Cancer. 1995;60:73-81. 2. Singh M, Del Carpio-Cano F, Belcher JY, et al. Crit Rev Eukaryot Gene Expr. 2010;20(4):341-357. 3. Rose AAN, Grosset A-A, Dong Z, et al. Clin Cancer Res. 2010;16(7):2147-2156. 4. Maric G, Rose AAN, Annis MG, Siegel PM. Onco Targets Ther. 2013;6:839-852. 5. Burris HA III. 2013 ASCO Educ Book. 2013:e99-e102. ©2014 Celldex Therapeutics, Inc.

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Integrative Oncology Ketogenic Diet continued from page 97

binding proteins 1, 2, and 3. Many studies have implied, without solid proof, that IGF-1 initiates and spreads cancer, as IGF-1 stimulates cell proliferation. Recent evidence also suggests that dairy products increase circulating IGF-1. It is not clear whether this is from absorption of IGFs already present in cow’s milk, or if certain amino acids in the dairy proteins casein and whey upregulate IGF-1 expression or prevent its clearance from the body.6 An emerging relationship is coming to light among carbohydrates, insulin, IGF-1, IGF binding proteins, and cancer initiation, promotion, and proliferation. These findings are the foundation of the hypothesis that a ketogenic diet decreases the insulin response and might delay the progression of certain cancers. The published evidence to date is preliminary.7

Human Studies Both low-carbohydrate and ketogenic diets have been shown to reduce tumor size in mice.8,9 Recent research provides some evidence that the diet may delay cancer progression in humans. A 1995 paper published in the Journal of the American College of Nutrition examined two case reports of female pediatric oncology patients with astrocytoma. These children were placed on a ketogenic diet, and their diets were supplemented with medium-chain triglycerides, an easily digested form of oil that was added to shakes. The study demonstrated that glucose uptake at the tumor sites was significantly decreased. Moreover, one of the children exhibited marked clinical improvement in skill development and mood. She remained on the ketogenic diet for 12 months with no disease progression. The authors of the study stated that they did not believe the diet would be a replacement for standard cancer treatment, but suggested that their results raised interesting clinical possibilities.10

Several case reports suggest that the ketogenic diet may reduce tumor progression, particularly in brain malignancies.12,13 As of this writing, no randomized controlled trials of the verylow-carbohydrate ketogenic diet have been conducted in patients with cancer. Studies to date have been pilot trials that focused on safety and feasibility.14 Recently, a paper by Fine et al demonstrated that inhibition of insulin by way of the ketogenic diet may be a possible adjuvant treatment for patients with cancer. In this pilot study of nine patients with various cancer diagnoses and preexisting rapid disease progression, the five subjects who exhibited threefold or higher ketosis markers had stable disease or partial remission compared to those with continued disease progression.15 Studies are underway to further examine the potential of the ketogenic diet in the treatment of cancer (for numerous examples, see www.clinicaltrials.gov). Research conducted to date clearly indicates the need for welldesigned randomized trials to further explore the role that diet might play in cancer prevention, initiation, progression, management, and treatment.

Patient Perceptions The general public is aware of the ketogenic diet, especially via its popular incarnation as the Atkins weightloss approach. Over the past few decades, many have experimented with this diet in efforts to achieve weight management goals, as evidenced by the popularity of the Atkins weight loss books. Today, many cancer patients are familiar with the ketogenic diet and its possible role as an adjuvant cancer treatment. An Internet search leads patients to articles by practitioners who advocate for the diet’s application in cancer treatment. Some Internet sites describe ways to self-monitor blood sugar and ketone bodies. Savvy patients also visit scientific

websites such as clinicaltrials.gov, where they read about ongoing and planned research. A problem faced by oncologists and other clinicians is how to respond to patient inquiries about the diet as a potential anticancer approach. Patients may decide to pursue the ketogenic diet on their own, assuming that, since it is “only” a diet, it can do little harm. However, patients undergoing chemotherapy may be at risk for malnourishment due to the side effects associated with their treatment.16 Introducing a restrictive diet may be potentially harmful. Patients who are tolerating cancer treatment well or who are on a break from treatment may also be at risk for harmful effects from a ketogenic diet. The concern here is that the longerterm effects of a high-fat, very-low-carbohydrate diet that maintains a state of ketosis are unknown. Given the absence of solid data on the merits and potential negative consequences, patients should pursue this diet only via participation in a clinical trial. n Disclosure: Drs. Garrity and Cassileth reported no potential conflicts of interest.

References 1. Paoli A, Rubini A, Volek JS, et al: Beyond weight loss: A review of the therapeutic uses of the very-low-carbohydrate (ketogenic) diets. Eur J. Clin Nutr 67:789796, 2013. 2. Warburg O: On the origin of cancer cells. Science 123:309-314, 1956. 3. Warburg O: On respiratory impairment in cancer cells. Science 124:267-272, 1956. 4. Hanahan D, Weinberg RA: Hallmarks of cancer: The next generation. Cell 144:646-674, 2011. 5. Nutt R: 1999 ICP Distinguished Scientist Award. The history of positron emission tomography. Mol Imaging Biol 4:11-26, 2002 6. Crowe FL, Key TJ, Allen NE, et al: The association between diet and serum concentrations of IGF-1, IGFBP-1, IGFBP2, IGFBP-3 in the European Prospective Investigation Into Cancer and Nutri-

tion. Cancer Epidemiol Biomarkers Prev 18:1333-1340, 2009. 7. Klement RJ, Kammerer U: Is there a role for carbohydrate restriction in the treatment and prevention of cancer? Nutr Metab (Lond) 8:75, 2011. 8. Ho VW, Leung K, Hsu A, et al: A low carbohydrate, high protein diet slows tumor growth and prevent cancer initiation. Cancer Res 71:4484-4493, 2011. 9. Otto C, Kaemmerer U, Illert B, et al: Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 8:122, 2008. 10. Nebeling LC, Miraldi F, Shurin SB, et al: Effects of a ketogenic diet on tumor metabolism and nutritional status in pediatric oncology patients: Two case reports. J Am Coll Nutr 14:202-208, 1995. 11. Zuccoli G, Marcello N, Pisanello A, et al: Metabolic management of glioblastoma multiforme using standard therapy together with a restricted ketogenic diet: Case report. Nutr Metab (Lond) 7:33, 2010. 12. Seyfried TN, Marsh J, Shelton LM, et al: Is the restricted ketogenic diet a viable alternative to the standard of care for managing malignant brain cancer? Epilepsy Res 100:310-326, 2012. 13. Zhou W, Mukherjee P, Kiebish MA, et al: The calorically restricted ketogenic diet, an effective alternative therapy for malignant brain cancer. Nutr Metab (Lond) 4:5, 2007. 14. Schmidt M, Pfetzer N, Schwab M, et al: Effects of a ketogenic diet on the quality of life in 16 patients with advanced cancer. Nutr Metab (Lond) 8:54, 2011. 15. Fine EJ, Segal-Isaacson CJ, Feinman RD, et al: Targeting insulin inhibition as a metabolic therapy in advanced cancer: A pilot safety and feasibility dietary trial in 10 patients. Nutrition 28:1028-1035, 2012. 16. Huebner J, Marienfeld S, Abbenhardt C, et al: Counseling patients on cancer diets: A review of the literature and recommendations for clinical practice. Anticancer Res 34:39-48, 2014.

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JCO Spotlight Survivorship

Long-Term Decline in Neuropsychological Function Seen After Cranial Radiotherapy for Pediatric Lymphoid Malignancy By Matthew Stenger

White Matter Integrity and Neuropsychological Performance

Study Design

Patients who had received cranial radiotherapy had significantly decreased fractional anisotropy (all P < .05) compared with controls in frontal, parietal, and temporal white matter tracts (orbitofrontal white matter, genu, anterior body, and forceps minor of the corpus callosum, cingulum [frontal and parietal], and inferior fronto-occipital fasciculus, superior longitudinal fasciculus, and uncinate fasciculus). Those who had received chemotherapy alone had trends for lower fractional anisotropy in frontal white matter tracts. Fractional anisotropy values for frontal, parietal, and temporal white matter tracts were significantly corre-

entral nervous system–directed chemotherapy and cranial radiotherapy for childhood acute lymphoblastic leukemia or lymphoma have neurotoxic effects. In a study reported in Journal of Clinical Oncology, Ilse Schuitema, MSc, of Leiden University, and colleagues evaluated white matter changes and neuropsychological function in Dutch or Belgian patients 20 to 30 years after receiving chemotherapy or cranial radiotherapy for childhood lymphoid malignancy.1 They found that cranial radiotherapy was associated with decreased white matter integrity (which significantly correlated with age at diagnosis and age at assessment) and poorer neuropsychological function. In the study, 93 patients treated between 1978 and 1990 at various intensities with (n = 44) and without (n = 49) cranial radiotherapy and 49 healthy controls were assessed with magnetic resonance diffusion tensor imaging and neuropsychological testing. Patients in the cranial radiotherapy group had been treated with radiotherapy at doses ranging from 15 to 30 Gy. Chemotherapy in both the radiotherapy and chemotherapy groups consisted of various regimens of intrathecal or intravenous methotrexate or intrathecal and intravenous methotrexate. Differences in fractional anisotropy—a diffusion tensor imaging measure of white matter microstructure—were analyzed using whole-brain voxel-based analysis. Neuropsychological function was assessed using the Amsterdam Neuropsychological Tasks program (larger values indicate worse performance) to measure executive function and the short form of the Wechsler Adult Intelligence Scale–Revised to estimate intelligence quotient.

for group factor), and visuospatial sequencing (8.2 vs 3.2; P < .001 for group factor) compared with controls, whereas those who had received chemotherapy alone had smaller, nonsignificant deficits compared with controls (intelligence quotient, 103.4; visuomotor accuracy, 3.5; visuomotor stability, 2.1; sustained attention work pace, 8.5; visuospatial sequencing, 4.5).

Correlations With Age Patients who had received cranial radiotherapy had significant positive correlations between fractional anisotropy values and age at diagnosis (corrected for age at assessment) for frontal and parietal white matter and significant negative correlations between fractional anisotropy values and age at

Cranial [radiotherapy]-treated survivors show decreased white matter integrity reflected by significantly decreased [fractional anisotropy] and associated neuropsychological dysfunction 25 years after treatment, although effects of chemotherapy alone seem mild. —Ilse Schuitema, MSc, and colleagues

lated with measures of visuomotor control, visuospatial sequencing, and sustained attention work pace (all P < .05). Patients who had received cranial radiotherapy had significantly poorer (all significant on simple contrast vs controls) intelligence quotient (mean, 96.9 vs 107.4; P = .116 for group factor), visuomotor accuracy (3.9 vs 3.3; P = .045 for group factor) and stability (2.6 vs 2.1; P = .052 for group factor), sustained attention work pace (9.5 vs 8.2; P = .005

Late Effects of Cranial Radiotherapy ■■ Patients with childhood lymphoid malignancy who had received cranial radiotherapy had significantly worse white matter integrity and associated performance on neuropsychological testing 20 to 30 years later. ■■ Worse white matter integrity was associated with younger age at diagnosis and older age at assessment. ■■ The study findings suggest that cranial radiotherapy but not chemotherapy may be associated with accelerated aging of the brain and increased risk of early onset dementia.

assessment (corrected for age at diagnosis, with younger age being worse), for frontal, parietal, and temporal white matter (all P < .05). In control subjects, correlations with age at assessment were not significant. No significant correlations with age at assessment or diagnosis were observed in the chemotherapy group.

Correlations With Dosage Higher dosage of cranial radiotherapy was associated with significantly worse white matter integrity (P < .05) in mainly frontal, but clusters throughout the brain (including corpus callosum, corona radiata, inferior fronto-occipital fasciculus, and uncinate fasciculus), whereas no interactions or correlations with doses of intravenous or intrathecal methotrexate could be established. No correlations with doses of intravenous or intrathecal methotrexate were found in the che-

motherapy group. No effects of doses of cranial radiotherapy or intrathecal or intravenous methotrexate on neuropsychological outcome were found. The investigators concluded: “Cranial [radiotherapy]-treated survivors show decreased white matter integrity reflected by significantly decreased [fractional anisotropy] and associated neuropsychological dysfunction 25 years after treatment, although effects of chemotherapy alone seem mild. Accelerated aging of the brain and increased risk of early onset dementia are suspected after cranial [radiotherapy], but not after chemotherapy.”

‘Wake-up Call’ In an accompanying editorial,2 F. Daniel Armstrong, MD, of the University of Miami Miller School of Medicine and Holtz Children’s Hospital, University of Miami/Jackson Memorial Medical Center, commented, Although the challenges of providing treatment and support to the adult survivors and their families who experience long-term problems associated with long-ago therapy are daunting, there is an opportunity to embark on studies that may bring about changes in treatment and long-term outcomes for the children we are treating today. The potential impact of this late effect in terms of both financial cost and burden to the patient and family is great; a similarly great response from the scientific and funding community is needed. Schuitema et al have issued a wake-up call. The scientific community should not hit the snooze button. n Disclosure: The study authors and Dr. Armstrong reported no potential conflicts of interest.

References 1. Schuitema I, Deprez S, Van Hecke W, et al: Accelerated aging, decreased white matter integrity, and associated neuropsychological dysfunction 25 years after pediatric lymphoid malignancies. J Clin Oncol. August 19, 2013 (early release online). 2. Armstrong FD: Implications of 25year follow-up of white matter integrity and neurocognitive function of childhood leukemia survivors: A wake-up call. J Clin Oncol. August 19, 2013 (early release online).

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Expert’s Corner Breast Cancer

How to Approach the Problem of CNS Metastasis in HER2-Positive Patients By Caroline Helwick

entral nervous system (CNS) metastasis is a pervasive problem in the setting of HER2-positive breast cancer. While some patients can be managed easily, others are challenging, said Eric P. Winer, MD, Chief of the Division of Women’s Cancers and the Thompson Senior Investigator for Breast Cancer Research at Dana-Farber Cancer Institute, and Professor of Medicine at Harvard Medical School, Boston, who shared his perspective on treating HER2-related CNS metastasis with The ASCO Post. Studies have consistently demonstrated that the risk of CNS involvement is high in patients with HER2positive metastatic breast cancer. Incidence ranges from 15% to 55%, depending on length of follow-up and stringency of screening. Within the HER2-positive cohort, estrogen receptor (ER)-negative disease confers a greater risk than ER-positive disease. In a 3,000-plus patient cohort from a National Comprehensive Cancer Network database, women with ER-negative disease had a 63% increased risk over ER-positive patients, he said.

Treatment Goals “Our treatment goals are to prolong survival, palliate neurologic symptoms, and prevent symptom progression. And we have to balance treatment-related toxicities with overall brain control and minimize the risk of ‘neurologic’ death—that is, death from the progression of the CNS metastases,” Dr. Winer said. Balancing treatment-related toxicities with overall disease control in the breast can be difficult, especially for patients expected to live long enough to develop complications from their metastatic disease, he noted. This is where treatment individualization is important and where tumor subtype may be informative. It is important to recognize that the natural history of brain metastases differs by disease subtype. For example, compared to patients with triple-negative breast cancer, those with HER2-positive disease have a longer time from metastatic diagnosis to CNS relapse (approximately 1 year vs < 6 months), greater control of extracranial disease at the time of CNS relapse (50% vs rarely), and longer median overall survival from

the time of CNS relapse (1–2 years vs 3–5 months). However, patients with triple-negative disease rarely die as a result of CNS progression alone, whereas up to 50% of those with HER2-positive disease do, he pointed out. Elaborating on these differences, Dr. Winer noted that patients with triple-negative breast cancer tend to develop CNS metastases earlier in their disease course. Patients with triple-negative disease have a shorter overall survival compared to those with HER2-positive disease, and treatment with radiotherapy is usu-

limited disease, stereotactic radiosurgery is often considered, and for those with multiple metastases, we usually choose whole-brain radiotherapy, with or without stereotactic radiosurgery,” he added. “There has been lively debate as to whether the patient who has received stereotactic radiosurgery for a limited number of metastases should receive whole-brain radiotherapy,” he continued. “Some believe we should give whole-brain radiotherapy to all these patients, and others strongly believe we should not.” Whole-brain radiotherapy after

If you need to treat the patient with progression in the brain after prior radiotherapy, and the patient has not received capecitabine, that [capecitabine/ lapatinib] is the regimen to consider. —Eric P. Winer, MD

ally the only treatment that is needed. The vast majority of patients succumb to their systemic disease before they have progression of disease in the brain. In contrast, patients with HER2-positive disease often develop progressive CNS disease after an initial course of treatment. “Treatment must be individualized,” Dr. Winer emphasized. “It’s very much a balancing act.”

Individualized Options The chief treatment options for local therapy include surgery, wholebrain radiotherapy, stereotactic radiosurgery, and their various combinations, depending on the number of metastatic lesions. A number of cytotoxic, targeted, and endocrine agents are also used, but radiosensitizers have proven ineffective. “The local therapy option depends on the extent of disease in the brain. With a single lesion, it’s usually surgery with or without stereotactic radiosurgery or whole-brain radiotherapy, and in a lesion that is not surgically amenable to resection, stereotactic radiosurgery with or without whole-brain radiotherapy,” Dr. Winer said. “For patients with more than a single metastasis but with somewhat

stereotactic radiosurgery has not been shown to improve survival, but it can extend the time before disease in the brain progresses, he explained. The problem with whole-brain radiotherapy is that it can lead to late toxicity, including a decline in cognitive function. Such symptoms can be quite troubling to patients, but they need to be balanced against the risk of uncontrolled CNS disease. “My experience is that patients do not want to receive whole-brain radiotherapy upfront, and they delay this as long as possible,” he added.

Therapeutic Agents Patients with HER2-positive disease who receive local therapy as the primary approach to CNS metastasis often develop progression over the ensuing months and years. A myriad of small trials and case reports suggest that several agents can be effective in treating brain metastases, including some that would not appear to penetrate the blood-brain barrier. Theoretically, lapatinib (Tykerb), a small-molecule tyrosine kinase inhibitor, should penetrate the CNS, and demonstrated some promise in small early trials. In a larger phase II trial the response rate was only 6%

and median time to progression was 2.4 months.1 The CNS response rate to lapatinib monotherapy was similar to the systemic response rate in patients previously treated with trastuzumab (Herceptin). “Responses occurred, but they were by no means frequent,” Dr. Winer noted. In combination with capecitabine, the data for lapatinib are more encouraging, and this has become the single most-evaluated regimen for CNS relapse. In patients with refractory disease, the CNS response rate has ranged from approximately 15% to 30%, with time to progression of 3.6 to 5.5 months in various studies. “If you need to treat the patient with progression in the brain after prior radiotherapy, and the patient has not received capecitabine, that [capecitabine/lapatinib] is the regimen to consider,” Dr. Winer advised. There is some indication that patients who have not received radiotherapy may respond better to this approach. This was shown in the French LANDSCAPE trial of 43 patients, in which upfront treatment with capecitabine/lapatinib yielded a 67% response rate and a median time to progression of 5.5 months, which are significantly better outcomes than seen in other studies of this combination.2 It is unknown whether this is a result of patient selection, or the possibility that disease that has not been irradiated is more sensitive to this regimen. “It raises the possibility of using systemic therapy upfront in highly selected patients, though we are not sure which patients these would be,” he added. “For most of them, you would treat with local therapy first.” A number of agents are in development for brain metastasis, with newer anti-HER2 agents and PI3K inhibitors high on the list.

