TAP Vol 4 Issue 7 by Harborside Press LLC

CancerLinQ Prototype

| Prolonged VEGF Inhibition

| Rally for Medical Research

VOLUME 4, ISSUE 7

MAY 1, 2013

Editor-in-Chief, James O. Armitage, MD

ASCOPost.com

AACR Annual Meeting

Higher HER2 Expression Linked to Best Results with T-DM1 in Patients with HER2-positive Metastatic Breast Cancer

Ibrutinib CLL Trial: Where Is the Equipoise?

By Alice Goodman

By Susan O’Brien, MD

biomarker analysis of the pivotal EMILIA trial suggests that women with metastatic HER2positive breast cancer with tumors that have high expression of HER2 derive the most robust benefit from treatment with the antibody-drug conjugate T-DM1 (also now known as ado-trastuzumab emtansine [Kadcyla]). The study, which was presented at the Annual Meeting José Baselga, MD of the American Association for Cancer Research,1 also suggests that the presence of PI3 kinase (PIK3CA) mutations in HER2positive breast tumors does not compromise the

effectiveness of T-DM1, but does lead to poorer responses to conventional HER2-targeted therapies such as trastuzumab (Herceptin) and lapatinib (Tykerb).

Not a Uniform Disease “HER2-positive breast cancer is not a uniform disease. Each patient is different. The findings [related to HER2 expression and PIK3CA] are an important step toward identifying the best therapy for individual patients with HER2-positive breast cancer. These data will help us as we identify a panel of molecular features that we can use to make informed treatment decisions,” stated José Baselga, MD, Physician-in-Chief at Memorial Sloan-Kettering Cancer Center in New York.

he RESONATE trial is randomly assigning patients with refractory or relapsed CLL to either ofatumumab (Arzerra) or the investigational oral agent ibrutinib. Ofatumumab is an anti-CD20 monoclonal antibody like rituximab (Rituxan), but is more potent as a single agent. It was approved for refractory CLL about 3½ years ago. Ibrutinib is a novel Bruton’s tyrosine kinase (BTK) inhibitor that has shown promising results in early data for CLL, leading to the current RESONATE trial that just recently completed enrollment. The primary endpoint is progression-free survival; however, overall survival is one of the secondary endpoints. Once the primary continued on page 25

continued on page 10

SSO Annual Cancer Symposium

Does Every Melanoma Patient with a Positive Sentinel Node Need More Lymph Nodes Removed?

Dr. O’Brien is Ashbel Smith Professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center, Houston.

MORE IN THIS ISSUE

By Caroline McNeil

hen sentinel node biopsy was shown to predict whether early melanoma had spread to regional lymph nodes, it revolutionized care. Before that, dissection of all regional lymph nodes was the norm for most patients. After that, the standard of care

became a sentinel node biopsy and then—only if the sentinel node or nodes were positive—a completion lymph node dissection. Another revolution may now be brewing: A major, current question in melanoma is whether even patients with a positive sentinel node need to undergo a completion lymph node dissection. That question was We create the potential for explored in a formal debate between Daniel G. Coit, significant complications with these MD, a surgical oncologist at operations [completion lymph node Memorial Sloan-Kettering Cancer Center, New York, dissections]. and Charles M. Balch, —Daniel G. Coit, MD MD, Professor of Surgery at The University of Texas

Oncology Meetings Coverage NCCN Conference�� 3 SSO Symposium �� 7 AACR Annual Meeting��10 Metastatic Colorectal Cancer�� 11 Access to Care ��18 Ibrutinib’s Road to Approval �� 24 Direct from ASCO �� 30-33 FDA Update �� 37, 39 Younger Women with Breast Cancer �� 40 Clinical Data on Cancer Management �� 50

continued on page 7

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The ASCO Post | MAY 1, 2013

PAGE 2

News Technology

CancerLinQ Prototype Demonstrates Use of Big Data in Clinical Care

Editorial Board

By Caroline McNeil

James O. Armitage, MD Editor-in-Chief

Michael P. Link, MD Stanford University Medical Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

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

Associate Editors

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

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 Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD National Comprehensive Cancer Network Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology

William T. McGivney, PhD Philadelphia, Pennsylvania James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

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

International Editors

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Bishoy Morris Faltas, MD Weill Cornell Medical College John A. Fracchia, MD New York Urological Associates Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

—Sandra M. Swain, MD, FACP

Stanley H. Winokur, MD Singer Island, Florida

Nancy E. Davidson, MD University of Pittsburgh Cancer Institute

David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

[The CancerLinQ prototype] was built to confirm that it’s possible to do and to show proof of principle, and it has.