Current Approach Dr. Winer summarized what he considers the best approach to HER2positive CNS disease at the current time. Initial treatment is local therapy in the vast majority of patients. For patients with limited disease, surgery or stereotactic radiosurgery, with or without whole-brain radiotherapy, is recommended. For those with extensive disease, whole-brain radiotherapy, continued on page 102

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Expert’s Corner CNS Metastasis continued from page 101

with stereotactic radiosurgery for larger lesions, is advised. “In my opinion, there is no need to change systemic therapy in a patient for whom it is working,” he said. “Systemic therapy alone is acceptable in highly selected patients. The patient who did well on trastuzumab and who develops brain metastasis can stay on it. There is no need to switch to lapatinib at that point.” Upon progression, localized disease can sometimes still be treated with local therapy. Systemic therapy, outside of a clinical trial, usually consists of capecitabine/lapatinib, but other regimens can also be effective, he said. Dr. Winer cautioned against “treating ev-

ery lesion just because it’s there,” noting that many small lesions revealed by imaging can remain quiescent for an extended period, and some represent radionecrosis. In the future, research may explain why the brain is a common site of disease spread for patients with HER2positive breast cancer, and offer a means

of better treatment, he concluded. n Disclosure: Dr. Winer reported no potential conflicts of interest.

References 1. Lin NU, Diera V, Paul D, et al: Multicenter phase IIS:6.75” study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Can-

cer Res 15:1452-1459, 2009. 2. Bachelot TD, Romieu G, Campone M, et al: LANDSCAPE: An FNCLCC phase II study with lapatininb and capecitabine in patients with brain metastases from HER2-positive metastatic breast cancer before whole-brain radiotherapy. J Clin Oncol 29(15 suppl): Abstract 509, 2011.

COMETRIQ™ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC).

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COMETRIQ™ inhibits the activity of tyrosine kinases including RET, MET and VEGFRs. These receptor tyrosine kinases are involved in both normal cellular function and in pathologic processes such as oncogenesis, metastasis, tumor angiogenesis, and maintenance of the tumor microenvironment. IMPORTANT SAFETY INFORMATION WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE • Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. • Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and 1 GI fistula was fatal (<1%). Non-GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo

(3% vs 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs 3% and arterial thromboembolism: 2% vs 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop an acute myocardial infarction or any other clinically significant arterial thromboembolic complication. Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension (modified JNC criteria stage 1 or 2 hypertension identified in 61% of COMETRIQ-treated patients compared with 30% of placebo, respectively). Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. Osteonecrosis of the Jaw: Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery.

B:1

T:1

Supportive Care

Music Therapy Yields Positive Effects on Coping Skills, Social Integration, and Family Environment for Young Patients With Cancer when participating with a board-certified music therapist in a therapeutic music protocolS:6.75” that includes writing song lyrics and producing videos. The study’s findings were published recent-

ly in Cancer and provide evidence supporting the use of a music-based intervention delivered by music therapists to help patients with cancer cope with challenging treatments.1

SMART Study Sheri L. Robb, PhD, MT-BC and Joan E. Haase, PhD, RN, FAAN, of Indiana University led the research team. The continued on page 104

PROD

collaborative multisite study has found that teens and young adults undergoing stem cell transplantation as part of cancer treatment gain coping skills and resilience-related outcomes

COMETRIQ™ demonstrated significant efficacy in a phase 3 trial (N=330) in metastatic MTC patients with radiographically confirmed disease progression.*

median

months

11.2

ED AE/AS AD

4.0

COMETRIQ™ (n=219)

Progression-free survival (PFS)

> Significantly prolonged progression-free survival vs placebo (HR=0.28; 95% CI: 0.19, 0.40; P<0.0001) > COMETRIQ™ demonstrated a greater than 2.5-fold increase in median PFS vs placebo —Median PFS was 11.2 months with COMETRIQ™ vs 4.0 months with placebo > Partial response rate was 27% with COMETRIQ™ vs 0% with placebo (P<0.0001) —Median duration of objective response was 14.7 months (95% CI: 11.1, 19.3) > Adverse reactions occurring in ≥25% of patients treated with COMETRIQ™ and more frequently than with placebo (≥5% between-arm difference) in order of decreasing frequency were: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation; the most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased ALP, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia

TC QC PG

Adverse Reactions: Adverse reactions which occurred in ≥25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥5% included, in order of decreasing frequency: diarrhea, stomatitis, PPES, decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). In clinical trials, the dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo.

B:11.25”

S:9.75”

Please see brief summary of full Prescribing Information on next page.

COMETRIQ.com

DATE

SIGNOFF

You are encouraged to report negative side effects of prescription drugs to the FDA. Visit fda.gov/medwatch or call 1-800-FDA-1088.

Disk release

Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. Palmar-Plantar Erythrodysesthesia Syndrome (PPES): PPES occurred in 50% of patients treated with COMETRIQ and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. Proteinuria: Proteinuria was observed in 4 (2%) patients receiving COMETRIQ, including 1 with nephrotic syndrome. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): RPLS occurred in 1 (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion, or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

T:10.25”

*Results of the international, multicenter, randomized, double-blind EXAM study in patients (N=330) with progressive, metastatic MTC. Primary endpoint: PFS; secondary endpoints: objective response rate and overall survival (OS). OS data are not yet mature.

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Cosmos Commu

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Supportive Care Music Therapy continued from page 103

SMART study, “Stories and Music for Adolescent and Young Adult Resilience During Transplant,” involved 11 sites with 49 board-certified music therapists supporting the protocol. The study included 113 patients aged 11 to 24 years who were undergoing stem cell transplant treat-

Sheri L. Robb, PhD, MT-BC

Joan E. Haase, PhD, RN, FAAN

COMETRIQ™ (cabozantinib) capsules BRIEF SUMMARY OF PRESCRIBING INFORMATION Initial U.S. Approval: 2012 WARNING: PERFORATIONS AND FISTULAS, and HEMORRHAGE See full prescribing information for complete boxed warning. Perforations and Fistulas: Gastrointestinal perforations occurred in 3% and fistula formation in 1% of COMETRIQ-treated patients. Discontinue COMETRIQ in patients with perforation or fistula. (5.1) Hemorrhage: Severe, sometimes fatal, hemorrhage including hemoptysis and gastrointestinal hemorrhage occurred in 3% of COMETRIQ-treated patients. Monitor patients for signs and symptoms of bleeding. Do not administer COMETRIQ to patients with severe hemorrhage. (5.2) 1. INDICATIONS AND USAGE COMETRIQ is indicated for the treatment of patients with progressive, metastatic medullary thyroid cancer (MTC). 2. DOSAGE AND ADMINISTRATION 2.1 Recommended Dose The recommended daily dose of COMETRIQ is 140 mg (one 80-mg and three 20-mg capsules). Do not administer COMETRIQ with food. Instruct patients not to eat for at least 2 hours before and at least 1 hour after taking COMETRIQ. Continue treatment until disease progression or unacceptable toxicity occurs. Swallow COMETRIQ capsules whole. Do not open COMETRIQ capsules. Do not take a missed dose within 12 hours of the next dose. Do not ingest foods (e.g., grapefruit, grapefruit juice) or nutritional supplements that are known to inhibit cytochrome P450 during COMETRIQ. 2.2 Dosage Adjustments: For Adverse Reactions : Withhold COMETRIQ for NCI CTCAE Grade 4 hematologic adverse reactions, Grade 3 or greater non-hematologic adverse reactions or intolerable Grade 2 adverse reactions. Upon resolution/improvement of the adverse reaction (i.e., return to baseline or resolution to Grade 1), reduce the dose as follows: • If previously receiving 140 mg daily dose, resume treatment at 100 mg daily (one 80-mg and one 20-mg capsule) • If previously receiving 100 mg daily dose, resume treatment at 60 mg daily (three 20-mg capsules) • If previously receiving 60 mg daily dose, resume at 60 mg if tolerated, otherwise, discontinue COMETRIQ Permanently discontinue COMETRIQ for any of the following: development of visceral perforation or fistula formation; severe hemorrhage; serious arterial thromboembolic event (e.g., myocardial infarction, cerebral infarction); nephrotic syndrome; malignant hypertension, hypertensive crisis, persistent uncontrolled hypertension despite optimal medical management; osteonecrosis of the jaw; reversible posterior leukoencephalopathy syndrome. In Patients with Hepatic Impairment : COMETRIQ is not recommended for use in patients with moderate and severe hepatic impairment. In Patients Taking CYP3A4 Inhibitors : Avoid the use of concomitant strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) in patients receiving COMETRIQ. For patients who require treatment with a strong CYP3A4 inhibitor, reduce the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 100 mg daily or from 100 mg to 60 mg daily). Resume the dose that was used prior to initiating the CYP3A4 inhibitor 2 to 3 days after discontinuation of the strong inhibitor. In Patients Taking Strong CYP3A4 Inducers : Avoid the chronic use of concomitant strong CYP3A4 inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) if alternative therapy is available. Do not ingest foods or nutritional supplements (e.g., St. John’s Wort (Hypericum perforatum)) that are known to induce cytochrome P450 activity. For patients who require treatment with a strong CYP3A4 inducer, increase the daily COMETRIQ dose by 40 mg (for example, from 140 mg to 180 mg daily or from 100 mg to 140 mg daily) as tolerated. Resume the dose that was used prior to initiating the CYP3A4 inducer 2 to 3 days after discontinuation of the strong inducer. The daily dose of COMETRIQ should not exceed 180 mg. 4. CONTRAINDICATIONS None 5. WARNINGS AND PRECAUTIONS 5.1 Perforations and Fistulas: Gastrointestinal (GI) perforations and fistulas were reported in 3% and 1% of COMETRIQ-treated patients, respectively. All were serious and one GI fistula was fatal (< 1%). Non GI fistulas including tracheal/esophageal were reported in 4% of COMETRIQ-treated patients. Two (1%) of these were fatal. Monitor patients for symptoms of perforations and fistulas. Discontinue COMETRIQ in patients who experience a perforation or a fistula. 5.2 Hemorrhage: Serious and sometimes fatal hemorrhage occurred with COMETRIQ. The incidence of Grade ≥3 hemorrhagic events was higher in COMETRIQ-treated patients compared with placebo (3% vs. 1%). Do not administer COMETRIQ to patients with a recent history of hemorrhage or hemoptysis. 5.3 Thrombotic Events: COMETRIQ treatment results in an increased incidence of thrombotic events (venous thromboembolism: 6% vs. 3% and arterial thromboembolism: 2% vs. 0% in COMETRIQ-treated and placebo-treated patients, respectively). Discontinue COMETRIQ in patients who develop

ments for cancer. Patients were randomly assigned to be part of a Therapeutic Music Video intervention group or to be part of a control group that received audiobooks. Participants completed six sessions over 3 weeks. The music therapists’ role included helping patients identify

an acute myocardial infarction or any other clinically significant arterial thromboembolic complication 5.4 Wound Complications: Wound complications have been reported with COMETRIQ. Stop treatment with COMETRIQ at least 28 days prior to scheduled surgery. Resume COMETRIQ therapy after surgery based on clinical judgment of adequate wound healing. Withhold COMETRIQ in patients with dehiscence or wound healing complications requiring medical intervention. 5.5 Hypertension: COMETRIQ treatment results in an increased incidence of treatment-emergent hypertension with Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (modified JNC criteria) stage 1 or 2 hypertension identified in 61% in COMETRIQ-treated patients compared with 30% of placebo-treated patients in the randomized trial. Monitor blood pressure prior to initiation and regularly during COMETRIQ treatment. Withhold COMETRIQ for hypertension that is not adequately controlled with medical management; when controlled, resume COMETRIQ at a reduced dose. Discontinue COMETRIQ for severe hypertension that cannot be controlled with anti-hypertensive therapy. 5.6 Osteonecrosis of the Jaw (ONJ): Osteonecrosis of the jaw (ONJ) occurred in 1% of COMETRIQ-treated patients. ONJ can manifest as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration or erosion, persistent jaw pain or slow healing of the mouth or jaw after dental surgery. Perform an oral examination prior to initiation of COMETRIQ and periodically during COMETRIQ therapy. Advise patients regarding good oral hygiene practices. For invasive dental procedures, withhold COMETRIQ treatment for at least 28 days prior to scheduled surgery, if possible. 5.7 Palmar-Plantar Erythrodysesthesia Syndrome: Palmar-plantar erythrodysesthesia syndrome (PPES) occurred in 50% of patients treated with cabozantinib and was severe (≥ Grade 3) in 13% of patients. Withhold COMETRIQ in patients who develop intolerable Grade 2 PPES or Grade 3-4 PPES until improvement to Grade 1; resume COMETRIQ at a reduced dose. 5.8 Proteinuria: Proteinuria was observed in 4 (2%) of patients receiving COMETRIQ, including one with nephrotic syndrome, as compared to none of the patients receiving placebo. Monitor urine protein regularly during COMETRIQ treatment. Discontinue COMETRIQ in patients who develop nephrotic syndrome. 5.9 Reversible Posterior Leukoencephalopathy Syndrome: Reversible Posterior Leukoencephalopathy Syndrome (RPLS), a syndrome of subcortical vasogenic edema diagnosed by characteristic finding on MRI, occurred in one (<1%) patient. Perform an evaluation for RPLS in any patient presenting with seizures, headache, visual disturbances, confusion or altered mental function. Discontinue COMETRIQ in patients who develop RPLS. 5.10 Drug Interactions: Avoid administration of COMETRIQ with agents that are strong CYP3A4 inducers or inhibitors. 5.11 Hepatic Impairment: COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment. 5.12 Embryo-fetal Toxicity: COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. 6. ADVERSE REACTIONS 6.1 Clinical Trial Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The safety of COMETRIQ was evaluated in 330 patients with progressive medullary thyroid cancer randomized to receive 140 mg COMETRIQ (n = 214) or placebo (n = 109) administered daily until disease progression or intolerable toxicity in a randomized, double-blind, controlled trial. The data described below reflect a median exposure to COMETRIQ for 204 days. The population exposed to COMETRIQ was 70% male, 90% white, and had a median age of 55 years. Adverse reactions which occurred in ≥ 25% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 5% included, in order of decreasing frequency: diarrhea, stomatitis, palmar-plantar erythrodysesthesia syndrome (PPES), decreased weight, decreased appetite, nausea, fatigue, oral pain, hair color changes, dysgeusia, hypertension, abdominal pain, and constipation. The most common laboratory abnormalities (>25%) were increased AST, increased ALT, lymphopenia, increased alkaline phosphatase, hypocalcemia, neutropenia, thrombocytopenia, hypophosphatemia, and hyperbilirubinemia. Grade 3-4 adverse reactions and laboratory abnormalities which occurred in ≥ 5% of COMETRIQ-treated patients occurring more frequently in the COMETRIQ arm with a between-arm difference of ≥ 2% included, in order of decreasing frequency; diarrhea, PPES, lymphopenia hypocalcemia, fatigue hypertension, asthenia, increased ALT, decreased weight, stomatitis, and decreased appetite (see Table 1, Table 2). Fatal adverse reactions occurred in 6% of patients receiving COMETRIQ and resulted from hemorrhage, pneumonia, septicemia, fistulas, cardiac arrest, respiratory failure, and unspecified death. Fatal adverse reactions occurred in 5% of patients receiving

and write about what was important to them through writing song lyrics, while also supporting their efforts to connect with health-care providers, peers, and family through the process of creating their music video. While the intervention tested in this study requires delivery from a credentialed music therapist, it fosters involvement from patients’ entire team.

placebo and resulted from septicemia, pneumonia, and general deterioration. The dose was reduced in 79% of patients receiving COMETRIQ compared to 9% of patients receiving placebo. The median number of dosing delays was one in patients receiving COMETRIQ compared to none in patients receiving placebo. Adverse reactions led to study treatment discontinuation in 16% of patients receiving COMETRIQ and in 8% of patients receiving placebo. The most frequent adverse reactions leading to permanent discontinuation in patients treated with COMETRIQ were: hypocalcemia, increased lipase, PPES, diarrhea, fatigue, hypertension, nausea, pancreatitis, tracheal fistula formation and vomiting. Increased levels of thyroid stimulating hormone (TSH) were observed in 57% of patients receiving COMETRIQ after the first dose compared to 19% of patients receiving placebo (regardless of baseline value). Ninety-two percent (92%) of patients on the COMETRIQ arm had a prior thyroidectomy, and 89% were taking thyroid hormone replacement prior to the first dose. Table 1. Per-Patient Incidence of Selected Adverse Reactions in Protocol XL184-301 Occurring at a Higher Incidence in COMETRIQ-Treated Patients [Between Arm Difference of ≥ 5% (All Grades)1 or ≥ 2% (Grades 3-4)] Cabozantinib Placebo (n=214) (n=109) MedDRA System Organ Class/ Preferred Terms All Grades All Grades Grades 3-4 Grades 3-4 GASTROINTESTINAL DISORDERS DIARRHEA 63 16 33 2 STOMATITIS2 51 5 6 0 NAUSEA 43 1 21 0 ORAL PAIN3 36 2 6 0 CONSTIPATION 27 0 6 0 ABDOMINAL PAIN4 27 3 13 1 VOMITING 24 2 2 1 DYSPHAGIA 13 4 6 1 DYSPEPSIA 11 0 0 0 HEMORRHOIDS 9 0 3 0 GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS FATIGUE 41 9 28 3 ASTHENIA 21 6 15 1 INVESTIGATIONS DECREASED WEIGHT 48 5 10 0 METABOLISM AND NUTRITION DISORDERS DECREASED APPETITE 46 5 16 1 DEHYDRATION 7 2 2 1 MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS ARTHRALGIA 14 1 7 0 MUSCLE SPASMS 12 0 5 0 MUSCULOSKELETAL CHEST PAIN 9 1 4 0 NERVOUS SYSTEM DISORDERS DYSGEUSIA 34 0 6 0 HEADACHE 18 0 8 0 DIZZINESS 14 0 7 0 PARESTHESIA 7 0 2 0 PERIPHERAL SENSORY 7 0 0 0 NEUROPATHY PERIPHERAL NEUROPATHY 5 0 0 0 PSYCHIATRIC DISORDERS ANXIETY 9 0 2 0 RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS DYSPHONIA 20 0 9 0 SKIN AND SUBCUTANEOUS TISSUE DISORDERS PPES5 50 13 2 0 HAIR COLOR CHANGES/ 34 0 1 0 DEPIGMENTATION, GRAYING RASH 19 1 10 0 DRY SKIN 19 0 3 0 ALOPECIA 16 0 2 0 ERYTHEMA 11 1 2 0 HYPERKERATOSIS 7 0 0 0 VASCULAR DISORDERS HYPERTENSION 33 8 4 0 HYPOTENSION 7 1 0 0

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Supportive Care Outcomes Were Positive

protective factors helped adolescents and young adults to be resilient in the face of cancer treatments. These factors included spiritual beliefs and practices, having a strong family environment characterized by adaptability, cohesion, and positive communication, and feeling socially connected and supported by friends and healthcare providers.

After the intervention, the Therapeutic Music Video group reported significantly better courageous coping. One hundred days after stem cell transplant the Therapeutic Music Video group reported significantly better social integration and family environment. The investigators found that several

Table 2. Percent-Patient Incidence of Laboratory Abnormalities Occurring at a Higher Incidence in COMETRIQ-Treated Patients in Protocol XL184-301 [Between Arm Difference of ≥ 5% (All Grades) or ≥ 2% (Grades 3-4)] COMETRIQ (n=214) Placebo (n=109) ADVERSE EVENT All Grade All Grade Grades 3-4 Grades 3-4 CHEMISTRIES INCREASED AST 86 3 35 2 INCREASED ALT 86 6 41 2 INCREASED ALP 52 3 35 3 HYPOCALCEMIA 52 12 27 3 HYPOPHOSPHATEMIA 28 3 10 1 HYPERBILIRUBINEMIA 25 2 14 5 HYPOMAGNESEMIA 19 1 4 0 HYPOKALEMIA 18 4 9 3 HYPONATREMIA 10 2 5 0 HEMATOLOGIC LYMPHOPENIA 53 16 51 11 NEUTROPENIA 35 3 15 2 THROMBOCYTOPENIA 35 0 4 3 ALT, alanine aminotransferase; ALP, alkaline phosphatase; AST, aspartate aminotransferase Nearly all COMETRIQ-treated patients (96% vs. 84% placebo) experienced elevated blood pressure and there was a doubling in the incidence of overt hypertension in COMETRIQ-treated patients over placebo-treated patients (61% vs. 30%) according to modified Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC) staging criteria. No patients developed malignant hypertension. National Cancer Institute Common Terminology Criteria for Adverse Events Version 3.0 Includes the following terms: stomatitis, aphthous stomatitis, mouth ulceration, mucosal inflammation 3 Includes the following terms: oral pain, oropharyngeal pain, glossitis, burning mouth syndrome, glossodynia 4 Includes the following terms: abdominal pain, abdominal pain lower, abdominal pain upper, abdominal rigidity, abdominal tenderness, esophageal pain 5 Palmar-plantar erythrodysesthesia syndrome 1

Table 3. Per-Patient Incidence of Hypertension in Protocol XL184-301 COMETRIQ Placebo HYPERTENSION, JNC1 STAGE N=2113 (%) N=1073 (%) Normal: Grade 0: Systolic 4 15 < 120 mmHg and Diastolic < 80 mmHg Pre-hypertension: Systolic 34 54 ≥ 120 mmHg or Diastolic ≥ 80 mmHg Stage 1: Systolic ≥ 140 mmHg 46 25 or Diastolic ≥ 90 mmHg Stage 2: Systolic ≥ 160 mmHg 15 5 or Diastolic ≥ 100 mmHg Malignant: Diastolic 0 0 ≥ 120 mmHg Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure, JAMA 2003: 289:2560. Criteria applied were modified, as multiple readings were not available per timepoint, and therefore not averaged. 2 Subjects classified by highest category based on all recorded blood pressure readings beginning after the first dose through 30 days after last dose. 3 Subjects with at least two blood pressure measurements after the first dose 1

7. DRUG INTERACTIONS 7.1 Effect of CYP3A4 Inhibitors: Administration of a strong CYP3A4 inhibitor, ketoconazole (400 mg daily for 27 days) to healthy subjects increased singledose plasma cabozantinib exposure (AUC0-inf) by 38%. Avoid taking a strong CYP3A4 inhibitor (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole) when taking COMETRIQ. 7.2 Effect of CYP3A4 Inducers: Administration of a strong CYP3A4 inducer, rifampin (600 mg daily for 31 days) to healthy subjects decreased singledose plasma cabozantinib exposure (AUC0-inf) by 77%. Avoid chronic coadministration of strong CYP3A4 inducers (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutine, rifapentin, phenobarbital, St. John’s Wort) with COMETRIQ. 8. USE IN SPECIFIC POPULATIONS 8.1 Pregnancy: Pregnancy Category D. Risk Summary : Based on its mechanism of action, COMETRIQ can cause fetal harm when administered to a pregnant woman. Cabozantinib was embryolethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be

“These protective factors influence the ways adolescents and young adults cope, gain hope, and find meaning in the midst of their cancer journey,” said Dr. Haase. “Adolescents and young adults who are resilient have the ability to rise above their illness, gain a sense of mastery and confidence in how they have dealt with their cancer, and dem-

apprised of the potential hazard to the fetus. Animal Data: In an embryo-fetal development study in which pregnant rats were administered daily doses of cabozantinib during organogenesis, increased loss of pregnancy compared to controls was observed at doses as low as 0.03 mg/kg (less than 1% of the human exposure by AUC at the recommended dose). Findings included delayed ossifications and skeletal variations at doses equal to or greater than 0.01 mg/kg/day (approximately 0.03% of the human exposure by AUC at the recommended dose). In pregnant rabbits administered cabozantinib daily during organogenesis there were findings of visceral malformations and variations including reduced splenic size and missing lung lobe at 3 mg/kg (approximately 11% of the human exposure by AUC at the recommended dose). 8.2 Nursing Mothers: It is unknown whether cabozantinib or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from COMETRIQ, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.3 Pediatric Use: The safety and effectiveness of COMETRIQ in pediatric patients have not been studied. 8.4 Geriatric Use: Clinical studies of COMETRIQ did not include sufficient numbers of patients aged 65 years and over to determine whether they respond differently from younger patients. 8.5 Females and Males of Reproductive Potential: Contraception: Use effective contraception during treatment with COMETRIQ and up to 4 months after completion of therapy. Infertility : There are no data on the effect of COMETRIQ on human fertility. Cabozantinib impaired male and female fertility in animal studies. 8.6 Hepatic Impairment: Cabozantinib pharmacokinetics has not been studied in patients with hepatic impairment. There are limited data in patients with liver impairment (serum bilirubin greater than 1.5 times the upper limit of normal). COMETRIQ is not recommended for use in patients with moderate or severe hepatic impairment, as safety and efficacy have not been established. 8.7 Renal Impairment: No dose adjustment is recommended for patients with mild or moderate renal impairment. There is no experience with COMETRIQ in patients with severe renal impairment. 10. OVERDOSAGE One case of overdosage was reported in a patient who inadvertently took twice the intended dose (200 mg daily) for nine days. The patient suffered Grade 3 memory impairment, Grade 3 mental status changes, Grade 3 cognitive disturbance, Grade 2 weight loss, and Grade 1 increase in BUN. The extent of recovery was not documented. Distributed by Exelixis, Inc. 12/2012 © 2012 Exelixis, Inc. 210 East Grand Avenue, So. San Francisco, CA 94080 Printed in USA 12/12 [24523]

onstrate a desire to reach out and help others,” she added.

Parent Communication Component a Next Step When the investigators interviewed the patients’ parents, they found that the videos gave parents insights into their children’s cancer experiences; however, parents needed help to initiate and sustain important conversations about messages shared through their children’s videos. To address this need, the study team has received funding from the National Institutes of Health and the Children’s Oncology Group to examine the potential benefits of adding a parent communication component to their intervention.

Next Steps The study’s findings provide evidence supporting the use of a music-based intervention delivered by a music therapist to help adolescents and young adults positively cope with high-risk, high-intensity cancer treatments. The authors and the American Music Therapy Association advocate that nurses and other interdisciplinary team members collaborate with music therapists to identify patients/families who might benefit from this specific intervention, and use opportunities for involvement in the intervention to connect with their patients. “The availability of music therapy services from a board-certified music therapist in the United States has become more widespread, and through studies like this one, we hope to see increased availability and access to this important allied health service,” said Dr. Robb. She added that one challenge in health care is “making sure that research findings from studies such as ours are used to inform health-care practices and service delivery. One of our team’s next steps is to disseminate findings, train professional music therapists on this intervention, and then conduct an implementation study to examine how the intervention may change as it moves into the standard care setting and whether, in the presence of these changes, patient benefits are maintained.” For more information about music therapy for patients with cancer, visit the American Music Therapy Association at info@musictherapy.org. n Reference 1. Robb SL, Burns DS, Haase J, et al: Randomized clinical trial of therapeutic music video intervention for resilience outcomes in adolescents/young adults undergoing hematopoietic stem cell transplant: A report from the Children’s Oncology Group. Cancer. January 27, 2014 (early release online).

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JCO Spotlight Supportive Care

Cognitive-Behavioral Therapy Plus Hypnosis Controls Fatigue in Breast Cancer Patients Receiving Radiotherapy By Matthew Stenger

n a study reported in the Journal of Clinical Oncology,1 Guy H. Montgomery, PhD, Icahn School of Medicine at Mount Sinai, New York, and colleagues found that an intervention consisting of cognitive-behavioral therapy plus hypnosis produced better control of fatigue than supportive meetings with trained interventionists for women undergoing radiotherapy for breast cancer.

Study Details In the study, 200 consecutive patients with breast cancer at Mount Sinai Medical Center, New York, who were scheduled for a 6-week course of external-beam radiotherapy were randomly assigned to receive cognitivebehavioral therapy/ hypnosis with trained clinical psychologist interventionists (n = 100) or interventionist attention without cognitive-behavioral therapy/hypnosis (n = 100) during the period of radiotherapy. In both groups, the initial intervention session, scheduled for the patients’ radiotherapy verification day, lasted for 30 minutes. Patients met with an interventionist twice weekly during the course of radiotherapy, with each session lasting 15 minutes. The final intervention session, scheduled for the penultimate day of radiotherapy, lasted for 30 minutes. For control group patients, the interventionist did not lead the patient in cognitive-behavioral techniques of imagery, relaxation, or evaluation of thought processes or in discussion; the interventionist allowed the patient to direct the

flow of the conversation and provided supportive/empathic comments. Fatigue was measured using the Functional Assessment of Chronic Illness Therapy (FACIT)-Fatigue subscale, the primary outcome measure, and visual analog scales for fatigue and muscle weakness at baseline, end of radiotherapy, and at 4 weeks and 6 months after radiotherapy. Comparisons were made in the intent-to-treat population and were adjusted for multiple comparisons. The cognitive-behavioral therapy/ hypnosis group and the control group were balanced for age (mean, 56 years in

41 on a standardized fidelity checklist). There were no significant differences between groups in FACIT-Fatigue score or visual analog scores for fatigue or muscle weakness at baseline.

Reduced Fatigue and Muscle Weakness The cognitive-behavioral therapy/ hypnosis group had significantly lower levels of fatigue as measured by the FACIT-Fatigue scale at the end of radiotherapy (z = 6.73, P < .001), at 4-week followup (z = 6.98, P < .001), and at 6-month follow-up (z = 7.99, P < .001). This group

The results support [cognitive-behavioral therapy plus hypnosis] as an evidence-based intervention to control fatigue in patients undergoing radiotherapy for breast cancer. —Guy H. Montgomery, PhD, and colleagues

both), education (college degree or higher for 66% in both), marital status (53% and 51% currently married), race (69% and 66% white), receipt of chemotherapy before radiotherapy (43% and 38%), Karnofsky performance score (mean, 94 in both), adjuvant hormone treatment (tamoxifen in 30% and 31%, aromatase inhibitor in 44% and 42%), disease stage (0 in 29% and 32%, I in 39% and 38%, II in 21% and 19%, and III in 11% in both), and total radiation dose (mean, 62 Gy in both). Groups were also balanced for neuroticism (mean scores of 21 and 20 on the NEO Neuroticism Subscale) and treatment credibility (mean scores of 43 and

also had significantly reduced fatigue according to visual analog scale scores at the end of treatment (z = 5.81, P < .001) and at 6 months (z = 4.56, P < .001), with a trend toward reduction at 4 weeks (z =

2.38, P < .07). Muscle weakness visual analog scale scores were significantly lower in the cognitive-behavioral therapy/hypnosis group at end of treatment (z = 9.30, P < .001) and at 6 months (z = 3.10, < .02), but not at 4 weeks (z = 2.1, P < .13). The investigators concluded, “The results support [cognitive-behavioral therapy plus hypnosis] as an evidencebased intervention to control fatigue in patients undergoing radiotherapy for breast cancer. [Cognitive-behavioral therapy plus hypnosis] is noninvasive, has no adverse effects, and its beneficial effects persist long after the last intervention session. [Cognitive-behavioral therapy plus hypnosis] seems to be a candidate for future dissemination and implementation.” n

Disclosure: The study was supported by National Cancer Institute and American Cancer Society grants. The study authors reported no potential conflicts of interest.

Reference 1. Montgomery G, Daniel D, Kangas M, et al: Randomized controlled trial of a cognitive-behavioral therapy plus hypnosis intervention to control fatigue in patients undergoing radiotherapy for breast cancer. J Clin Oncol 32:557-563, 2014.

Cognitive-Behavioral Therapy and Fatigue ■■ Cognitive-behavioral therapy plus hypnosis was associated with significantly reduced fatigue on the FACIT-Fatigue scale at the end of radiotherapy, at 4 weeks, and at 6 months as well as on a visual analog scale at the end of therapy and at 6 months. ■■ Cognitive-behavioral therapy/hypnosis was associated with significantly reduced muscle weakness on a visual analog scale at the end of radiotherapy and at 6 months.

Don’t Miss These Important Reports in This Issue of The ASCO Post

Karen Lisa Smith, MD, MPH, and Vered Stearns, MD, on adjuvant therapy for breast cancer see page 76

David B. Solit, MD, on the genomes of exceptional responders see page 89

Richard J. Boxer, MD, FACS, on telemedicine in cancer screening and outreach see page 92

Donald Garrity, RD, CDN, on the ketogenic diet in cancer control see page 97

Eric P. Winer, MD, on CNS metastasis in patients with HER2-positive breast cancer see page 101

Visit The ASCO Post online at ASCOPost.com

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Patient’s Corner

Cancer Has Allowed Me to Put My Goals First

Getting a diagnosis of uterine cancer helped me realize the importance of taking control of my life. By Sharon Timins, as told to Jo Cavallo

espite my family history of cancer—my father had colorectal cancer, his father had gallbladder cancer, and my father’s mother died of what was believed to be uterine cancer— when I complained to my gynecologist about postmenopausal bleeding in the spring of 2011, I was told not to worry about it. By the next year, after the bleeding had resumed, an ultrasound picked up a uterine polyp that looked benign. A biopsy from a follow-up dilation and curettage procedure found the presence of cancer cells, but the original site was unclear. After numerous tests (including a colonoscopy and a CT scan) turned up nothing, my doctor recommended that I have a complete hysterectomy, and that’s when it was determined that the polyp was in fact malignant. The diagnosis was carcinosarcoma of the uterus, also known as malignant mixed Mullerian tumor, with lymphovascular invasion. Biopsies of 72 lymph nodes taken from the surrounding area were clear of malignancy, and my cancer was staged as IA. My oncologist recommended six rounds of adjuvant carboplatin and paclitaxel, and my radiologist recommended both vaginal brachytherapy and external-beam radiation therapy.

Second and Third Opinions Being told by my gynecologist that nothing was wrong after I first began

having symptoms of uterine cancer had taught me the lesson of being proactive in my health care. I was determined to be fully informed before making any medical decisions, so I decided to seek out a second opinion. The second evaluation of the pathology report determined that I didn’t have carcinosarcoma after all

faced with questioning the need for both internal and external radiation if I didn’t have carcinosarcoma, but did have lymphovascular invasion. My radiologist said I should have—what else?—a second opinion. The consulting radiologist recommended that I only have vaginal brachytherapy.

Hearing that you have cancer can be daunting. For some, it may be easier to accept what is being advised, no questions asked. But when you have cancer, you’re in for the fight of your life. You have to take ownership of your fate and not give up. Your very life may depend on it. —Sharon Timins

and that I didn’t have lymphovascular invasion. Because my treatment protocol was entirely based on my original diagnosis and I wanted to be sure of getting treatment that would give me the best chance for a cure, I sought a third opinion. The third evaluation concurred with the second that I didn’t have malignant mixed Mullerian tumor— good news—but found that I did have lymphovascular invasion. The process was maddening because now I was

After all the surgery, chemotherapy, and radiation therapy, I don’t know whether I’m actually cancer-free, but I’m happy to say there have been no signs of any errant cancer cells making their way throughout my body.

Putting Yourself First Always an avid bicyclist, after my cancer diagnosis I became even more passionate about the sport. I joined a LIVESTRONG program at my local YMCA, took spinning classes to

build up my strength and endurance, and recently led a 65-mile bicycle ride across my home state of Connecticut. I’m now in the best physical and mental shape of my life and feel better prepared to face whatever might happen next. Before cancer paid me a visit, my family and work always came first. Now, cancer has allowed me to put my goals first.

Taking Ownership of Your Fate I was fortunate to have an oncology team that encouraged me to have a second and even a third opinion after my diagnosis, but I know other patients may not feel comfortable questioning their oncologist’s recommendations. All patients with cancer have a right to pursue multiple opinions if that is what it takes to make them feel better prepared to face the challenge of beating this disease. Hearing that you have cancer can be daunting. For some, it may be easier to accept what is being advised, no questions asked. But when you have cancer, you’re in for the fight of your life. You have to take ownership of your fate and not give up. Your very life may depend on it. n Sharon Timins is a vice president of an insurance company. She lives in South Windsor, Conneticut.

Historical Timeline Major Cancer Milestones in History, From ASCO’s CancerProgress.Net Visit CancerProgress.Net to View the Interactive Timeline

1949 First chemotherapy drug approved for cancer

o help tell the story of progress against cancer, ASCO launched CancerProgress.Net in 2011. The site is intended as a resource for media, policymakers, oncologists, advocates, and the public. One central feature of the site is an interactive timeline of major milestones in cancer treatment, prevention, and detection, covering 18 different cancer types. The site was developed under the guidance of an ASCO editorial board of expert oncologists.

Cancer chemotherapy got a start at New Haven Hospital when two Yale scientists, Alfred A. Gilman (left) and Louis Goodman (right), studying nitrogen mustard, found the deadly gas that had been used in World War I could shrink tumors. Source: NIH.

Following results of clinical trials conducted in 1946 and 1947, nitrogen mustard is approved by the U.S. Food and Drug Administration (FDA) for the treatment of Hodgkin lymphoma. Nitrogen mustard, also known as mustard gas and stockpiled as a weapon in World War II, kills cancer cells by modifying their DNA. Its discovery spurs rapid advancements in chemotherapy, and the drug still receives some use today in combination chemotherapy for Hodgkin lymphoma.