Lynn D. Wilson, MD Yale University School of Medicine

Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria

Paul F. Engstrom, MD Fox Chase Cancer Center

“we’ve shown that we can compile and analyze data in any format, in real time,” said ASCO President Sandra M. Swain, MD, FACP, who is Medical Director of the Washington Cancer Institute at the MedStar Washington Hospital Center in Washington, DC. The prototype also showed that it was

Steven T. Rosen, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

E. David Crawford, MD University of Colorado

George D. Demetri, MD Dana-Farber Cancer Institute

SCO has unveiled the prototype of a computer system that will allow oncologists, from their desks, to leverage “big data” to measure the quality of care that their practices provide. The prototype is a major step in the development of CancerLinQ, a system that will eventually allow millions

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 Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

of electronic health records to interact with analytic software and clinical decision-making tools. The prototype was shown at the National Press Club on March 27 in conjunction with a panel discussion on big data in cancer care. With more than 100,000 patient records entered by several different cancer centers around the country,

possible to provide decision support in the clinic and give physicians feedback related to quality practice. Although CancerLinQ is a multiyear effort, this functional prototype is a major step forward. “It was built to confirm that it’s possible to do and to show proof of principle,” Dr. Swain said, “and it has.” continued on page 36

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 wendy@harborsidepress.com or fax (631) 692-0805. Copyright ©2013 by Harborside Press®, LLC. All rights reserved. Reproduction in whole or in part, in any form, without prior written permission of the publisher is prohibited. 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.

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PAGE 3

National Comprehensive Cancer Network Annual Conference Gastrointestinal Oncology

Medical Oncologists Underestimate Resectability of Liver Metastases By Caroline Helwick

edical oncologists are apt to underestimate the resectability of liver metastases in patients with colorectal cancer and therefore often fail to refer potential surgical candidates for surgical consultation, according to a study presented at the 18th Annual Conference of the National Comprehensive Cancer Network (NCCN).1 For metastases limited to the liver, resectability can often be curative. Thus, it is important for oncologists to identify appropriate surgical candidates.

and distribution of liver metastases. Investigators recruited 200 medical oncologists (190 evaluable) from the Net-

Ongoing Controversy

work for Oncology Communication and Research to participate. All had been practicing for 5 to 35 years and saw an average of 15 patients with colorectal cancer per month. The participants were queried regarding a single patient profile with 10 different sets of liver CT images, representing liver metastases of varying extent. On reviewing the images and a summary radiologic report, respondents were asked to assess resectability based on their expectation that all gross disease could be resected. They designated each case as currently resectable, poten-

“Despite published surgical guidelines concerning definitions of resectability, there is still controversy about which patients are optimal candidates for immediate resection and when such patients should have a surgical consultation,” said Michael A. Choti, MD, of Johns Hopkins University, Baltimore. This study explored medical oncologists’ assessment of the technical aspects of resectability by using a standard clinical scenario to control for oncologic variability while varying the anatomic parameters of metastatic size, number,

tially convertible with chemotherapy response, or unresectable. They were also asked whether surgical consultation was

Significant inconsistencies continue to exist among clinicians regarding the definition of resectability, the need for surgical consultation, and the use of preoperative chemotherapy in potentially resectable liver-limited metastatic colorectal cancer patients. —Michael A. Choti, MD

About 50% of the medical oncologists considered these cases to be potentially convertible to resectability after a significant response to systemic therapy. About 40% deemed the cases to be unresectable as displayed now or after a chemotherapy response. Overall, medical oncologists’ resectability ratings were congruent with those of the expert surgeons in only 37% of the cases. For all cases considered to be resectable (8 of the 10), only 50% of the medical oncologists would have recommended surgical consultation, Dr. Choti reported.