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2014-2015 Oncology Meetings March

April

Society of Surgical Oncology Annual Cancer Symposium March 13 - 16 • Phoenix, Arizona For more information: www.surgonc.org

ESTRO 33 April 4-8 • Vienna, Austria For more information: www.estro.org/congressesmeetings/items/estro-33

24th Annual Interdisciplinary Breast Cancer Conference March 15-19 • Las Vegas, Nevada For more information: www.breastcare.org/ 9th European Breast Cancer Conference March 19-21 • Glasglow, Scotland For more information: www.ecco-org.eu

American Association for Cancer Research Annual Meeting April 5-9 • San Diego, California For more information: www.aacr.org

20th Annual Blood-Brain Barrier and Neuro-Oncology Meeting March 20-22 • Sunriver, Oregon For more information: www.ohsu.edu/bbb

15th Annual Meeting of the American Society of Breast Surgeons April 30-May 4 • Las Vegas, Nevada For more information: www.breastsurgeons.org/index.php

Illinois Medical Oncology Society 2014 Membership Conference March 21 • Chicago, Illinois For more information: www.imos-illinois.com/ ELCC 2014 European Lung Cancer Conference March 26-29 • Geneva, Switzerland For more information: www.esmo.org/Conferences/ ELCC-2014-Lung-Cancer ACCC 40th Annual National Meeting March 31-April 2 • Arlington, Virginia For more information: www.accc-cancer.org/meetings/ AM2014.asp

May Oncology Nursing Society 39th Annual Congress May 1-4 • Anaheim, California For more information: www.ons.org Association for Value-Based Cancer Care – 4th Annual Conference May 6-9 • Los Angeles, California For more information: http:// avbcconline.org/ Accelerating Anticancer Agent Development and Validation Workshop May 7-9 • Bethesda, Maryland For more information: www.acceleratingworkshop.org/

2014-2015

ASPHO’s 27th Annual Meeting May 14-17 • Chicago, Illinois For more information: www.aspho.org Oral Oncology: Oncologic Dentistry and Maxillofacial Prosthetics Symposium May 15-17 • Houston, Texas For more information: www.mdanderson.org/conferences 2014 State of the Art Radiation Therapy: Practical Treatment, Biology and Imaging May 16-18 • San Antonio, Texas For more information: www.astro.org

ASCO 50th Annual Meeting May 30-June 3 • Chicago, Illinois For more information: http://am.asco.org

June

July 2014 Pan Pacific Lymphoma Conference July 21-25 • Kohala Coast, Hawaii For more information: www.unmc.edu/cce/ panpacificlymphoma.htm

5th World Congress of International Federation of Head and Neck Oncologic Societies Annual Meeting of American Head and Neck Society July 26-30 • New York, New York For more information: www.ahns.info/meetings/index. php AACR/ASCO Methods in Clinical Cancer Research Workshop July 26-August 1 • Vail, Colorado For more information: www.aacr.org

August

6th International Workshop on Advances in the Molecular Pharmacology and Therapeutics of Bone Disease June 28-July 2 • Oxford, United Kingdom For more information: www.oxfordbonepharm.org/ 16th International Symposium on Pediatric Neuro-Oncology June 28-July 2 • Singapore For more information: www.ispno2014.com

Best of ASCO® Boston August 8-9 • Boston, Massachusetts For more information: boa.asco.org/ continued on page 114

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2014-2015 Oncology Meetings continued from page 108

Advances in Melanoma: From Biology to Therapy September 20-23 • Philadelphia, Pennsylvania For more information: www.aacr. org/home/scientists/meetings-workshops/special-conferences/ advances-in-melanoma-frombiology-to-therapy.aspx European Society for Medical Oncology 2014 Congress September 26-30 • Madrid, Spain For more information: www.esmo.org/Conferences/ESMO2014-Congress

ASCO’s Palliative Care in Oncology Symposium October 24-25 • Boston. Massachusetts For more information: www.palliative.asco.org 11th International Conference of the Society for Integrative Oncology October 26-28 • Houston, Texas For more information: www.integrativeonc.org American College of Surgeons Clinical Congress October 26-30 • San Francisco, California For more information: www.facs.org/meetings_events/ future_congress/future

Critical Issues in Tumor Microenvironment, Angiogenesis and Metastasis: From Bench to Bedside to Biomarkers September 29 - October 2 • Cambridge, Massachusetts For more information: http://steelelab.mgh.harvard.edu

October ACCC 31st National Oncology Conference October 8-11 • San Diego, California For more information: www.accc-cancer.org 2014 Second Annual Breast Cancer Symposium October 11 • Miami, Florida For more information: http://cme.baptisthealth.net/ breastcancer/pages/index.aspx 2014 Quality Care Symposium October 17-18 • Boston, Massachusetts For more information: quality.asco.org 16th World Congress of PsychoOncology and Psychosocial Academy October 20-24 • Lisbon, Portugal For more information: www.ipos2014.com/

2014-2015

November Chemotherapy Foundation Symposium November 4 - 8 • New York, New York For more information: www.chemotherapyfoundation symposium.org

Diagnostic Error in Medicine 5th International Conference November 11-14 • Baltimore, Maryland For more information: www.hopkinscme.edu/CourseDetail. aspx/80028747 Multidisciplinary Update in Breast Disease 2014 November 12-15 • Atlantic Beach, Florida For more information: http://www .mayo.edu/cme/surgical-specialties2014s306

3rd Annual World Cutaneous Malignancies Congress October 29-31 • San Francisco, California For more information: http://www.cutaneousmalignancies .com 20th Annual Cancer Institute Symposium October 30 • Hershey, Pennsylvania For more information: www.pennstatehershey.org/web/ce/ home/programs/physicians 2014 Chicago Multidisciplinary Symposium in Thoracic Oncology October 30-November 1 • Chicago, Illinois For more information: http://thoracicsymposium.org 3rd Annual Global Biomarkers Consortium Conference October 31 – November 1 • San Francisco, California For more information: www.globalbiomarkersconsortium .com

EORTC-NCI-AACR International Symposium on Molecular Targets and Cancer Therapeutics November 18-21 • Barcelona, Spain For more information: www.aacr.org European Multidisciplinary Colorectal Cancer Congress (EMCCC) November 23-25 • Amsterdam, The Netherlands For more information: www.dccg.nl RSNA 2014 Radiological Society of North America November 30 - December 5 • Chicago, Illinois For more information: www.rsna.org

December American Association for Cancer Research: Tumor Immunology December 1-4 • Orlando, Florida For more information: www.aacr.org

World Cancer Congress December 3-6 • Melbourne, Australia For more information: www.worldcancercongress.org 37th Annual San Antonio Breast Cancer Symposium December 9-13 • San Antonio, Texas For more information: www.sabcs.org

January 2015 Gastrointestinal Cancers Symposium January 15-17 • San Francisco, California For more information: www.gicasym.org The Society of Thoracic Surgeons 51st Annual Meeting January 24-28 • San Diego, California For more information: www.sts.org/education-meetings/ educational-meetings-activities/ future-meetings

February 2015 BMT Tandem Meeting American Society for Blood and Marrow Transplantation February 11 - 15 • San Diego, California For more information: www.asbmt.org Genitourinary Cancers Symposium February 26-28 • Orlando, Florida For more information: www.gucasym.org

March Society of Surgical Oncology Annual Meeting March 25-28 • Houston, Texas For more information: www.surgonc.org/

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ASCO State Affiliates Focus on the Virginia Association of Hematologists and Oncologists By Jo Cavallo

Richard Ingram, MD

he state of Virginia encompasses a vast area of 40,000 square miles and is divided into five regions: the Atlantic Coastal Plain, the Piedmont, the Blue Ridge, the Appalachian Ridge and Valley Region, and the Appalachian Plateau. The diverse geography of the state creates unique challenges for patients with cancer seeking access to care and for oncologists providing it. The mission of the Virginia Association of Hematologists and Oncologists (VAHO), founded in 1990, is to ensure that quality oncology care is available to all patients with cancer throughout the state. With 185 members, VAHO represents the interests of a majority of oncologists throughout the state, and its members provide care to over 80% of the patients with cancer in Virginia. This ASCO State Affiliate is also one of the most legislatively active and successfully helped gain passage, in 2012, of Virginia’s Oral Chemotherapy Coverage Parity Act. VAHO is also leading the

way to help pass legislation to exempt reimbursement of cancer drugs from the funding cuts imposed on the Centers for Medicare & Medicaid Services under the Budget Control Act of 2011. The ASCO Post talked with VAHO President Richard Ingram, MD, about his Society’s accomplishments and its unique challenges.

Good Reciprocal Relationship Why was it important for VAHO to become an ASCO State Affiliate? There are many benefits to being an ASCO State Affiliate. First of all, it gives us the ability to network with colleagues throughout the state, and that networking and sharing of information is very valuable. Second, it gives us the

Legislative Efforts VAHO has been very active in helping pass state legislation to improve patient care. Please talk about VAHO’s involvement in some recent legislative and advocacy efforts. In 2011, we started working with a government relations professional, and we have accomplished a good deal since then. For example, we led the charge on the state’s Oral Chemotherapy Coverage Parity Act, which was passed in 2012. And earlier this year, we submitted letters to the Virginia General Assembly regarding the importance of setting safety standards in a biosimilar medication bill the legislature is considering. Several years ago, we worked in collaboration with the Medical Society of Virginia to pass legislation for a drug-

My overall goal for our Society is to put under one organization the different components that touch a patient’s experience with cancer. —Richard Ingram, MD

ability to link with a powerful partner in ASCO, to advocate for our patients on both a local and national level. And it gives us the ability to keep ASCO in the loop as well on what is happening at the state advocacy level to help our patients, so it’s a good reciprocal relationship.

Fast Facts ■■ The Virginia Association of Hematologists and Oncologists (VAHO) was founded in 1990. ■■ The current President is Richard Ingram, MD. ■■ The Immediate Past President is James T. May, MD. ■■ VAHO has 185 members. ■■ VAHO’s mission is to improve the quality of cancer care throughout Virginia; to maintain and advance the standards of cancer care; to support oncology education; to facilitate the development and use of new cancer management techniques in the community; to provide effective representation of the oncology field for its members and the public; to foster effective communication enhancing access to scientific, socioeconomic, research, and other relevant data; and to promote the collegial relationships among oncologists in Virginia. ■■ VAHO holds two meetings each year, one in the spring and one in the fall. Topics may include practice management, the establishment of electronic medical records, transitioning to ICD-10 code sets for Medicare and Medicaid Services, CME activities, updates on ASCO’s Quality Oncology Practice Initiative (QOPI®), and hospital/physician– and payer/physician–relations. VAHO also holds monthly teleconferences for office managers to discuss day-to-day operational concerns.

compounding safety bill, so we have a history of successful activism.

Unique Challenges What challenges do you face that are unique to your Society? I’m sure we share a lot of similar challenges other ASCO State Affiliates are coping with, but the geographic nature of our state, which includes a mixture of rural and metropolitan areas, presents unique challenges for us. In many parts of the state, access to clinical care is difficult and patients have to travel many miles to see the nearest cancer specialist. Also, because we are located close to Washington, DC, and Baltimore, two cities with a large underserved or undocumented immigrant population, we are often called upon to treat patients who don’t have health insurance. There are a lot of pitfalls in trying to find access to care for these patients. In Virginia, as in other states, oncologists and hematologists are having difficulty maintaining their private practices because many community practices are being integrated into medical centers. That shifting of care from a cost-effective outpatient environment to a more costly

in-hospital environment poses a lot of financial issues for patients who now have to deal with higher insurance copays.

Future Goals What are VAHO’s goals for the future? My overall goal for our Society is to put under one organization the different components that touch a patient’s experience with cancer, so I’m trying to expand our membership to include more physician extenders. We already have a good representation of active physician extenders, including office managers, billers, coders, pharmacists, and nurses, but I would like to increase their numbers and target meeting topics and teleconferences to their interests. This will give all of those stakeholders value-added features to motivate their participation in our Society. I am also continuing to partner with our academic institutions to encourage their fellows in training to get involved in VAHO. When I was a fellow at the University of Virginia, I became very active in VAHO and it was such a valuable experience to meet practicing physicians and learn about legislative and advocacy issues that impact both oncologists and patients. These are the types of topics young physicians aren’t exposed to when they are learning about the nuts and bolts of disease, but that are essential in helping advance cancer care—from learning how to apply for basic research funding from the National Institutes of Health to designing and enrolling patients in clinical trials. Our meetings cover the whole spectrum of oncology care, so I would love to see more fellows in training be involved in VAHO. We are working very hard with fellowship directors in Virginia to encourage and support the attendance of fellows by offering them travel scholarships to our meetings. I am also trying to increase our coverage of national oncology meetings, including ASCO highlights and the best of ASH, by encouraging our colleagues from the University of Virginia and Virginia Commonwealth University and other regional academic institutions to come to our meetings and give us updates. n Disclosure: Dr. Ingram reported no potential conflicts of interest.

Experience the Full Value of ASCO Membership ASCO members save an average of 50%* on the nonmember registration rate at the 2014 Annual Meeting

JOIN TODAY! Visit benefits.asco.org for a membership application and for a comprehensive list of member benefits.

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Clinical Trials Resource Guide

Ongoing Clinical Trials Actively Recruiting Patients With Gastrointestinal Cancers Compiled By Jo Cavallo

This Clinical Trials Resource Guide is meant to increase awareness of currently recruiting NCI- or academic institution–sponsored clinical studies for your patients with gastrointestinal cancers. All of the studies are listed on the National Institutes of Health website at ClinicalTrials.gov, and include nonrandomized, randomized, interventional, and observational studies.

GASTROINTESTINAL CANCERS Study Type: Observational Study Title: Tissue Procurement for Gastric Cancer, Gastrointestinal Stromal Tumors (GIST), Esophageal Cancer, Pancreas Cancer, Hepatocellular Cancer, Biliary Cancer, Neuroendocrine, Peritoneal Mesothelioma, Anal Cancer and Colorectal Cancer in Patients Undergoing Surgery or Biopsy Study Sponsor and Collaborators: University of Chicago Purpose: To collect and store normal and malignant tissue and blood samples from patients with gastric cancer, gastrointestinal stromal tumor, esophageal cancer, pancreas cancer, hepatocellular cancer, biliary cancer, neuroendocrine tumor, peritoneal mesothelioma, anal cancer, and colorectal cancer to create a database for the collected tissue and allow access to relevant clinical information for current and future protocols. An additional goal is to create tissue microarrays for each gastrointestinal cancer subtype to facilitate future molecular studies. Ages Eligible for Study: Not available Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Collect and store blood samples (time frame: 1 year); create a database for collected tissue (time frame: 1 year) Principal Investigator: Daniel Catenacci, MD, University of Chicago; 773-702-7596; dcatenac@medicine. bsd.uchicago.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01416714 Study Type: Observational Study Title: Investigation of the

Immune Response to Gastrointestinal Tumors and Development of Novel Biomarkers for the Presence of Gastrointestinal Cancer Study Sponsor and Collaborators: University of Pittsburgh Purpose: To learn more about the immune response to more common gastrointestinal cancers. The first goal of this study is to collect blood and tissues samples from patients with early- or late-stage gastrointestinal cancers. The samples will be evaluated to better understand the immune response to these two cancers. The second goal is to evaluate the specimens of these patients for changes and genetic markers that correlate with the presence of cancer. The information gathered from the studies will enhance the ability of researchers to design, conduct, and monitor novel immunotherapeutic protocols for the treatment of patients with gastrointestinal cancer. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: To collect cells from the peripheral blood, tumor draining lymph nodes, and tumor infiltrating lymphocytes in patients with early- or late-stage gastrointestinal cancers (time frame: not available) Principal Investigator: Herber J. Zeh, MD, University of Pittsburgh; 412-692-2852; zehh@upmc.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT00633334 Study Type: Nonrandomized/interventional Study Title: Prevention of Nausea and Vomiting Secondary to FOLFIRINOX Chemotherapy in Gastrointestinal Cancer Patients Study Sponsor and Collaborators: Barbara Ann Karmanos Cancer Institute; National Cancer Institute Purpose: To study fosaprepitant dimeglumine in the prevention of nausea and vomiting in patients with gastrointestinal cancer receiving combination chemotherapy. Antiemetic drugs, such as fosaprepitant dimeglumine, may help lessen or prevent nausea and vomiting in patients treated with chemotherapy. Ages Eligible for Study: 19 years and older

Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Control of vomiting (time frame: from 0–120 hours after first course of chemotherapy) Principal Investigator: Minsig Choi, MD, Barbara Ann Karmanos Cancer Institute; 800-527-6266 For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01504711

ous adverse events; patient is unable to tolerate more than 25% of treatments using proton radiotherapy; acute toxicity (time frame: 90 days) Principal Investigator: John Plastaras, MD, PhD, Abramson Cancer Center of the University of Pennsylvania; 855-216-0098; Penncancertrials@ emergingmed.com For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01449864

Study Type: Phase II nonrandomized/interventional Study Title: A Pilot/Phase II Study of Gamma Knife Radiosurgery for Brain Metastases Using 3Tesla MRI and Rational Dose Selection Study Sponsor and Collaborators: Yale University Purpose: To collect prospective data for use as a comparator for future subsequent studies attempting to increase the efficacy or reduce the toxicity of gamma knife radiosurgery Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Rate of local control over time (RECIST criteria; time frame: up to 2 years) Principal Investigator: James B. Yu, MD, Yale University; 203-7855703; james.b.yu@yale.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT02005614

Study Type: Pilot randomized/interventional Study Title: Influence of Meditation-Based Breathing Training on Target Motion Management and Distress During Radiation for Abdominal and Lung Malignancies Study Sponsor and Collaborators: Albert Einstein College of Medicine of Yeshiva University; National Cancer Institute Purpose: This randomized pilot clinical trial is studying mediationbased breathing training in improving target motion management and reducing stress in patients with abdominal or lung cancer undergoing radiation therapy. Meditation-based breathing training may decrease breathing-related movement and the amount of stress in patients with abdominal or lung cancer undergoing radiation therapy. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Change in duty cycle, defined as the fraction of time of the breathing cycle that the beam is on, before and after breath coaching (time frame: baseline to up to 5 weeks). Changes in the length of the end expiration or end inspiration, defined as when the breathing trace or internal motion change direction (time frame: baseline to up to 5 weeks). Changes in gate width (time frame: baseline to up to 5 weeks). Principal Investigator: Alyson Moadel, PhD, Albert Einstein College of Medicine/Montefiore Medical Center; 718-430-2380; alyson.moadel@ einstein.yu.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01939210

Study Type: Interventional Study Title: A Feasibility and Registration Study of Proton Radiotherapy for Upper Gastrointestinal Malignancies Study Sponsor and Collaborators: Abramson Cancer Center of the University of Pennsylvania Purpose: To determine feasibility and the acute toxicity profile of proton therapy with concurrent continuousinfusion fluorouracil chemotherapy. Secondary objectives are to determine late toxicities and to generate preliminary data on clinical efficacy. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Seri-

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Clinical Trials Resource Guide Ongoing Trials in Gastrointestinal Cancer continued from page 117

Study Type: Phase I nonrandomized/interventional Study Title: Phase I Study of Aurora A Kinase Inhibitor (MLN8237) Given in Combination With Selective VEGFR Inhibitor Pazopanib (Votrient)

for Therapy in Solid Tumors Study Sponsor and Collaborators: University of Illinois at Chicago Purpose: This phase I dose escalation study will evaluate alisertib, an Aurora A kinase inhibitor, when given in combination with the selective vascular endothelial growth factor receptor (VEGFR) inhibitor pazopanib in pa-

tients with advanced, previously treated nonhematologic solid tumors. Ages Eligible for Study: 18 years and older Genders Eligible for Study: Both Accepts Healthy Volunteers: No Primary Outcome Measures: Optimally tolerated dose (time frame: at end of cycle 1 [approximately day 21]; com-

plete all planned treatment for cycle 1 (defined as 14 doses of alisertib and daily pazopanib without dose-limiting toxicity and patients are able to start cycle 2 with no more than a 2 week delay). Principal Investigator: Arkadiusz Z. Dudek, MD, University of Illinois at Chicago; 312-413-8878; adudek@uic.edu For More Information: Visit ClinicalTrials.gov and refer to this study by its identifier: NCT01639911 n

National Colorectal Cancer Awareness Month Statement by Assistant Secretary for Health Dr. Howard K. Koh

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arch is Colorectal Cancer Awareness Month, and the U.S. Department of Health and Human Services is committed to boosting public awareness about the importance of screening and treatment for colorectal cancer. Colorectal cancer poses the greatest risk to adults over age 50, and the U.S. Preventive Services Task Force (USPSTF) recommends that all individuals aged 50 to 75 be screened for colorectal cancer as part of routine preventive health care. Currently, about 1 in 3 adults between the ages of 50 and 75 are not receiving recommended screening. These are most likely to be Hispanics, those aged 50 to 64, men, American Indian or Alaska natives, those who don’t live in a city, and people with lower education and income. With the implementation of the Affordable Care Act, a major barrier to regular screening—cost of access to preventive care—has been removed. For the first time in our nation’s history, many Americans can receive without cost sharing high value preventive services, such as screening for colorectal cancer and other diseases that threaten health and shorten lives. Colorectal cancer screening has been proven to save lives. We are committed to eliminating colorectal cancer as a major public health problem. Increasing the nation’s screening rate to 80% by the year 2018 is absolutely possible, but there is much work to be done. We need greater national efforts to inform and remind appropriate patients that they are due for colorectal cancer screening, and ensure that all Americans between the ages of 50 and 75 receive this important life-saving intervention. n

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In the News Dermatologic Oncology

Dermatologists Defend Mohs Surgery as Effective and Cost-Efficient With Low Rate of Recurrence By Charlotte Bath

he headline, “Patients’ Costs Skyrocket, Specialists’ Incomes Soar,” aptly encapsulates the theme of a recent article in the New York Times,1 part of a series entitled, “Paying Till It Hurts.” “Oncologists benefit from the ability to mark up (and profit from) each dose of chemotherapy they administer in private offices,” according to the article, which also pointed out rising incomes for oncologists, gastroenterologists, and dermatologists over the past several years. But particular scrutiny was leveled at dermatologists’ use of Mohs micrographic surgery for treating skin cancers. “Use of the surgery has skyrocketed in the United States—over 400 percent in a little over a decade—to the point that last summer Medicare put it at the top of its ‘potentially misvalued’ list of overused or overpriced procedures, the Times article declared.