Significant Inconsistencies

Assessing Resectability of Liver Metastases ■ In a study comparing medical oncologists’ resectability ratings for liver

metastases with those of expert surgeons, opinions matched in only 37% of the cases.

■ For all cases considered to be resectable by the expert panel, only 50% of

the medical oncologists would have recommended surgical consultation.

■ Given that resectability can often be curative for metastases limited to

the liver, the identification of surgical candidates is important, and future investigations should examine the reasons for the discordant opinions.

warranted. Their recommendations were compared with those of an expert panel of three hepatic surgical oncologists.

Medical Oncologists Miss Resectable Cases “While the rank order of potentially resectable disease was similar between medical oncologists and expert surgeons, the medical oncologists were much less likely to consider a patient resectable compared to the expert panel,” Dr. Choti reported. “Even among resectable or convertible patients, medical oncologists were less likely to recommend initial surgical consultation. In situations in which the medical oncologist considered patients to be clearly resectable, initial resection was recommended only 62% of the time.” Three tumors were deemed most resectable by the expert panel, but only 89%, 64%, and 63% of the medical oncologists, respectively, thought so. All three of these scan sets showed disease restricted to one lobe of the liver and the presence of two or fewer lesions in total.

“Even with increasing awareness regarding the benefit of multimodality therapy for potentially curable patients with colorectal liver metastases and NCCN guidelines regarding management, significant inconsistencies continue to exist among clinicians regarding the definition of resectability, the need for surgical consultation, and the use of preoperative chemotherapy in potentially resectable liver-limited metastatic colorectal cancer patients,” he concluded. He suggested future studies should evaluate the reasons for this discordance with expert opinion, and added that oncologists clearly need more education on this topic. n

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

Reference 1. Choti MA, Green MR, Wong SL, et al: Medical oncologists’ assessment of resectability in patients with liver-limited metastatic colorectal cancer. Abstract AB2013-3. Presented March 15, 2013.

Visit The ASCO Post at the ASCO Annual Meeting May 31 - June 4, 2013 The ASCO Post BOOTH 12096 • Harborside Press BOOTH 13096 Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press®, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and

the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press®, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

Important Safety Information

Additional Important Safety Information

Boxed WARNING: Embryo-Fetal Toxicity • Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception — Verify pregnancy status prior to the initiation of PERJETA. 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 — Encourage women who may be exposed to PERJETA during pregnancy to enroll in the MotHER Pregnancy Registry by contacting 1-800-690-6720 — Monitor patients who become pregnant during PERJETA therapy for oligohydramnios

Left Ventricular Dysfunction • Left ventricular dysfunction, which includes symptomatic left ventricular systolic dysfunction (LVSD) (congestive heart failure) and decreases in left ventricular ejection fraction (LVEF), occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group • Assess LVEF prior to initiation of PERJETA and at regular intervals (eg, every 3 months) during treatment to ensure that LVEF is within your institution’s normal limits • Withhold PERJETA and Herceptin and repeat LVEF assessment within 3 weeks in patients with significant decrease in LVEF. Discontinue PERJETA and Herceptin if the LVEF has not improved or has declined further Infusion‑Associated Reactions, Hypersensitivity Reactions/Anaphylaxis • PERJETA has been associated with infusion and hypersensitivity reactions • When all drugs were administered on the same day, the most common infusion reactions in the PERJETA-treated group (≥1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting

F O R T H E F I R S T‑ L I N E T R E AT M E N T O F H E R 2 +* M E TA S TAT I C B R E A S T C A N C E R

STRENGTHEN HER DEFENSE

Indication: PERJETA® (pertuzumab) is a HER2/neu receptor antagonist indicated in combination with Herceptin® (trastuzumab) and docetaxel for the treatment of patients with HER2‑positive metastatic breast cancer who have not received prior anti‑HER2 therapy or chemotherapy for metastatic disease.

Extend progression‑free survival (PFS) with an FDA‑approved HER2 dimerization inhibitor1,2 were observed across several • Consistent PFS results 1

•

Placebo + Herceptin + docetaxel

PERJETA + Herceptin + docetaxel

100 90

HR = 0.62‡ 95% CI [0.51‑0.75] P<0.0001

80 70

18.5 MONTHS

60 PFS (%)

•

patient subgroups At the time of analysis, there were 191 (47.5%) and 242 (59.6%) patients with a PFS event in the PERJETA + Herceptin + docetaxel and placebo + Herceptin + docetaxel arms, respectively1 The most common adverse reactions (ARs) (>30%) seen with the PERJETA-based regimen were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy1

6.1-Month Improvement in Median IRF†-Assessed PFS1

12.4 MONTHS

40 30 20 10 0

* HER2+ = human epidermal growth factor receptor 2 positive. † IRF = independent review facility. ‡ Stratified by prior treatment status and geographic region.

402 406

345 311

267 209

139 93

32 17

10 7

0 0

MONTHS P+H+D Pl+H+D

83 42 Patients at risk

• In the randomized trial, the overall frequency of hypersensitivity reactions/anaphylaxis

was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group • If a significant infusion reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions HER2 Testing • Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown Most Common Adverse Reactions • The most common adverse reactions (>30%) seen with PERJETA in combination with Herceptin and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy Please see brief summary of PERJETA full Prescribing Information including Boxed WARNING for additional Important Safety Information on the following pages. 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. For more information, scan the QR code or visit www.PERJETA.com.

PER0001010502

References: 1. PERJETA Prescribing Information. Genentech, Inc. June 2012. 2. Baselga J, Cortés J, Kim S‑B, et al; CLEOPATRA Study Group. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109‑119.

Printed in USA.

(01/13)

PERJETA® (pertuzumab) INJECTION, FOR INTRAVENOUS USE INITIAL U.S. APPROVAL: 2012 WARNING: EMBRYO-FETAL TOXICITY See full prescribing information for complete boxed warning. Exposure to PERJETA can result in embryo-fetal death and birth defects. Studies in animals have resulted in oligohydramnios, delayed renal development, and death. Advise patients of these risks and the need for effective contraception. (5.1, 8.1, 8.6)