‘A Wonderful Tool’ Brett M. Coldiron, MD, Clinical Associate Professor of Dermatology at the University of Cincinnati, was quoted extensively in the Times article, asserting that dermatologists were “very cost-efficient” and that Mohs surgery is “a wonderful tool” that is “not generally overvalued.” He expanded on the appropriate use of Mohs surgery in

response to follow-up questions from The ASCO Post. “Mohs surgery has been intensely and repeatedly evaluated by the American Medical Association’s Relative Value Scale Update Committee and the Centers for Medicare & Medicaid Services (CMS), as recently as 3 months ago, and its valuation has de-

low rate of cancer recurrence.” During Mohs micrographic surgery, cancerous tissue is removed one layer at a time and examined under a microscope until the skin cancer has been completely removed. This means that “the surgeon removes only the tissue that contains cancer. So the patient keeps as much healthy tissue as possi-

Mohs has a success rate approaching 99% for difficult-to-treat basal and squamous cell cancers and is a very cost-effective treatment option fo nonmelanoma skin cancer. —Brett M. Coldiron, MD

creased considerably in the past 15 years. It is not an overvalued service. It has been removed from the CMS list of potentially overvalued services,” Dr. Coldiron stated. “Mohs has a success rate approaching 99% for difficult-to-treat basal and squamous cell cancers and is a very cost-effective treatment option for nonmelanoma skin cancer,” Dr. Coldiron continued. “Another benefit of Mohs surgery is that the entire margin of the tumor is examined for remaining cancer, essentially resulting in an extremely

ble,” Dr. Coldiron added. “This is especially important when the skin cancer develops in sensitive areas, such as the face, an ear, a finger or toe, or the genitals, but the procedure is not limited to just treating sensitive areas.”

Most Procedures in Office The Times narrative focused on a woman whose positive skin biopsy “was a prelude to a daylong medical odyssey” billed at more than $25,000 and involving a dermatologist who performed Mohs surgery, an anesthe-

Expect Questions About the Appropriate Use of Mohs Surgery

“M

ohs surgery can be an effective treatment option for nonmelanoma skin cancer, as well as for more rare but aggressive skin cancers. In addition, Mohs can be particularly helpful to treat patients with skin cancers that have recurred,” Brett M. Coldiron, MD, Clinical Associate Professor of Dermatology at the University of Cincinnati, told The ASCO Post. Overall, he summarized, “Mohs micrographic surgery offers the highest cure rate, with the smallest possible defect, at a very reasonable cost.” To answer questions from patients about whether they might be good candidates for Mohs surgery, physicians can turn to the Mohs surgery appropriate use criteria document, a resource for dermatologists and other

physicians who encounter skin cancer in their practices. To develop the appropriate use criteria, the American Academy of Dermatology (AAD), in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery, reviewed, categorized, and rated the appropriateness of Mohs surgery for 270 scenarios in which Mohs surgery is often considered. Dr. Coldiron was a member of the task force that developed the appropriate use criteria and is President-Elect of the AAD.

Free App The criteria were published in both the Journal of the American

Academy of Dermatology and Dermatologic Surgery. In addition, “the Academy has developed a free app for the Mohs appropriate use criteria, which includes decision support on the appropriateness of Mohs surgery for 270 unique scenarios; guided navigation through tumor and patient characteristics; color-coded body maps for high-, medium-, and low-risk areas; supplemental clinical algorithms; and a quick reference guide that can be shared with referring physicians and patients,” Dr. Coldiron said. For more information about the app or to download the appropriate use criteria, visit the American Academy of Dermatology website at www .aad.org. n

siologist, and an ophthalmologist who practices plastic surgery to close the wound. That is not the case with the majority of Mohs surgeries, which are completed by a dermatologist in an office setting, without hospital charges, according to Dr. Coldiron. “About 90% are either allowed to heal by second intention or closed the same day by the dermatologist in the office setting,” he said. “This is decided by the patient, in consultation with the physician, and is based on the size and depth of the wound as well as its location. In some circumstances, the Mohs surgeon may refer the patient to another specialist for reconstruction, and in some cases, patients are referred by other specialists for Mohs surgery prior to their reconstruction by the referring surgeon.” This view was corroborated by one of several letters to the editor from dermatologists and others prompted by the Times article. “You seem to imply that dermatologists have driven medical expenses up sharply by citing a few extreme examples. To the contrary, most dermatologists keep treatment costs low by diagnosing, treating and curing the vast majority of lesions in an office setting. This is often accomplished efficiently without incurring expensive hospital charges and consulting fees,” wrote Douglas Altchek, MD, Clinical Professor of Dermatology at the Icahn School of Medicine at Mount Sinai in New York.2

Determining Factors Determining factors for Mohs surgery include the type, size, and location of the skin cancer, as well as the patient’s overall health. “For example, Mohs surgery would be appropriate in a healthy or immunocompromised patient with an aggressive, nodular, or superficial basal cell carcinoma greater than 0.5 cm in the ‘mask areas’ of the face (central face, eyelids, eyebrows, nose, lips, chin, ear, and periauricular skin/sulci, temple), genitalia (including perineal and perianal), hands, feet, nail units, ankles, and nipples/areola,” Dr. Coldiron explained. “It is also useful for cancers greater than 1 cm in size on the rest of the head and neck, or trunk and extremities. It is the most effective way to continued on page 121

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In the News Mohs Surgery continued from page 119

eradicate recurrent tumors and some rare aggressive tumors,” according to Dr. Coldiron. “It is usually not needed for superficial basal cell carcinomas on the trunk and extremities, and not in the treatment of actinic keratoses.” Mohs surgery may also be used for melanoma in situ on the face, as it “may result in a smaller wound when treating melanoma in situ,” Dr. Coldiron remarked. He added that some melanomas may require additional treatment with chemotherapy or radiation therapy.

Appropriate Use Criteria The American Academy of Dermatology (AAD), in collaboration with the American College of Mohs Surgery, the American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery, reviewed, categorized, and rated the appropriateness of Mohs surgery for 270 scenarios for which Mohs surgery is often considered. The results were used to develop appropriate use criteria to guide clinical decision-making.3 “This is a resource for all dermatologists and other physicians who encounter skin cancer in their practices,” commented Dr. Coldiron, who was a member of the task force that developed the appropriate use criteria and is President-Elect of the AAD. “We analyzed all the available evidence on the use of Mohs surgery and followed the RAND/UCLA appropriateness method [a process originated in the 1980s to measure overuse and underuse of medical and surgical interventions by determining relative risks and harms] that has been well-established for development of appropriate use criteria in other specialties. This means that the appro-

priate indications were determined by a majority of dermatologists who do not perform Mohs surgery,” he added. “To clarify, the Mohs appropriate use criteria do not say that Mohs should be used for certain skin cancers, rather, that in some instances Mohs can be an appropriate choice, and in others it is not. For example, surgical excision with margin control is also appropriate for most skin cancers but may result in a larger hole and a slightly lower cure rate,” Dr. Coldiron stated. “Mohs surgery is beneficial for the removal of many skin cancers, and there are a number of studies that demon-

of general frustration with medical prices.” He stands by that, but added, “Many specialists have been targeted in the past few years. Physician’s fees are a small part of the problem—about 17% of the cost of health care. Dermatologists fall in the middle of specialists in terms of reimbursements,” he noted. “Dermatologists have at least 4 years of residency, and Mohs surgeons have an additional year of fellowship, and so the treatments are highly specialized,” he continued. “Consideration in reimbursement should be given to specialists who receive this additional training and have expertise in their field. One of the

To clarify, the Mohs appropriate use criteria do not say that Mohs should be used for certain skin cancers, rather, that in some instances Mohs can be an appropriate choice, and in others it is not. —Brett M. Coldiron, MD

strate this efficacy in addition to the vast clinical experience with this surgery,” he said. Other studies have found Mohs surgery to be safe and cost-effective.4-6 Dr. Coldiron has served as an author for several of those studies. “The Mohs appropriate use criteria highlighted several areas where additional research would be helpful, and ideally this would also include comparative effectiveness research. There are few blinded comparative studies on the surgical treatment of most cancers,” Dr. Coldiron stated.

Unfairly Targeted? In the New York Times article, Dr. Coldiron was quoted as saying that the specialty of dermatology “was being unfairly targeted by insurers because

fears is that new physicians coming into medical practice will choose not to specialize, and long waits could develop.” According to Dr. Coldiron, “The actual reimbursement to perform Mohs surgery and repair the wound has gone down by over 20% in the past 15 years. An increase in Mohs utilization may be justified on the basis of the skin cancer epidemic.7 The procedure offers the highest cure rate for difficult-to-treat basal and squamous cell cancers. Furthermore, the number of skin cancers treated with Mohs surgery has leveled off in recent years to about the same rate as the increase in skin cancer incidence,” he said. “Additionally, there is an increase in the number of dermatologist providers who have been trained to perform Mohs micrographic surgery as prac-

tice gaps have been filled in around the United States,” he noted. For dermatologists, the increased incidence of skin cancers in recent years has caused a shift in practice patterns since skin cancers are so potentially serious they go to the head of the line to be treated, Dr. Coldiron observed. Basal cell carcinoma and squamous cell carcinoma “are the two most common forms of skin cancer but are easily treated if detected early.” n Disclosure: Dr. Coldiron reported no potential conflicts of interest.

References 1. Rosenthal E: Patients’ costs skyrocket; specialists’ incomes soar. New York Times, January 18, 2004. 2. Altchek D: The costs of a trip to the doctor. Letters. New York Times, January 21, 2014. 3. Connolly SM, Baker DR, Coldiron BM, et al: AAD/ACMS/ASDSA/ASMS 2012 appropriate use criteria for Mohs micrographic surgery: A report of the American Academy of Dermatology, American College of Mohs Surgery, American Society for Dermatologic Surgery Association, and the American Society for Mohs Surgery. J Am Acad Dermatol 67:531-550, 2012, and Dermatol Surg 38:1582-1603, 2012. 4. Merritt BG, Lee NY, Brodland DG, et al: The safety of Mohs surgery: A prospective multicenter cohort study. J Am Acad Dermatol 67:1302-1309, 2012. 5. Rogers HW, Coldiron BM: A relative value unit-based cost comparison of treatment modalities for nonmelanoma skin cancer: Effect of the loss of the Mohs multiple surgery reduction exemption. J Am Acad Dermatol 61:96-103, 2009. 6. Ravitskiy L, Brodland DG, Zitelli JA: Cost analysis: Mohs micrographic surgery. Dermatol Surg 38:585-594, 2012. 7. Donaldson MR, Coldiron BM: No end in sight: The skin cancer epidemic continues. Semin Cutan Med Surg 30:3-5, 2011.

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Brief Summary: Consult package insert for complete Prescribing Information INDICATIONS AND USAGE: Bone Metastasis from Solid Tumors. Xgeva is indicated for the prevention of skeletal-related events in patients with bone metastases from solid tumors. Important Limitation of Use. Xgeva is not indicated for the prevention of skeletal-related events in patients with multiple myeloma (see Clinical Trials in full Prescribing Information). DOSAGE AND ADMINISTRATION: Recommended Dosage. The recommended dose of Xgeva is 120 mg administered as a subcutaneous injection every 4 weeks in the upper arm, upper thigh, or abdomen. Administer calcium and vitamin D as necessary to treat or prevent hypocalcemia (see Warnings and Precautions). Preparation and Administration. Visually inspect Xgeva for particulate matter and discoloration prior to administration. Xgeva is a clear, colorless to pale yellow solution that may contain trace amounts of translucent to white proteinaceous particles. Do not use if the solution is discolored or cloudy or if the solution contains many particles or foreign particulate matter. Prior to administration, Xgeva may be removed from the refrigerator and brought to room temperature (up to 25°C/77°F) by standing in the original container. This generally takes 15 to 30 minutes. Do not warm Xgeva in any other way (see How Supplied/Storage and Handling). Use a 27-gauge needle to withdraw and inject the entire contents of the vial. Do not re-enter the vial. Discard vial after single-use or entry. CONTRAINDICATIONS: Hypocalcemia. Pre-existing hypocalcemia must be corrected prior to initiating therapy with Xgeva (see Warnings and Precautions). Hypersensitivity. Xgeva is contraindicated in patients with known clinically significant hypersensitivity to Xgeva (see Warnings and Precautions and Adverse Reactions). WARNINGS AND PRECAUTIONS: Drug Products with Same Active Ingredient. Xgeva includes the same active ingredient (denosumab) found in Prolia. Patients receiving Xgeva should not take Prolia. Hypersensitivity. Clinically significant hypersensitivity including anaphylaxis has been reported with use of Xgeva. Reactions may include hypotension, dyspnea, upper airway edema, lip swelling, rash, pruritus, and urticaria. If an anaphylactic or other clinically significant allergic reaction occurs, initiate appropriate therapy and discontinue Xgeva therapy permanently (see Contraindications and Adverse Reactions). Hypocalcemia. Xgeva can cause severe symptomatic hypocalcemia, and fatal cases have been reported. Correct pre-existing hypocalcemia prior to Xgeva treatment. Monitor calcium levels and administer calcium, magnesium, and vitamin D as necessary. Monitor levels more frequently when Xgeva is administered with other drugs that can also lower calcium levels. In the postmarketing setting, severe symptomatic hypocalcemia has been reported (see Adverse Reactions). Advise patients to contact a healthcare professional for symptoms of hypocalcemia (see Contraindications, Adverse Reactions, and Patient Counseling Information in full Prescribing Information). Based on clinical trials using a lower dose of denosumab, patients with a creatinine clearance less than 30 mL/min or receiving dialysis are at greater risk of severe hypocalcemia compared to patients with normal renal function. In a trial of 55 patients, without cancer and with varying degrees of renal impairment, who received a single dose of 60 mg denosumab, 8 of 17 patients with a creatinine clearance less than 30 mL/min or receiving dialysis experienced corrected serum calcium levels less than 8.0 mg/dL as compared to 0 of 12 patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance less than 30 mL/min or receiving dialysis. Osteonecrosis of the Jaw (ONJ). Osteonecrosis of the jaw (ONJ) can occur in patients receiving Xgeva, manifesting as jaw pain, osteomyelitis, osteitis, bone erosion, tooth or periodontal infection, toothache, gingival ulceration, or gingival erosion. Persistent pain or slow healing of the mouth or jaw after dental surgery may also be manifestations of ONJ. In clinical trials, in patients with osseous metastasis, the incidence of ONJ was higher with longer duration of exposure (see Adverse Reactions). Seventy-nine percent of patients with ONJ had a history of tooth extraction, poor oral hygiene, or use of a dental appliance as a predisposing factor. Perform an oral examination and appropriate preventive dentistry prior to the initiation of Xgeva and periodically during Xgeva therapy. Advise patients regarding oral hygiene practices. Avoid invasive dental procedures during treatment with Xgeva. Patients who are suspected of having or who develop ONJ while on Xgeva should receive care by a dentist or an oral surgeon. In these patients, extensive dental surgery to treat ONJ may exacerbate the condition. Atypical Subtrochanteric and Diaphyseal Femoral Fracture. Atypical femoral fracture has been reported with Xgeva (see Adverse Reactions). These fractures can occur anywhere in the femoral shaft from just below the lesser trochanter to above the supracondylar flare and are transverse or short oblique in orientation without evidence of comminution. Atypical femoral fractures most commonly occur with minimal or no trauma to the affected area. They may be bilateral and many patients report prodromal pain in the affected area, usually presenting as dull, aching thigh pain, weeks to months before a complete fracture occurs. A number of reports note that patients were also receiving treatment with glucocorticoids (e.g. prednisone) at the time of fracture. During Xgeva treatment, patients should be advised to report new or unusual thigh, hip, or groin pain. Any patient who presents with thigh or groin pain should be suspected of having an atypical fracture and should be evaluated to rule out an incomplete femur fracture. Patient presenting with an atypical femur fracture should also be assessed for symptoms and signs of fracture in the contralateral limb. Interruption of Xgeva therapy should be considered, pending a risk/benefit assessment, on an individual basis. EMBRyO-FETAL TOxICITy: Xgeva can cause fetal harm when administered to a pregnant woman. Based on findings in animals, Xgeva is expected to result in adverse reproductive effects. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent peripheral lymph nodes, abnormal bone growth, and decreased neonatal growth (see Use in Specific Populations). Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after with the last dose of Xgeva. Apprise the patient of the potential hazard to a fetus if Xgeva is used during pregnancy or if the patient becomes pregnant while patients are exposed to Xgeva. Advise patients to contact their healthcare provider if they become pregnant or a pregnancy is suspected during this time (see Use in Specific Populations). ADVERSE REACTIONS: The following adverse reactions are discussed below and elsewhere in the labeling: • Hypocalcemia (see Warnings and Precautions) • Osteonecrosis of the Jaw (see Warnings and Precautions) The most common adverse reactions in patients receiving Xgeva (per-patient incidence greater than or equal to 25%) were fatigue/asthenia, hypophosphatemia, and nausea (see Table 1). The most common serious adverse reaction in patients receiving Xgeva was dyspnea. The most common adverse reactions resulting in discontinuation of Xgeva were osteonecrosis and hypocalcemia. Clinical Trials Experience. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in practice. The safety of Xgeva was evaluated in three randomized, double-blind, double-dummy trials (see Clinical Trials in full Prescribing Information) in which a total of 2841 patients with bone metastasis from prostate cancer, breast cancer, or other solid tumors, or lytic bony lesions from multiple myeloma received at least one dose of Xgeva. In Trials 1, 2, and 3, patients were randomized to receive either 120 mg of Xgeva every 4 weeks as a subcutaneous injection or 4 mg (dose adjusted for reduced renal function) of zoledronic acid every 4 weeks by intravenous (IV) infusion. Entry criteria included serum calcium (corrected) from 8 to 11.5 mg/dL (2 to 2.9 mmol/L) and creatinine clearance 30 mL/min or greater.