1 INDICATIONS AND USAGE PERJETA is indicated for use in combination with trastuzumab and docetaxel for the treatment of patients with HER2-positive metastatic breast cancer who have not received prior anti-HER2 therapy or chemotherapy for metastatic disease. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity PERJETA can cause fetal harm when administered to a pregnant woman. Treatment of pregnant cynomolgus monkeys with pertuzumab resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal death. If PERJETA is administered during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to a fetus [see Use in Specific Populations (8.1)]. Verify pregnancy status prior to the initiation of PERJETA. 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 PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, 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)]. Monitor patients who become pregnant during PERJETA therapy for oligohydramnios. If oligohydramnios occurs, perform fetal testing that is appropriate for gestational age and consistent with community standards of care. The efficacy of intravenous hydration in the management of oligohydramnios due to PERJETA exposure is not known. 5.2 Left Ventricular Dysfunction Decreases in LVEF have been reported with drugs that block HER2 activity, including PERJETA. In the randomized trial, PERJETA in combination with trastuzumab and docetaxel was not associated with increases in the incidence of symptomatic left ventricular systolic dysfunction (LVSD) or decreases in LVEF compared with placebo in combination with trastuzumab and docetaxel [see Clinical Studies (14.1)]. Left ventricular dysfunction occurred in 4.4% of patients in the PERJETA-treated group and 8.3% of patients in the placebo-treated group. Symptomatic left ventricular systolic dysfunction (congestive heart failure) occurred in 1.0% of patients in the PERJETA-treated group and 1.8% of patients in the placebotreated group [see Adverse Reactions (6.1)]. Patients who have received prior anthracyclines or prior radiotherapy to the chest area may be at higher risk of decreased LVEF. PERJETA has not been studied in patients with a pretreatment LVEF value of ≤ 50%, a prior history of CHF, decreases in LVEF to < 50% during prior trastuzumab therapy, or conditions that could impair left ventricular function such as uncontrolled hypertension, recent myocardial infarction, serious cardiac arrhythmia requiring treatment or a cumulative prior anthracycline exposure to > 360 mg/m2 of doxorubicin or its equivalent. Assess LVEF prior to initiation of PERJETA and at regular intervals (e.g., every three months) during treatment to ensure that LVEF is within the institution’s normal limits. If LVEF is < 40%, or is 40% to 45% with a 10% or greater absolute decrease below the pretreatment value, withhold PERJETA and trastuzumab and repeat LVEF assessment within approximately 3 weeks. Discontinue PERJETA and trastuzumab if the LVEF has not improved or has declined further, unless the benefits for the individual patient outweigh the risks [see Dosage and Administration (2.2)]. 5.3 Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis PERJETA has been associated with infusion and hypersensitivity reactions [see Adverse Reactions (6.1)]. An infusion reaction was defined in the randomized trial as any event described as hypersensitivity, anaphylactic reaction, acute infusion reaction or cytokine release syndrome occurring during an infusion or on the same day as the infusion. The initial dose of PERJETA was given the day before trastuzumab and docetaxel to allow for the examination of PERJETA-associated reactions. On the first day, when only PERJETA was administered, the overall frequency of infusion reactions was 13.0% in the PERJETA-treated group and 9.8% in the placebo-treated group. Less than 1% were grade 3 or 4. The most common infusion reactions (≥ 1.0%) were pyrexia, chills, fatigue, headache, asthenia, hypersensitivity, and vomiting. During the second cycle when all drugs were administered on the same day, the most common infusion reactions in the PERJETAtreated group (≥ 1.0%) were fatigue, dysgeusia, hypersensitivity, myalgia, and vomiting. In the randomized trial, the overall frequency of hypersensitivity/ anaphylaxis reactions was 10.8% in the PERJETA-treated group and 9.1% in the placebo-treated group. The incidence of Grade 3 – 4 hypersensitivity/anaphylaxis reactions was 2% in the PERJETAtreated group and 2.5% in the placebo-treated group according to National Cancer Institute – Common Terminology Criteria for Adverse Events (NCI - CTCAE) (version 3). Overall, 4 patients in PERJETA-treated group and 2 patients in the placebo-treated group experienced anaphylaxis. Observe patients closely for 60 minutes after the first infusion and for 30 minutes after subsequent infusions of PERJETA. If a significant infusion-associated reaction occurs, slow or interrupt the infusion and administer appropriate medical therapies. Monitor patients carefully until complete resolution of signs and symptoms. Consider permanent discontinuation in patients with severe infusion reactions [see Dosage and Administration (2.2)]. 5.4 HER2 Testing Detection of HER2 protein overexpression is necessary for selection of patients appropriate for PERJETA therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage (1) and Clinical Studies (14)]. In the randomized trial, patients with breast cancer were required to have evidence of HER2 overexpression defined as 3+ IHC by

Dako Herceptest™ or 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 but did not demonstrate protein overexpression 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. 6 ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Embryo-Fetal Toxicity [see Warnings and Precautions (5.1)] • Left Ventricular Dysfunction [see Warnings and Precautions (5.2)] • Infusion-Associated Reactions, Hypersensitivity Reactions/ Anaphylaxis [see Warnings and Precautions (5.3)] 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. In clinical trials, PERJETA has been evaluated in more than 1400 patients with various malignancies and treatment with PERJETA was predominantly in combination with other anti-neoplastic agents. The adverse reactions described in Table 1 were identified in 804 patients with HER2-positive metastatic breast cancer treated in the randomized trial. Patients were randomized to receive either PERJETA in combination with trastuzumab and docetaxel or placebo in combination with trastuzumab and docetaxel. The median duration of study treatment was 18.1 months for patients in the PERJETA-treated group and 11.8 months for patients in the placebo-treated group. No dose adjustment was permitted for PERJETA or trastuzumab. The rates of adverse events resulting in permanent discontinuation of all study therapy were 6.1% for patients in the PERJETA-treated group and 5.3% for patients in the placebo-treated group. Adverse events led to discontinuation of docetaxel alone in 23.6% of patients in the PERJETA-treated group and 23.2% of patients in the placebo-treated group. Table 1 reports the adverse reactions that occurred in at least 10% of patients on the PERJETA-treated group. The most common adverse reactions (> 30%) seen with PERJETA in combination with trastuzumab and docetaxel were diarrhea, alopecia, neutropenia, nausea, fatigue, rash, and peripheral neuropathy. The most common NCI - CTCAE (version 3) Grade 3 – 4 adverse reactions (> 2%) were neutropenia, febrile neutropenia, leukopenia, diarrhea, peripheral neuropathy, anemia, asthenia, and fatigue. An increased incidence of febrile neutropenia was observed for Asian patients in both treatment arms compared with patients of other races and from other geographic regions. Among Asian patients, the incidence of febrile neutropenia was higher in the pertuzumab-treated group (26%) compared with the placebo-treated group (12%). Table 1 Summary of Adverse Reactions Occurring in ≥ 10% of Patients on the PERJETA Treatment Arm in the Randomized Trial PERJETA Placebo Body System/ + trastuzumab + trastuzumab Adverse Reactions + docetaxel + docetaxel n=407 n=397 Frequency rate % All Grades %

Grades 3-4 %

Frequency rate % All Grades %

General disorders and administration site conditions Fatigue 37.6 2.2 36.8 Asthenia 26.0 2.5 30.2 Edema peripheral 23.1 0.5 30.0 Mucosal inflammation 27.8 1.5 19.9 Pyrexia 18.7 1.2 17.9 Skin and subcutaneous tissue disorders Alopecia 60.9 0.0 60.5 Rash 33.7 0.7 24.2 Nail disorder 22.9 1.2 22.9 Pruritus 14.0 0.0 10.1 Dry skin 10.6 0.0 4.3 Gastrointestinal disorders Diarrhea 66.8 7.9 46.3 Nausea 42.3 1.2 41.6 Vomiting 24.1 1.5 23.9 Constipation 15.0 0.0 24.9 Stomatitis 18.9 0.5 15.4 Blood and lymphatic system disorders Neutropenia 52.8 48.9 49.6 Anemia 23.1 2.5 18.9 Leukopenia 18.2 12.3 20.4 Febrile neutropenia* 13.8 13.0 7.6 Nervous system disorders Neuropathy peripheral 32.4 3.2 33.8 Headache 20.9 1.2 16.9 Dysgeusia 18.4 0.0 15.6 Dizziness 12.5 0.5 12.1 Musculoskeletal and connective tissue disorders Myalgia 22.9 1.0 23.9 Arthralgia 15.5 0.2 16.1 Infections and infestations Upper respiratory tract infection 16.7 0.7 13.4 Nasopharyngitis 11.8 0.0 12.8 Respiratory, thoracic and mediastinal disorders Dyspnea 14.0 1.0 15.6 Metabolism and nutrition disorders Decreased appetite 29.2 1.7 26.4 Eye disorders Lacrimation increased 14.0 0.0 13.9 Psychiatric disorders Insomnia 13.3 0.0 13.4

Grades 3-4 %

3.3 1.5 0.8 1.0 0.5 0.3 0.8 0.3 0.0 0.0 5.0 0.5 1.5 1.0 0.3 45.8 3.5 14.6 7.3 2.0 0.5 0.0 0.0 0.8 0.8 0.0 0.3 2.0 1.5 0.0 0.0

*In this table this denotes an adverse reaction that has been reported in association with a fatal outcome The following clinically relevant adverse reactions were reported in < 10% of patients in the PERJETA-treated group: Skin and subcutaneous tissue disorders: Paronychia (7.1% in the