Patients who had received IV bisphosphonates were excluded, as were patients with prior history of ONJ or osteomyelitis of the jaw, an active dental or jaw condition requiring oral surgery, non-healed dental/oral surgery, or any planned invasive dental procedure. During the study, serum chemistries including calcium and phosphorus were monitored every 4 weeks. Calcium and vitamin D supplementation was recommended but not required. The median duration of exposure to Xgeva was 12 months (range: 0.1 – 41) and median duration on-study was 13 months (range: 0.1 – 41). Of patients who received Xgeva, 46% were female. Eighty-five percent were White, 5% Hispanic/Latino, 6% Asian, and 3% Black. The median age was 63 years (range: 18 – 93). Seventy-five percent of patients who received Xgeva received concomitant chemotherapy. Table 1. Per-patient Incidence of Selecteda Adverse Reactions of Any Severity (Trials 1, 2, and 3)

xgeva n = 2841 %

Zoledronic Acid n = 2836 %

GASTROINTESTINAL Nausea Diarrhea

31 20

32 19

GENERAL Fatigue/ Asthenia

INVESTIGATIONS Hypocalcemiab Hypophosphatemiab

18 32

9 20

NEUROLOGICAL Headache

RESPIRATORy Dyspnea Cough

21 15

18 15

Body System

Adverse reactions reported in at least 10% of patients receiving Xgeva in Trials 1, 2, and 3, and meeting one of the following criteria: • At least 1% greater incidence in Xgeva-treated patients, or • Between-group difference (either direction) of less than 1% and more than 5% greater incidence in patients treated with zoledronic acid compared to placebo (US Prescribing Information for zoledronic acid) b Laboratory-derived and below the central laboratory lower limit of normal [8.3 – 8.5 mg/dL (2.075 – 2.125 mmol/L) for calcium and 2.2 – 2.8 mg/dL (0.71 – 0.9 mmol/L) for phosphorus] Severe Mineral/Electrolyte Abnormalities • Severe hypocalcemia (corrected serum calcium less than 7 mg/dL or less than 1.75 mmol/L) occurred in 3.1% of patients treated with Xgeva and 1.3% of patients treated with zoledronic acid. Of patients who experienced severe hypocalcemia, 33% experienced 2 or more episodes of severe hypocalcemia and 16% experienced 3 or more episodes (see Warnings and Precautions and Use in Specific Populations). • Severe hypophosphatemia (serum phosphorus less than 2 mg/dL or less than 0.6 mmol/L) occurred in 15.4% of patients treated with Xgeva and 7.4% of patients treated with zoledronic acid. Osteonecrosis of the Jaw In the primary treatment phases of Trials 1, 2, and 3, ONJ was confirmed in 1.8% of patients in the Xgeva group (median exposure of 12.0 months; range 0.1 – 40.5) and 1.3% of patients in the zoledronic acid group. The trials in patients with breast (Trial 1) or prostate (Trial 3) cancer included an Xgeva open label extension treatment phase where patients were offered Xgeva 120 mg once every 4 weeks (median overall exposure of 14.9 months; range 0.1 – 67.2). The patient-year adjusted incidence of confirmed ONJ was 1.1% during the first year of treatment and 4.1% thereafter. The median time to ONJ was 20.6 months (range: 4 – 53) (See Warnings and Precautions). Atypical Subtrochanteric and Diaphyseal Fracture Atypical femoral fracture has been reported with Xgeva (see Warnings and Precautions). Postmarketing Experience. Because postmarketing reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. The following adverse reactions have been identified during post approval use of Xgeva: • Hypocalcemia: Severe symptomatic hypocalcemia, including fatal cases. • Hypersensitivity, including anaphylactic reactions. Immunogenicity. As with all therapeutic proteins, there is potential for immunogenicity. Using an electrochemiluminescent bridging immunoassay, less than 1% (7/2758) of patients with osseous metastases treated with denosumab doses ranging from 30 – 180 mg every 4 weeks or every 12 weeks for up to 3 years tested positive for binding antibodies. No patient with positive binding antibodies tested positive for neutralizing antibodies as assessed using a chemiluminescent cell-based in vitro biological assay. There was no evidence of altered pharmacokinetic profile, toxicity profile, or clinical response associated with binding antibody development. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of a positive antibody (including neutralizing antibody) test result may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of antibodies to denosumab with the incidence of antibodies to other products may be misleading. DRUG INTERACTIONS: No formal drug-drug interaction trials have been conducted with Xgeva. In clinical trials in patients with breast cancer metastatic to bone, Xgeva was administered in combination with standard anticancer treatment. Serum denosumab concentrations at 1 and 3 months and reductions in the bone turnover marker uNTx/Cr (urinary N-terminal telopeptide corrected for creatinine) at 3 months were similar in patients with and without prior intravenous bisphosphonate therapy. There was no evidence that various anticancer treatments affected denosumab systemic exposure and pharmacodynamic effect. Serum denosumab concentrations at 1 and 3 months were not altered by concomitant chemotherapy and/or hormone therapy. The median reduction in uNTx/Cr from baseline to month 3 was similar between patients receiving concomitant chemotherapy and/or hormone therapy (see Clinical Pharmacology in full Prescribing Information). USE IN SPECIFIC POPULATIONS: Pregnancy: Category D [see Warnings and Precautions]. Risk Summary: Xgeva can cause fetal harm when administered to a pregnant woman based on findings in animals. In utero denosumab exposure in cynomolgus monkeys resulted in increased fetal loss, stillbirths, and postnatal mortality, along with evidence of absent lymph nodes, abnormal bone growth and decreased neonatal growth. There are no adequate and well-controlled studies with Xgeva in pregnant women. Women should be advised not to become pregnant when taking Xgeva. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus. Women who become pregnant during Xgeva treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Clinical Considerations: The effects of Xgeva are likely to be greater during the second and third trimesters of pregnancy. Monoclonal antibodies are transported across the placenta in a linear fashion as pregnancy progresses, with the largest amount transferred during the third trimester. If the patient becomes pregnant during Xgeva therapy, consider the risks and benefits in continuing or discontinuing treatment with Xgeva. a

Animal Data: The effects of denosumab on prenatal development have been studied in both cynomolgus monkeys and genetically engineered mice in which RANK ligand (RANKL) expression was turned off by gene removal (a “knockout mouse”). In cynomolgus monkeys dosed subcutaneously with denosumab throughout pregnancy at a pharmacologically active dose, there was increased fetal loss during gestation, stillbirths, and postnatal mortality. Other findings in offspring included absence of axillary, inguinal, mandibular, and mesenteric lymph nodes; abnormal bone growth, reduced bone strength, reduced hematopoiesis, dental dysplasia and tooth malalignment; and decreased neonatal growth. At birth out to one month of age, infants had measurable blood levels of denosumab (22-621% of maternal levels). Following a recovery period from birth out to 6 months of age, the effects on bone quality and strength returned to normal; there were no adverse effects on tooth eruption, though dental dysplasia was still apparent; axillary and inguinal lymph nodes remained absent, while mandibular and mesenteric lymph nodes were present, though small; and minimal to moderate mineralization in multiple tissues was seen in one recovery animal. There was no evidence of maternal harm prior to labor; adverse maternal effects occurred infrequently during labor. Maternal mammary gland development was normal. There was no fetal NOAEL (no observable adverse effect level) established for this study because only one dose of 50 mg/kg was evaluated. In RANKL knockout mice, absence of RANKL (the target of denosumab) also caused fetal lymph node agenesis and led to postnatal impairment of dentition and bone growth. Pregnant RANKL knockout mice showed altered maturation of the maternal mammary gland, leading to impaired lactation (see Use in Nursing Mothers and Nonclinical Toxicology in full Prescribing Information). Nursing Mothers. It is not known whether Xgeva is excreted into human milk. Measurable concentrations of denosumab were present in the maternal milk of cynomolgus monkeys up to 1 month after the last dose of denosumab (≤ 0.5% milk:serum ratio). Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Xgeva, a decision should be made whether to discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother. Maternal exposure to Xgeva during pregnancy may impair mammary gland development and lactation based on animal studies in pregnant mice lacking the RANK/RANKL signaling pathway that have shown altered maturation of the maternal mammary gland, leading to impaired lactation postpartum. However, in cynomolgus monkeys treated with denosumab throughout pregnancy, maternal mammary gland development was normal, with no impaired lactation. Mammary gland histopathology at 6 months of age was normal in female offspring exposed to denosumab in utero; however, development and lactation have not been fully evaluated (see Nonclinical Toxicology in full Prescribing Information). Pediatric Use. Xgeva is not recommended in pediatric patients. The safety and effectiveness of Xgeva in pediatric patients have not been established. Treatment with Xgeva may impair bone growth in children with open growth plates and may inhibit eruption of dentition. In neonatal rats, inhibition of RANKL (the target of Xgeva therapy) with a construct of osteoprotegerin bound to Fc (OPG-Fc) at doses ≤ 10 mg/kg was associated with inhibition of bone growth and tooth eruption. Adolescent primates treated with denosumab at doses 5 and 25 times (10 and 50 mg/kg dose) higher than the recommended human dose of 120 mg administered once every 4 weeks, based on body weight (mg/kg), had abnormal growth plates, considered to be consistent with the pharmacological activity of denosumab. Cynomolgus monkeys exposed in utero to denosumab exhibited bone abnormalities, reduced hematopoiesis, tooth malalignment, decreased neonatal growth, and an absence of axillary, inguinal, mandibular, and mesenteric lymph nodes. Some bone abnormalities recovered once exposure was ceased following birth; however, axillary and inguinal lymph nodes remained absent 6 months post-birth (see Use in Specific Populations). Geriatric Use. Of patients who received Xgeva in Trials 1, 2, and 3, 1260 (44%) were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. Renal Impairment. In a trial of 55 patients without cancer and with varying degrees of renal function who received a single dose of 60 mg denosumab, patients with a creatinine clearance of less than 30 mL/min or receiving dialysis were at greater risk of severe hypocalcemia with denosumab compared to patients with normal renal function. The risk of hypocalcemia at the recommended dosing schedule of 120 mg every 4 weeks has not been evaluated in patients with a creatinine clearance of less than 30 mL/min or receiving dialysis (see Warnings and Precautions, Adverse Reactions, and Clinical Pharmacology in full Prescribing Information). Females and Males of Reproductive Potential. Contraception Females: Counsel patients on pregnancy planning and prevention. Advise females of reproductive potential to use highly effective contraception during therapy, and for at least 5 months after the last dose of Xgeva. Advise patients to contact their healthcare provider if they become pregnant, or a pregnancy is suspected, during treatment or within 5 months after the last dose of Xgeva [see Use in Specific Populations and Patient Counseling Information]. Males: The extent to which denosumab is present in seminal fluid is unknown. There is potential for fetal exposure to denosumab when a male treated with Xgeva has unprotected sexual intercourse with a pregnant partner. Advise males of this potential risk. OVERDOSAGE: There is no experience with overdosage of Xgeva. HOW SUPPLIED/STORAGE AND HANDLING: Xgeva is supplied in a single-use vial. Store Xgeva in a refrigerator at 2°C to 8°C (36°F to 46°F) in the original carton. Do not freeze. Once removed from the refrigerator, Xgeva must not be exposed to temperatures above 25°C/77°F or direct light and must be used within 14 days. Discard Xgeva if not used within the 14 days. Do not use Xgeva after the expiry date printed on the label. Protect Xgeva from direct light and heat. Avoid vigorous shaking of Xgeva. PATIENT COUNSELING INFORMATION: Advise patients to contact a healthcare professional for any of the following: • Symptoms of a hypersensitivity reaction, including rash, urticaria, pruritus, lip swelling, shortness of breath, hypotension and respiratory tract edema (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of hypocalcemia, including paresthesias or muscle stiffness, twitching, spasms, or cramps (see Contraindications, Warnings and Precautions, and Adverse Reactions) • Symptoms of ONJ, including pain, numbness, swelling of or drainage from the jaw, mouth, or teeth (see Warnings and Precautions and Adverse Reactions) • Persistent pain or slow healing of the mouth or jaw after dental surgery (see Warnings and Precautions) • Symptoms of atypical femoral fracture, including new or unusual thigh, hip, or groin pain (see Warnings and Precautions) • Pregnancy or nursing (see Warnings and Precautions and Use in Specific Populations) Advise patients of the need for: • Avoiding therapy with Xgeva if a serious allergic reaction occurred with prior Xgeva or Prolia therapy (see Contraindications and Warnings and Precautions) • Proper oral hygiene and routine dental care • Informing their dentist that they are receiving Xgeva • Avoiding invasive dental procedures during treatment with Xgeva • The use of highly effective contraception during and for at least 5 months after treatment with Xgeva for females of reproductive potential Advise patients that denosumab is also marketed as Prolia®. Patients should inform their healthcare provider if they are taking Prolia. Amgen Manufacturing Limited, a subsidiary of Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 ©2010-2013 Amgen Inc. All rights reserved. Printed in USA. 68257-R4-V1

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In the Literature

Emerging Clinical Data on Cancer Management COLORECTAL CANCER For Metastatic Colorectal Cancer, Bevacizumab Is More Commonly Included Than AntiEGFR Antibody Therapies Analysis of a large cohort of patients with metastatic colorectal cancer who received chemotherapy at academic, private, and community-based oncology practices using the same chemotherapy order entry system showed that “bevacizumab has been more consistently integrated into treatment regimens than antiEGFR antibody therapies, particularly in first-line therapy. However, treatment choices vary substantially according to specific patient, practice, and provider characteristics,” Thomas A. Abrams, MD, of Dana-Farber Cancer Institute in Boston, and colleagues reported in the Journal of the National Cancer Institute. The chemotherapy order entry system captured disease, patient, provider, and treatment data for patients who received chemotherapy between January 2004 and March 2011. Of the 4,877 eligible patients who received first-line chemotherapy for metastatic colorectal cancer, 2,575 (53%) went on to receive second-line treatment, 1,373 (28%) received third-line treatment, and 640 (13%) received fourth-line treatment. The investigators noted that between 2004 and 2007, bevacizumab (Avastin), cetuximab (Erbitux), and pantimumab (Vectibix) had all been approved for the treatment of metastatic colorectal cancer.

Most Common Combination “Throughout the study period, fluoropyrimidine/oxaliplatin combination was the most commonly used first-line chemotherapy regimen, representing 71% of first-line therapy by 2007. First-line bevacizumab use averaged 51%, peaking at 55% in 2006. Of those who received first-line bevacizumab, 34% continued to receive bevacizumab in the second-line,” the researchers wrote. Only 26% of the patients ever received an anti-EGFR monoclonal antibody, mostly cetuximab. “Patients treated at academic centers, with longer duration of first-line therapy, and at sites in the western United States were statistically more likely to receive an anti-EGFR antibody. Anti-EGFR antibody use fell by 18% after the US Food and Drug Administration limited its use to patients with KRAS wild-type tumors in June 2009,” the investigators stated. Oncologists at academic centers and

those who treated higher volumes patients with colorectal cancer “were more likely to prescribe combination chemotherapy as compared with monotherapy, were more likely to prescribe a biologic agent in the first-line setting, and were more likely to continue bevacizumab into the second-line therapy after progression of a bevacizumab-containing first-line regimen,” the researchers found. Ongoing studies are evaluating the sequence of currently available therapies and “two new agents, ziv-aflibercept [Zaltrap] and regorafenib [Stivarga], were recently added to the arsenal of therapies for patients” with metastatic colorectal cancer. Abrams TA, et al: J Natl Cancer Inst 106(2):djt371, 2014.

OVARIAN CANCER Aspirin Associated With Reduced Risk of Ovarian Cancer, Especially in Low Daily Doses “Aspirin use was associated with a reduced risk of ovarian cancer, especially among daily users of low-dose aspirin,” according to an analysis of pooled individual data from the Ovarian Cancer Association Consortium. Analyzing data from 12 population-based case-control studies of ovarian cancer, with 7,776 case patients and 11,843 control subjects, researchers reported that their findings suggest “the same aspirin regimen proven to protect against cardiovascular events and several cancers could reduce the risk of ovarian cancer 20% to 34% depending on frequency and dose of use.” The results were published in the Journal of the National Cancer Institute. Regular aspirin use, defined as at least once a week, was reported by 18% of the study population, while 24% reported using nonaspirin nonsteroidal anti-inflammatory drugs (NSAIDs) regularly and 16% reported using acetaminophen regularly. The 20% risk reduction occurred among daily users of aspirin and the 34% risk reduction among regular users of low-dose aspirin (< 100 mg/d). “Aspirin use was associated with a reduced risk of ovarian cancer ([odds ratio (OR)] = 0.91; 95% confidence interval [CI] = 0.84 to 0.99),” reported Britton Trabert, PhD, and colleagues representing the National Cancer Institute and cancer centers in the United States, Europe, and Australia. “Results were similar but not statistically significant for nonaspirin NSAIDs, and there was no association with acetaminophen. In seven

studies with frequency data, the reduced risk was strongest among daily aspirin users (OR = 0.80; 95% CI = 0.67 to 0.96). In three studies with dose information, the reduced risk was strongest among users of low dose (< 100 mg) aspirin (OR = 0.66; 95% CI = 0.53 to 0.83), whereas for nonaspirin NSAIDs, the reduced risk was strongest for high dose (≥ 500 mg) usage (OR = 0.76; 95% CI = 0.64 to 0.91).” The authors acknowledged that “complications associated with aspirin use, including peptic ulcer, upper gastrointestinal bleeding, and hemorrhagic stroke, pose serious threats” and that “current risk–benefit analyses favor aspirin use among high-risk groups but not for largescale, population-based chemoprevention.” The estimates this study provided on the effect of aspirin on ovarian cancer risk “should be considered in risk–benefit analyses for preventive aspirin use,” the researchers stated. “However, detailed questions about frequency, dose, and duration will need to be evaluated in future studies including pooled data from cohort studies.” Trabert B, et al: J Natl Cancer Inst 106(2):djt431, 2014.

PROSTATE CANCER Dietary Lycopene Linked to Reduced Risk of Lethal Prostate Cancer, Less Tumor Angiogenesis “Dietary intake of lycopene was associated with reduced risk of lethal prostate cancer and with a lesser de-

gree of angiogenesis in the tumor,” Ke Zu, MD, of Harvard School of Public Health, Boston, and colleagues concluded after reviewing dietary information and total and lethal prostate cancer cases among 49,898 male health professionals. “Because angiogenesis is a strong progression factor, an endpoint of lethal prostate cancer may be more relevant than an endpoint of indolent prostate cancer for lycopene in the era of highly prevalent prostate-specific antigen screening,” the investigators wrote in the Journal of the National Cancer Institute. “Higher lycopene intake was inversely associated with total prostate cancer and more strongly with lethal prostate cancer (top vs bottom quintile: [hazard ratio (HR)] = 0.72; 95% CI = 0.56 to 0.94; P trend = .04),” the researchers reported. “In a restricted population of screened participants, the inverse associations became markedly stronger (for lethal prostate cancer: HR = 0.47; 95% CI = 0.29 to 0.75; P trend = .009). Comparing different measures of dietary lycopene, early intake, but not recent intake, was inversely associated with prostate cancer. Higher lycopene intake was associated with biomarkers in the cancer indicative of less angiogenic potential.” The study participants were dentists, optometrists, podiatrists, pharmacists, and veterinarians who were between 40 and 75 years old at baseline in 1986. Dietary intake was assessed by questionnaires, and prostate cancer diagnoses

continued on page 126

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In the Literature Emerging Clinical Data continued from page 125

were initially identified through reporting on questionnaires, then confirmed by a review of medical records and pathology reports. “Participants in the upper quintiles of lycopene intake were slightly younger and more likely to engage in vigorous physical activity. Men who consumed more lycopene in their diet also consumed less alcohol, coffee, and all three types of fats and slightly more fruits, vegetables, and dietary fiber,” the authors observed. “Lycopene, a carotenoid with multiple bioactivities, is found abundantly in tomato, tomato-based products, pink grapefruit, and watermelon,” the investigators noted. Some but not all previous studies had shown that dietary lycopene was associated with reduced risk of prostate cancer. In the current study, investigators “evaluated tumor biomarkers for various cellular and molecular events in relation to lycopene intake and found that higher lycopene intake was associated with lower angiogenic potential in the tumor based on the vessel size and shape. Based on these results,” the investigators stated, “we hypothesize that the consumption of a diet rich in lycopene-containing foods reduces the aggressive potential of prostate cancer by inhibiting the neoangiogenesis that occurs in tumor development.” Zu K, et al: J Natl Cancer Inst 106(2):djt430, 2014.

THYROID CANCER ‘Epidemic of Diagnosis’ of Thyroid Cancer Is Most Acute for Women The epidemiology of the increased incidence of thyroid cancer, which has nearly tripled since 1975, “suggests that it is not an epidemic of disease but rather an epidemic of diagnosis,” Louise Davies, MD, MS, and H. Gilbert Welch, MD, MPH, concluded after analyzing trends in patients diagnosed with thyroid cancer between 1975 and 2009. “Our findings demonstrate that the problem is due to the overdiagnosis of papillary thyroid cancer, an abnormality often present in people who never develop symptoms from it,” Drs. Davies and Welch wrote. “We also found that the major burden of overdiagnosis has fallen on women.” Women now have higher cancer detection rates by a 3:1 ratio.

“Over the past 35 years the absolute increase in thyroid cancer in women was almost 4 times greater than that in men. This is particularly notable because thyroid cancer prevalence at autopsy is actually greater in men than it is in women. This suggests that the problem of overdiagnosis of thyroid cancer in women has probably been present for decades,” the authors stated. Their study used data from men and women aged 18 and older diagnosed with cancer in nine geographic areas within the Surveillance, Epidemiology, and End Results (SEER) program, as well as thyroid cancer mortality from the National Vital Statistics System. Because thyroid cancer is “commonly found in people who have died of other causes, and because thyroid cancer mortality had been stable,” Dr. Davies and Dr. Welch had argued when previously reporting a doubling of thyroid cancer incidence that “the increased incidence represented overdiagnosis.” The most recent data from 2008 and 2009 showed that 39% of thyroid cancers detected were 1 cm or smaller, while tumors larger 2 cm represented a smaller portion, 33% vs 42% in 1988 to 1989. More than 90% of those diagnosed have surgery, and about 50% of those patients also receive radiation therapy. “Many also undergo a lymph node dissection,” the researchers reported. Drs. Welch and Davies are on staff at the Veterans Affairs Medical Center in White River Junction, Vermont. Dr. Welch, who is also Professor of Medicine at the Dartmouth Institute for Health Policy and Clinical Practice in Hanover, New Hampshire, recently coauthored a study—“Quantifying the benefits and harms of screening mammography” (JAMA Intern Med, December 30, 2013, early release online)— that raised the issue of overdiagnosis of breast cancer, and wrote a related op-ed piece about that study for The New York Times. (Dr. Welch discussed that study during an interview published in the February 15 issue of The ASCO Post.) He is also coauthor of a book entitled, Overdiagnosed: Making People Sick in the Pursuit of Health.

increase = 9.1 per 100,000; RR = 3.7; 95% CI = 3.4–4.0],” according to the current analysis. “The absolute increase in thyroid cancer in women [from 6.5 to 21.4 = 14.9 per 100,000 women] was almost 4 times greater than that of men [from 3.1 to 6.9 = 3.8 per 100,000 men]. The mortality rate from thyroid cancer was stable between 1975 and 2009 [approximately 0.5 deaths per 100,000].” Dr. Davies and Dr. Welch proposed several methods to address papillary thyroid cancer overdiagnosis and overtreatment. “Providing patients with randomized clinical trial data on an alternative approach—active surveillance of incidentally identified, asymptomatic, small papillary thyroid cancers—is the logical next step,” they stated. “We are pleased to see effort in this direction, both in Japan, where patients have been followed for up to 10 years with favorable results, and in the United States, where Memorial Sloan Kettering Cancer Center is successfully recruiting patients into an observational cohort,” they noted. Another approach would be to reclassify incidentally identified small thyroid neoplasms “using a term other than cancer.” In the meantime, physicians could “openly share with patients the uncertainty surrounding small thyroid cancers—explaining that many will never grow and cause harm to a patient—but it is not possible to know with certainty which ones fall into that category,” the authors advised. “Physicians’ thresholds to palpate, image, and biopsy the thyroid have likely fallen too far,” Drs. Davies and Welch added. “Clinicians need more than trial results; they also need to be asking themselves whether they are looking too hard for thyroid cancer. Patients— and in the case of thyroid cancer, particularly women—need protection not only from the harms of unnecessary treatment but also the harms of unnecessary diagnosis.” Davies L, Welch HG: JAMA Otolaryngol Head Neck Surg. February 20, 2014 (early release online).

Incidence Has Tripled

Task Force Recommends Against Beta-Carotene or Vitamin E Supplements for Primary Cancer Prevention

“Since 1975, the incidence of thyroid cancer has now nearly tripled, from 4.9 to 14.3 per 100,000 individuals [absolute increase = 9.4 per 100,000; relative rate (RR) = 2.9; 95% CI = 2.7–3.1]. Virtually the entire increase was attributable to papillary thyroid cancer: from 3.4 to 12.5 per 100,000 [absolute

PREVENTION

The U.S. Preventive Services Task Force (USPSTF) recommends against the use of beta-carotene or vitamin E supplementation for the primary prevention of cancer or cardiovascular

disease, according to an updated recommendation statement published in the Annals of Internal Medicine. “The USPSTF found adequate evidence that supplementation with [beta-carotene] increases risk for lung cancer in persons who are at increased risk for this condition,” the statement noted. Two trials—the Alpha-Tocopherol, Beta-Carotene Cancer Prevention trial and the Carotene and Retinol Efficacy Trial—showed an increased risk for lung cancer incidence and mortality and all-cause mortality in participants with a high baseline risk for lung cancer. A meta-analysis of beta-carotene trials reported an increased risk for lung cancer (pooled odds ratio= 1.24 [95% CI = 1.10 to 1.39]) in current smokers, according to the recommendation statement. Since its 2003 recommendation on vitamin supplementation, “new evidence on the use of vitamin E increased the USPSTF’s certainty about the lack of effectiveness in preventing cardiovascular disease or cancer.” This includes four randomized controlled trials that found no significant effect on cancer incidence or mortality rates and five trials showing no effect on allcause mortality. After conducting a systematic review of the evidence, the task force concluded that the current evidence is insufficient to assess the balance of benefits and harms of the use of multivitamins or single-nutrient or pairednutrient supplements (with the exception of beta-carotene and vitamin E) for the prevention of cardiovascular disease or cancer. “This recommendation applies to healthy adults without special nutritional needs (typically age 50 years and older),” the task force stated. “This recommendation does not apply to children, women who are pregnant or may become pregnant, or persons who are chronically ill, hospitalized, or have a known nutritional deficiency.” The task force added that “clinical decisions involve more considerations than evidence alone. Clinicians should understand the evidence but individualize decision making to the specific patient or situation. Similarly, the USPSTF notes that policy and coverage decisions involve considerations in addition to the evidence of clinical benefits and harms.” n Moyer V, on behalf of the U.S. Preventive Services Task Force, Ann Intern Med. February 25, 2014 (early release online).

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Letters to the Editor

Cancer Genes and Molecular Medicine: More Education Needed

read with interest and concern the Perspective piece, “Cancer Genes, Promiscuity, and the National Debt,” which appeared on page 1 of the February 1st issue of The ASCO Post. The underlying premise of this wide-ranging and provocative article would appear to be that in a rush to implement “genomics” (presumably precision therapy and molecular pathology) in oncology, old mistakes are being repeated in the absence of appropriate standardization and regulation, compounded by a detrimental “need for speed” in bringing this technology to the clinic. It would of course be difficult to argue this premise, were it in fact the case. Space limitation does not permit a point-by-point rebuttal of this rather lengthy editorial. Thus, my major concern is that there exists a major dearth of knowledge, among even our most highly trained academic oncologists, related to fundamental aspects of genomic medicine, especially as it pertains to next-generation sequencing technology and precision medicine.

Gene Expression vs Mutation Common, for example, is the conflation of “gene expression” and “gene mutation,” the latter of which is a driver

of tumorigenesis for which the related aberrant protein product represents the target, in several cases, of an FDA-approved drug based on level 1 evidence (eg, vemurafenib [Zelboraf] for a BRAF mutation in melanoma or erlotinib [Tarceva] for several EGFR mutations in non–small cell lung cancer). Gene expression, on the other hand, refers to one or more RNA products transcribed by a gene (or the genome), and is not the target of precision medicine or the output of next-generation sequencing in this context. The author writes, “Can someone explain to me the evidence-based standard algorithm for routine mathematical evaluation of gene-expression studies, including a way of dealing with the range of expressed mutations? Once that is done, perhaps we can start to consider a standard approach to the clinical interpretation of next-generation sequencing.” The answer is, “no,” because the question does not distinguish gene expression from gene mutation. Mutation is a dichotomous classification; the BRAF gene is mutant or wild-type, with no algorithm or mathematical evaluation required. Such biostatistical algorithms are required, however, for making sense of quantitative alterations in the expression of tens to hundreds of genes that

may relate to tumor classification, prognosis, or response to therapy.

Standardization and Cost Issues With respect to standardization and regulation, the responsible production of next-generation sequencing data from a patient’s tumor (or germ line), if this information is to be used to guide clinical intervention, is performed in a Clinical Laboratory Improvement Amendments (CLIA)-certified, College of American Pathologists (CAP)accredited laboratory context. Regarding “profligate expenditure in health care, which is becoming a huge component of the national debt,” readers may be interested to learn that it is rapidly becoming cheaper to sequence large panels of genes by next-generation sequencing than to sequence a handful of genes using traditional Sanger-based technology. Furthermore, next-generation sequencing is substantially more sensitive for mutation detection, a critical issue when dealing with tissue specimens of low tumor cellularity. The cost of precision drugs is and will be driving the cost of health care in this context, not the sequencing test.

Foundation of Knowledge Which brings me to my last point.

You’re not going to find it if you don’t look for it. The sequencing-based interrogation of the exomes of thousands of tumors has made feasible the creation of a comprehensive catalogue of genetic mutations as they exist in most tumor types. By using sequencing-based gene panels in the clinic, and performing whole “omics”based studies in the laboratory, we will soon know that mutations in theoretically druggable gene product X occur at a predictable frequency in tumor Y. This state of knowledge allows for the design of rational, precision therapy–based clinical trials, generating the gold standard level 1 evidence that we all seek, in a most orderly and refined fashion. Thus, “trial designs that are extrapolated from fundamental Bayesian theory” will not be necessary. I wholeheartedly agree that there exists a “need for rational thinking” in this space, but that is possible only upon a foundation of knowledge of the fundamentals of genomic medicine. n —Jeff Boyd, PhD Senior Vice-President, Molecular Medicine Fox Chase Cancer Center Philadelphia, Pennsylvania Disclosure: Dr. Boyd reported no potential conflicts of interest.

The Author Replies

read with interest the note from Jeff Boyd, PhD, Senior Vice-President for Molecular Medicine at Fox Chase Cancer Center, calling into question my recent commentary about the high costs of partly validated testing in the domain of molecular medicine. One of the oldest tricks in the book is to call into question the qualifications, knowledge, or comprehension of your critics, and it appears that Dr. Boyd has attempted to do that here. That strategy becomes more risky if you potentially have a conflict of interest when entering the debate. I absolutely agree with Dr. Boyd’s remonstration that I was careless in bracketing gene mutation and expression in a rather casual fashion in my commentary focused on cost and questionable profiteering in his line of work. In fact, if I had been sloppy in a paper focused on the science or application of molecular

biology, I would have been embarrassed for paying insufficient attention to detail and for having committed the sin of public conflation. However, I will note parenthetically that some of his note addresses the interface between targeting and tumorigenesis, which I didn’t even mention in my editorial. That said, my interest was to question a fiscal, social, and ethical set of issues and to pose questions about why our community is prepared to pay the laboratories that perform molecular assays large sums of money for technology that is not yet fully refined and where interpretation of data is still quite uncertain in many instances. I don’t have a conflict of interest in discussing this issue, beyond the fact that I don’t especially want my tax dollars to be expended on an expensive set of lab results that may not be accurate and which my clinicians (and their consulting molecu-

lar pathologists) may not yet be able to interpret. Dr. Boyd is correct that the costs are coming down, but many of the tests remain very expensive indeed. When Dr. Boyd comments that laboratories that do these tests are CLIA certified [Clinical Laboratory Improvement Amendments], that doesn’t make me feel better. That simply tells us that the laboratories and their staff have passed a defined standard; by analogy, not all FACT-certified bone marrow transplant units produce equivalent survival data, nor do all Joint Commission–certified hospitals have the same outcomes. Dr. Boyd implies—in contrast to the explicit phrasing in my editorial— that I am opposed to carrying out work in this important domain. In fact, my concern is that this is research, and much of it should not be funded by routine health-care payment systems,

but rather via research grants or venture capital, as is done in most other domains of science. VPs of Molecular Medicine are sometimes charged with carrying out science, but sometimes their key role is to run a profitable business. I know nothing of Dr. Boyd’s day job, but I hope he doesn’t have a huge conflict of interest and that concern for his bottom line isn’t the driver of his somewhat inaccurate and diversionary response. This should not detract from the question, “is this the right way to develop molecular oncology and to pay for it?” n —Derek Raghavan, MD, PhD, FACP, FRACP, FASCO President, Levine Cancer Institute Charlotte, North Carolina Disclosure: Dr. Raghavan reported no potential conflicts of interest Letters continued on page 129

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Perspective I Refuse to Capitulate continued from page 1

ordered some x-rays to rule out isthmic spondylolisthesis as a cause of the back pain, and when they came back negative, she suggested that I have physical therapy to strengthen my back muscles and take ibuprofen for the pain, which helped. Still, I had a nagging suspicion that things were not quite right. By May, my symptoms had exploded into spontaneous fevers, night sweats, and chest and back pain so severe, they kept me awake at night and frightened me. My weight, which had stabilized, started dropping again and I developed a slight cough. I knew something was seriously wrong, and I started considering cancers that commonly occur in young people, including testicular cancer, but I didn’t feel any masses, so that seemed unlikely. Next, I saw my dermatologist to check for melanoma, but I had no suspicious skin lesions. Finally, I went back to my primary care physician for a chest x-ray, which showed indistinct lesions on my lungs. I went to the hospital, was admitted, and had a CT scan performed. As I watched the images come on the screen, I could clearly see masses of lesions matting my lungs and deforming my spine. Although I’m not a thoracic oncologist, having reviewed dozens of patients’ scans for colleagues to determine if surgery offered any hope, I knew immediately what I was seeing: metastatic cancer. When I put the results of the scans together with my lab values, which showed anemia and other system ab-

normalities, I knew things looked grim. I thought to myself, I have a matter of months to live.

Seeking Survival Statistics After being in medical training for 11 years—and poised to launch an excellent career in neurosurgery and neuroscience—the news that I had stage IV non–small cell EGFR-positive lung cancer was devastating. When I saw my oncologist, I asked her what

was the study result in nonsmoking, 36-year-old neurosurgeons?

Having No Regrets I was prescribed erlotinib (Tarceva) and, fortunately, I’m having a really good response to the drug. The majority of the spots on my lungs have disappeared, and the primary lung nodule has shrunk. I’ve put back all the weight I lost, and last November I returned to work full-time.

I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way? —Paul Kalanithi, MD

my Kaplan-Meier survival estimate was. She flatly refused to tell me. Instead, she appropriately laid out my treatment options. What was interesting to me is that when she talked about my options, she suggested that I could go back to work someday. Even though my oncologist wouldn’t give me statistics on my prognosis, I knew from my own research that large general studies showed that between 70% and 80% of patients with lung cancer died within 2 years of their diagnosis. Of course, most of those patients were older and heavy smokers. What

Some days I feel that maybe I should be in a less demanding, less stressful job, but doing that would be a capitulation to cancer. Yes, life is harder now. I’m a little more tired than I used to be, and everything takes a bit more effort, but I can operate every day, sometimes for more than 12 hours a day. As I continue to get stronger, I’m beginning to feel that it’s possible I will have a very long career, although I still realize I may not. At least I know what’s important to me. You have to ask yourself, which do you want more: to have a career and life that

you love, knowing that they can come crashing down if you get sick again, or to not do those things and feel regret? I aim toward the former.

Appreciating the Stresses of Living At the moment, my life is at the maximum point of uncertainty. I need to get my career trajectory fully back on course, and my wife is pregnant with our first child. So life is really exciting—and stressful. But these are the stresses of living, not of dying. The fact that I get to deal with all of the worries of having a highly demanding career and a new family is a blessing. Being both a doctor and a patient has been an interesting experience. I’ve gotten occasional advice from well-meaning colleagues who say that coming back to neurosurgery is crazy. Some of their advice is quite useful because their feedback helps me assess whether I’m making the right decisions or in complete denial of the seriousness of my medical situation. But the flip side of their advice is that it can persuade you to limit your goals, and I’d rather not let cancer do that. I’ve been fortunate to overcome the immediate challenge of having advanced lung cancer and wondering how much time I have left. Now the question is, how do I proceed toward realizing my hopes and ambitions in a responsible and productive way? The answer may mean building backup plans into the equation in case the cancer becomes uncontrollable and aggressive. In the meantime, I’m pursuing the things that drive me. The fact of death is unsettling. Yet there is no other way to live. n

Letters to the Editor continued from page 127

After Next-Generation Sequencing: Guiding Patients to the Right Treatment

n the near future, community oncologists will be tasked with helping patients interpret the results of next-generation sequencing of their tumors. Specifically, we will help patients choose an academic center with a phase I targeted therapy program that is a plausible fit for their disease. Unfortunately, Web pages such as clinicaltrials.gov and institutionspecific sites that could provide this sort of information have proven no-

toriously difficult to maintain in real time. An e-mail or phone call to a specific investigator is often helpful, but if an oncologist is in a city or state with several academic institutions, this approach can prove impractical. And even the most informed investigator at a large institute cannot know the current status of all relevant trials at that facility. I propose a HIPAA-compliant, secure website where a patient’s clinical

and genomic data can be uploaded and viewed by academic oncologists in a specific geographic area for a brief, defined time period. Such a platform would allow for and encourage comments from investigators who might be from the same or different institutions. In addition to providing the patient and community oncologist with the current status of possible trials in a timely fashion, investigators and cli-

nicians who don’t frequently interact at the tumor boards would be updated as well. A sense of “competition” introduced might be uncomfortable at first, but the potential payoff—increased protocol enrollment—would be worth it. n —John Jakob, MD PhD Summa Cancer Institute Medina, Ohio Disclosure: Dr. Jakob reported potential conflicts of interest.