PERJETA-treated group vs. 3.5% in the placebo-treated group) Respiratory, thoracic and mediastinal disorders: Pleural effusion (5.2% in the PERJETA-treated group vs. 5.8% in the placebotreated group) Cardiac disorders: Left ventricular dysfunction (4.4% in the PERJETA-treated group vs. 8.3% in the placebo-treated group) including symptomatic left ventricular systolic dysfunction (CHF) (1.0% in the PERJETA-treated group vs. 1.8% in the placebotreated group) Immune system disorders: Hypersensitivity (10.1% in the PERJETA-treated group vs. 8.6% in placebo-treated group) Adverse Reactions Reported in Patients Receiving PERJETA and Trastuzumab after Discontinuation of Docetaxel In the randomized trial, adverse reactions were reported less frequently after discontinuation of docetaxel treatment. All adverse reactions in the PERJETA and trastuzumab treatment group occurred in < 10% of patients with the exception of diarrhea (19.1%), upper respiratory tract infection (12.8%), rash (11.7%), headache (11.4%), and fatigue (11.1%). 6.2 Immunogenicity As with all therapeutic proteins, there is the potential for an immune response to PERJETA. Patients in the randomized trial were tested at multiple time-points for antibodies to PERJETA. Approximately 2.8% (11/386) of patients in the PERJETA-treated group and 6.2% (23/372) of patients in the placebo-treated group tested positive for anti-PERJETA antibodies. Of these 34 patients, none experienced anaphylactic/ hypersensitivity reactions that were clearly related to the antitherapeutic antibodies (ATA). The presence of pertuzumab in patient serum at the levels expected at the time of ATA sampling can interfere with the ability of this assay to detect anti-pertuzumab antibodies. In addition, the assay may be detecting antibodies to trastuzumab. As a result, data may not accurately reflect the true incidence of anti-pertuzumab antibody development. 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. For these reasons, comparison of the incidence of antibodies to PERJETA with the incidence of antibodies to other products may be misleading.

If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, 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)]. 8.7 Renal Impairment Dose adjustments of PERJETA are not needed in patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) or moderate (CLcr 30 to 60 mL/min) renal impairment. No dose adjustment can be recommended for patients with severe renal impairment (CLcr less than 30 mL/min) because of the limited pharmacokinetic data available [see Clinical Pharmacology (12.3)]. 8.8 Hepatic Impairment No clinical studies have been conducted to evaluate the effect of hepatic impairment on the pharmacokinetics of pertuzumab. 10 OVERDOSAGE No drug overdoses have been reported with PERJETA to date.

7 DRUG INTERACTIONS No drug-drug interactions were observed between pertuzumab and trastuzumab, or between pertuzumab and docetaxel. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D Risk Summary There are no adequate and well-controlled studies of PERJETA in pregnant women. Based on findings in animal studies, PERJETA can cause fetal harm when administered to a pregnant woman. The effects of PERJETA are likely to be present during all trimesters of pregnancy. Pertuzumab administered to pregnant cynomolgus monkeys resulted in oligohydramnios, delayed fetal kidney development, and embryo-fetal deaths at clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. If PERJETA is administered during pregnancy, or if a patient becomes pregnant while receiving PERJETA, the patient should be apprised of the potential hazard to the fetus. If PERJETA is administered during pregnancy or if a patient becomes pregnant while receiving PERJETA, 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)]. Animal Data Reproductive toxicology studies have been conducted in cynomolgus monkeys. Pregnant monkeys were treated on Gestational Day (GD)19 with loading doses of 30 to 150 mg/kg pertuzumab, followed by bi-weekly doses of 10 to 100 mg/kg. These dose levels resulted in clinically relevant exposures of 2.5 to 20-fold greater than the recommended human dose, based on Cmax. Intravenous administration of pertuzumab from GD19 through GD50 (period of organogenesis) was embryotoxic, with dose-dependent increases in embryo-fetal death between GD25 to GD70. The incidences of embryo-fetal loss were 33, 50, and 85% for dams treated with bi-weekly pertuzumab doses of 10, 30, and 100 mg/kg, respectively (2.5 to 20-fold greater than the recommended human dose, based on Cmax). At Caesarean section on GD100, oligohydramnios, decreased relative lung and kidney weights and microscopic evidence of renal hypoplasia consistent with delayed renal development were identified in all pertuzumab dose groups. Pertuzumab exposure was reported in offspring from all treated groups, at levels of 29% to 40% of maternal serum levels at GD100. 8.3 Nursing Mothers It is not known whether PERJETA is excreted in human milk, but human IgG is excreted in human milk. Because many drugs are secreted in human milk and because of the potential for serious adverse reactions in nursing infants from PERJETA, a decision should be made whether to discontinue nursing, or discontinue drug, taking into account the elimination half-life of PERJETA and the importance of the drug to the mother [See Warnings and Precautions (5.1), Clinical Pharmacology (12.3)]. 8.4 Pediatric Use The safety and effectiveness of PERJETA have not been established in pediatric patients. 8.5 Geriatric Use Of 402 patients who received PERJETA in the randomized trial, 60 patients (15%) were ≥ 65 years of age and 5 patients (1%) were ≥ 75 years of age. No overall differences in efficacy and safety of PERJETA were observed between these patients and younger patients. Based on a population pharmacokinetic analysis, no significant difference was observed in the pharmacokinetics of pertuzumab between patients < 65 years (n=306) and patients ≥ 65 years (n=175). 8.6 Females of Reproductive Potential PERJETA can cause embryo-fetal harm when administered during pregnancy. Counsel patients regarding pregnancy prevention and planning. Advise females of reproductive potential to use effective contraception while receiving PERJETA and for 6 months following the last dose of PERJETA.