T:10.25" S:9.5"

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Coming Next Month

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 This is a brief summary of information about AVASTIN. Before prescribing, please see full Prescribing Information. WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE

Issues in Oncology Breast Screening Mammography* Coming in The ASCO Post, April 15, 2014

A Journal Spotlight on the Recent Report by Miller AB, et al:

wenty-five year follow-up for breast cancer incidence and mortality of the Canadian National Breast Screening Study [CNBSS]: Randomised screening trial. Published in BMJ 348:g366, 2014. “No mortality benefit of mammography screening in 25-year followup of Canadian National Breast Screening Study”

With Commentary on the Study From: Daniel B. Kopans, MD, FACR, Professor of Radiology, Harvard Medical School, and Senior Radiologist, Breast Imaging Division, Massachusetts General Hospital, Boston T:13"

“The CNBSS was a large trial, but larger numbers do not compensate for major trial Daniel B. Kopans, MD, FACR errors… The results of the CNBSS should be dropped from the review [U.S. Preventive Services Task Force and American Cancer Society] or viewed, at best, with great s kepticism.” Therese B. Bevers, MD, Professor, Department of Clinical Cancer Prevention, The University of Texas MD Anderson Cancer Center, Houston “The strengths of the CNBSS are contrasted by a vast collection of flaws that render any findings, past or present, meaningless… At this Therese B. Bevers, MD time, our greatest tool for the early detection of breast cancer remains screening mammography.”

Sudhir Srivastava, PhD, MPH

Sudhir Srivastava, PhD, MPH, Chief, Cancer Biomakers Research Group, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda, and Barnett S. Kramer, MD, MPH, Director, Division of Cancer Prevention, National Cancer Institute, National Institutes of Health, Bethesda “While debates on the efficacy of mammography screening continue, we should not overlook strategies to mitigate harms. Specifically, how can we mitigate the harms of overdiagnosis?”

Barnett S. Kramer, MD, MPH

*Early release online, March 2014, ASCOPost.com

Visit The ASCO Post online at ASCOPost.com

Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin‑treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), Adverse Reactions (6.1).] 1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine‑irinotecan‑ or fluoropyrimidine‑ oxaliplatin‑based chemotherapy, is indicated for the second‑line treatment of patients with metastatic colorectal cancer who have progressed on a first‑line Avastin‑containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer. [See Clinical Studies (14.2).] 1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel. 1.3 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease in adult patients following prior therapy as a single agent. The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease‑related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).] 1.4 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).] The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever. Perforation can be complicated by intra‑abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin. Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).] 5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery. In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).] Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention. The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half‑life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).] Necrotizing fasciitis including fatal cases, has been reported in patients treated with Avastin; usually secondary to wound healing complications, gastrointestinal perforation or fistula formation. Discontinue Avastin therapy in patients who develop necrotizing fasciitis. [See Adverse Reactions (6.3).] 5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five‑fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade ≥ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%. [See Adverse Reactions (6.1).] Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non‑squamous non‑small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone. In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%). Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage. Do not administer Avastin to patients with recent history of hemoptysis of ≥ 1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

AVASTIN® (bevacizumab) 5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤ 0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy. Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).] 5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm. Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.6% compared to 0.8% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, diabetes, or age greater than 65 years. [See Use in Specific Populations (8.5).] The safety of resumption of Avastin therapy after resolution of an ATE has not been studied. Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).] 5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%. Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of Avastin. Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive encephalopathy. [See Dosage and Administration (2.4).] 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of < 0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).] 5.8 Proteinuria The incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy. Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection. Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is < 2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. [See Dosage and Administration (2.4).] Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post‑marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 5.10 Ovarian Failure The incidence of ovarian failure was higher (34% vs. 2%) in premenopausal women receiving Avastin in combination with mFOLFOX chemotherapy as compared to those receiving mFOLFOX chemotherapy alone for adjuvant treatment for colorectal cancer, a use for which Avastin is not approved. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. [See Adverse Reactions (6.1), Use in Specific Populations (8.6).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] • Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] • Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] • Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] • Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] • Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] • Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] • Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).] • Ovarian Failure [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).] The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions. 6.1 Clinical Trial Experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data below reflect exposure to Avastin in 4599 patients with CRC, non‑squamous NSCLC, glioblastoma, or mRCC trials including controlled (Studies 1, 2, 4, 5 and 8) or uncontrolled, single arm (Study 6) treated at the recommended dose and schedule for a median of 8 to 23 doses of Avastin. [See Clinical Studies (14).] The population was aged 18‑89 years (median 60 years), 45.4% male and 85.8% (3729/4345) White. The population included 2184 first‑ and second‑line mCRC patients who received a median of 10 doses of Avastin, 480 first‑line metastatic NSCLC patients who received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of

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AVASTIN® (bevacizumab) 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin. These data also reflect exposure to Avastin in 363 patients with metastatic breast cancer (MBC) who received a median of 9.5 doses of Avastin, 669 female adjuvant CRC patients who received a median of 23 doses of Avastin and exposure to Avastin in 403 previously untreated patients with diffuse large B‑cell lymphoma (DLBCL) who received a median of 8 doses of Avastin. Avastin is not approved for use in MBC, adjuvant CRC, or DLBCL. Surgery and Wound Healing Complications The incidence of post‑operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy. Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone. In Study 6, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] Venous Thromboembolic Events The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, more patients in the Avastin containing arm experienced deep venous thrombosis (34 vs. 19 patients ) and intra‑abdominal venous thrombosis (10 vs. 5 patients). The risk of developing a second thromboembolic event while on Avastin and oral anticoagulants was evaluated in two randomized studies. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event (VTE). Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone. In a second, randomized, 4‑arm study in 1401 patients with mCRC, prospectively evaluating the incidence of VTE (all grades), the overall incidence of first VTE was higher in the Avastin containing arms (13.5%) than the chemotherapy alone arms (9.6%). Among the 116 patients treated with anticoagulants following an initial VTE event (73 in the Avastin plus chemotherapy arms and 43 in the chemotherapy alone arms), the overall incidence of subsequent VTEs was also higher among the Avastin treated patients (31.5% vs. 25.6%). In this subgroup of patients treated with anticoagulants, the overall incidence of bleeding, the majority of which were Grade 1, was higher in the Avastin treated arms than the chemotherapy arms (27.4% vs. 20.9%). [See Dosage and Administration (2.4).]

Ovarian Failure The incidence of new cases of ovarian failure (defined as amenorrhoea lasting 3 or more months, FSH level ≥ 30 mIU/mL and a negative serum β‑HCG pregnancy test) was prospectively evaluated in a subset of 179 women receiving mFOLFOX chemotherapy alone (n = 84) or with Avastin (n = 95). New cases of ovarian failure were identified in 34% (32/95) of women receiving Avastin in combination with chemotherapy compared with 2% (2/84) of women receiving chemotherapy alone [relative risk of

Arm 2 IFL+ + Avastin (n = 392) 87%

7% 5% 5%

10% 8% 8%

2% 5% 1% 1%

12% 9% 3% 3%

25% 2%

34% 4%

31% 14%

37% 21%

AVASTIN® (bevacizumab) In patients receiving Avastin alone (N = 84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥ 3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection. In patients receiving Avastin alone or Avastin plus irinotecan (N = 163), the incidence of Avastin‑related adverse events (Grade 1–4) were bleeding/ hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%). Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 8. Grade 3–5 adverse events occurring at a higher incidence ( ≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma). Grade 1–5 adverse events occurring at a higher incidence ( ≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 3. Table 3 NCI‑CTC Grades 1−5 Adverse Events in Study 8 (Occurring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) System Organ Class/ IFN‑α + Placebo (n = 304) Preferred terma Gastrointestinal disorders Diarrhea 16% General disorders and administration site conditions Fatigue 27% Investigations Weight decreased 15% Metabolism and nutrition disorders Anorexia 31% Musculoskeletal and connective tissue disorders Myalgia 14% Back pain 6% Nervous system disorders Headache 16% Renal and urinary disorders Proteinuria 3% Respiratory, thoracic and mediastinal disorders Epistaxis 4% Dysphonia 0% Vascular disorders Hypertension 9%

Central laboratories were collected on Days 1 and 21 of each cycle. Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2.

Grade 1–4 adverse events which occurred at a higher incidence ( ≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued. Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1 (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109) Body as a Whole Pain Abdominal Pain Headache Cardiovascular Hypertension Hypotension Deep Vein Thrombosis Digestive Vomiting Anorexia Constipation Stomatitis Dyspepsia GI Hemorrhage Weight Loss Dry Mouth Colitis Hemic/Lymphatic Thrombocytopenia Nervous Dizziness Respiratory Upper Respiratory Infection Epistaxis Dyspnea Voice Alteration Skin/Appendages Alopecia Skin Ulcer Special Senses Taste Disorder Urogenital Proteinuria

55% 55% 19%

61% 61% 26%

62% 50% 26%

14% 7% 3%

23% 15% 9%

34% 7% 6%

47% 30% 29% 18% 15% 6% 10% 2% 1%

52% 43% 40% 32% 24% 24% 15% 7% 6%

47% 35% 29% 30% 17% 19% 16% 4% 1%

20%

26%

19%

39% 10% 15% 2%

47% 35% 26% 9%

40% 32% 25% 6%

26% 1%

32% 6%

6% 6%

14%

21%

24%

36%

IFN‑α + Avastin (n = 337) 21% 33% 20% 36% 19% 12% 24% 20% 27% 5% 28%

Adverse events were encoded using MedDRA, Version 10.1.

Avastin in Combination with FOLFOX4 in Second‑line mCRC Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2. Avastin in Combination with Fluoropyrimidine‑Irinotecan or Fluoropyrimidine‑ Oxaliplatin Based Chemotherapy in Second‑line mCRC Patients who have Progressed on an Avastin Containing Regimen in First‑line mCRC: No new safety signals were observed in Study 4 when Avastin was administered in second line mCRC patients who progressed on an Avastin containing regimen in first line mCRC. The safety data was consistent with the known safety profile established in first and second line mCRC. Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 5. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria (3% vs. 0%). Glioblastoma All adverse events were collected in 163 patients enrolled in Study 6 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 3: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) and pulmonary embolism (5 vs. 1). 6.2 Immunogenicity As with all therapeutic proteins, there is a potential for an immune response to Avastin. In clinical trials of adjuvant colon carcinoma, 14 of 2233 evaluable patients (0.63%) tested positive for treatment‑emergent anti‑bevacizumab antibodies detected by an electrochemiluminescent (ECL) based assay. Among these 14 patients, three tested positive for neutralizing antibodies against bevacizumab using an enzyme‑linked immunosorbent assay (ELISA). The clinical significance of these anti‑product antibody responses to bevacizumab is unknown. Immunogenicity assay results are highly dependent on the sensitivity and specificity of the test method and may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading. 6.3 Postmarketing Experience The following adverse reactions have been identified during post‑approval use of Avastin. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Body as a Whole: Polyserositis Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion Eye disorders (from unapproved intravitreal use for treatment of various ocular disorders): Permanent loss of vision; Endophthalmitis (infectious and sterile); Intraocular inflammation; Retinal detachment; Increased intraocular pressure; Hemorrhage including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Ocular hyperemia; Ocular pain or discomfort Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Hemic and lymphatic: Pancytopenia Hepatobiliary disorders: Gallbladder perforation Infections and infestations: Necrotizing fasciitis, usually secondary to wound healing complications, gastrointestinal perforation or fistula formation Musculoskeletal: Osteonecrosis of the jaw Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia Systemic Events (from unapproved intravitreal use for treatment of various ocular disorders): Arterial thromboembolic events, Hypertension, Gastrointestinal perforation, Hemorrhage 7 DRUG INTERACTIONS A drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8 patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. In Study 8, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.

AVASTIN® (bevacizumab) 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C There are no adequate or well controlled studies of bevacizumab in pregnant women. While it is not known if bevacizumab crosses the placenta, human IgG is known to cross the placenta Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab demonstrated teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).] Because of the observed teratogenic effects of bevacizumab in animals and of other inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus. 8.3 Nursing Mothers It is not known whether Avastin is secreted in human milk. Human IgG is excreted in human milk, but published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).] 8.4 Pediatric Use The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established. Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma. Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment. 8.5 Geriatric Use In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥ 65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients. In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue. In Study 5, patients aged ≥65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Precautions (5.8).] Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased cough, and voice alteration. In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥ 65 years and 1127 patients < 65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).] 8.6 Females of Reproductive Potential Avastin increases the risk of ovarian failure and may impair fertility. Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin. Long term effects of Avastin exposure on fertility are unknown. In a prospectively designed substudy of 179 premenopausal women randomized to receive chemotherapy with or without Avastin, the incidence of ovarian failure was higher in the Avastin arm (34%) compared to the control arm (2%). After discontinuation of Avastin and chemotherapy, recovery of ovarian function occurred in 22% (7/32) of these Avastin‑treated patients. [See Warnings and Precautions (5.10), Adverse Reactions (6.1).] 10 OVERDOSAGE The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

Avastin® (bevacizumab) Manufactured by: Genentech, Inc. A Member of the Roche Group 1 DNA Way South San Francisco, CA 94080‑4990

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Congestive Heart Failure (CHF) The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with metastatic breast cancer (MBC), an indication for which Avastin is not approved, the incidence of Grade 3–4 CHF was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied. In previously untreated patients with diffuse large B‑cell lymphoma (DLBCL), an indication for which Avastin is not approved, the incidence of CHF and decline in left‑ventricular ejection fraction (LVEF) were significantly increased in the Avastin plus R‑CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) arm (n=403) compared to the placebo plus R‑CHOP arm (n=379); both regimens were given for 6 to 8 cycles. At the completion of R‑CHOP therapy, the incidence of CHF was 10.9% in the Avastin plus R‑CHOP arm compared to 5.0% in the R‑CHOP alone arm [relative risk (95% CI) of 2.2 (1.3, 3.7)]. The incidence of a LVEF event, defined as a decline from baseline of 20% or more in LVEF or a decline from baseline of 10% or more to a LVEF value of less than 50%, was also increased in the Avastin plus R‑CHOP arm (10.4%) compared to the R‑CHOP alone arm (5.0%). Time to onset of left‑ventricular dysfunction or CHF was 1‑6 months after initiation of therapy in at least 85% of the patients and was resolved in 62% of the patients experiencing CHF in the Avastin arm compared to 82% in the control arm.

NCI‑CTC Grade 3‑4 Events Body as a Whole Asthenia Abdominal Pain Pain Cardiovascular Hypertension Deep Vein Thrombosis Intra‑Abdominal Thrombosis Syncope Digestive Diarrhea Constipation Hemic/Lymphatic Leukopenia Neutropeniaa

Arm 1 IFL+ + Placebo (n = 396) 74%

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Proteinuria Grade 3–4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4, 5 and 8. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 8, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 8). In an exploratory, pooled analysis of 8,273 patients treated in 7 randomized clinical trials, 5.4% (271 of 5037) of patients receiving Avastin in combination with chemotherapy experienced Grade ≥ 2 proteinuria. The Grade ≥ 2 proteinuria resolved in 74.2% (201 of 271) of patients. Avastin was re‑initiated in 41.7% (113 of 271) of patients. Of the 113 patients who re‑initiated Avastin, 47.8% (54 of 113) experienced a second episode of Grade ≥ 2 proteinuria. [See Warnings and Precautions (5.8).]

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double‑blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo. Avastin was administered at 5 mg/kg every 2 weeks. All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence ( ≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1. Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1 (Occurring at Higher Incidence [ ≥ 2 %] Avastin vs. Control)

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Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 5, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)]. In Study 6, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3–5 infection was 10%.

AVASTIN® (bevacizumab) 14 (95% CI 4, 53)]. After discontinuation of Avastin treatment, recovery of ovarian function at all time points during the post‑treatment period was demonstrated in 22% (7/32) of the Avastin‑treated women. Recovery of ovarian function is defined as resumption of menses, a positive serum β‑HCG pregnancy test, or a FSH level < 30 mIU/mL during the post‑ treatment period. Long term effects of Avastin exposure on fertility are unknown. [See Warnings and Precautions (5.10), Use in Specific Populations (8.6).]

In combination with IV 5-FU–based chemotherapy in first- or second-line MCRC or fluoropyrimidine-based chemotherapy following a first-line Avastin-containing regimen...

Think Avastin

Continuing to deliver proven overall survival Avastin is the only FDA-approved biologic proven to increase OS in 3 large Phase III trials in first- and second-line MCRC

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months months months

months months

Median OS Median MedianOS OS improvement* improvement* improvement*

Median MedianOS OS improvement improvement† †

1.4 1.4 months months

months

Median MedianOS OS OS ‡‡ ‡ improvement improvement improvement

First-line Study 2107:

Second-line Study E3200:

The TML study§:

A double-blind, controlled clinical trial in patients with previously untreated MCRC1,2

An open-label, controlled clinical trial in Avastin-naive MCRC patients1

An open-label, controlled clinical trial in patients who progressed on an Avastincontaining regimen1,3

*20.3 months with Avastin plus IFL (n=402) vs 15.6 months with placebo plus IFL (n=411) (HR=0.66 [95% CI, 0.54–0.81], P<0.001).1,4 13.0 months with Avastin plus FOLFOX4 (n=286) vs 10.8 months with FOLFOX4 alone (n=291) (HR=0.75 [95% CI, 0.63–0.89], P=0.001).1,4 ‡ 11.2 months with Avastin plus fluoropyrimidine-based chemotherapy|| (n=409) vs 9.8 months with fluoropyrimidine-based chemotherapy|| alone (n=411) (HR=0.81 [95% CI, 0.69–0.94], P=0.0057).1 § TML=Treatment through Multiple Lines (first and second line). || Chemotherapy combinations included either an irinotecan- or oxaliplatin-containing regimen. After first progression, chemotherapy was switched: oxaliplatin → irinotecan or irinotecan → oxaliplatin.1 †

IV=intravenous; 5-FU=5-fluorouracil; MCRC=metastatic colorectal cancer; OS=overall survival; IFL=5-FU/leucovorin (LV)/irinotecan; HR=hazard ratio; CI=confidence interval; FOLFOX4=5-FU/LV/oxaliplatin.

Indications

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy. Avastin, in combination with fluoropyrimidine-irinotecan- or fluoropyrimidineoxaliplatin-based chemotherapy, is indicated for the second-line treatment of patients with metastatic colorectal cancer who have progressed on a first-line Avastin-containing regimen. Limitation of Use: Avastin is not indicated for adjuvant treatment of colon cancer.

Boxed WARNINGS

Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls — The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies — Discontinue Avastin in patients with GI perforation Surgery and wound healing complications — The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients — Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined — Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound healing complications requiring medical intervention Hemorrhage — Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6% — Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood) — Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious adverse events

Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.6%) — Proteinuria (nephrotic syndrome, <1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%) Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

AVA0001557002

Printed in USA.

Inform females of reproductive potential of the risk of ovarian failure prior to starting treatment with Avastin

Most common adverse events

Across indications, the most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

Pregnancy warning

Avastin may impair fertility Based on animal data, Avastin may cause fetal harm Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother

Indication-specific adverse events

In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%). These data are likely to underestimate the true adverse event rates due to the reporting mechanisms used in this study When continued beyond first progression in MCRC, no new safety signals were observed in the TML study (ML18147) when Avastin was administered in second-line MCRC patients who progressed on an Avastin containing regimen in first-line MCRC. The safety data was consistent with the known safety profile established in first- and second-line MCRC You may report side effects to the FDA at (800) FDA-1088 or www.fda.gov/medwatch. You may also report side effects to Genentech at (888) 835-2555. Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. Avastin Prescribing Information. Genentech, Inc. March 2013. 2. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342. 3. Bennouna J, Sastre J, Arnold D, et al. Lancet Oncol. 2013;14:29-37. 4. Data on file. Genentech, Inc.

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