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

ASCOPost.com | MAY 1, 2013

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Society of Surgical Oncology Annual Cancer Symposium Melanoma and Lymph Node Removal

four prospective randomized trials that showed no difference in survival between patients who underwent initial elective lymph node dissection compared to those who underwent delayed therapeutic lymph node dissection if necessary. Dr. Coit also cited two retrospective observational studies that were unable to demonstrate any survival benefit associated with completion lymph node dissection compared to observation after positive sentinel lymph node biopsy. While these studies may reflect patient selection, he indicated that they do support equipoise in the two arms of the ongoing seminal randomized Multicenter Selective Lymphadenectomy Trial 2 (MSLT-2).

patients who have immediate completion lymph node discontinued from page 1 section, regional recurrence Southwestern Medical Center, Dallas, rates are very low compared to during the Annual Cancer Symposium of those in patients who present the Society of Surgical Oncology (SSO), later with macroscopic nodal held recently in Washington, DC.1 metastases. “The best evidence we Morbidity, Survival Rates have suggests that [compleCritics argue that about 80% of pation lymph node dissection] is Mark B. Faries, MD Donald L. Morton, MD tients with a positive sentinel node turn effective at achieving regional Critical Trial out to have no additional disease. That control,” said Dr. Balch. “I would emphaOne area of agreement among exmeans completion lymph node dissecsize that there are many circumstances in perts is the importance of completing tion puts 80% unnecessarily through which we operate on patients to achieve the MSLT-2 trial. Chaired by Donald a much longer and more costly operaregional disease control, even if it doesn’t L. Morton, MD, Chief of the Melation with its risk of per se increase survival.” noma Program at John Wayne Cancer complications and But Dr. Coit questioned the value Institute, Santa Monica, California, morbidities, such of the procedure for regional control. the trial is randomizing sentinel node as wound infection, positive patients into two groups, one lymphedema, and to have an immediate completion nerve damage. lymph node dissection, the other to “We create the potential for significant The best evidence we have suggests be monitored by nodal ultrasound complications with these operations,” and have a delayed completion dissaid Dr. Coit, who argued against comthat [completion lymph node section if necessary. The primary endpletion lymph node dissection. dissection] is effective at achieving point is melanoma-specific survival. The rate of morbidity associated with The trial’s accrual goal is 1,926 pacompletion lymph node dissection is regional control. tients. About 1,680 have been randomly from 5% to 10% according to large stud—Charles M. Balch, MD assigned to the two arms, said Mark B. ies. But skeptics point to smaller studies Faries, MD, Director of Melanoma Reand subgroup analyses suggesting the risk search at John Wayne Cancer Institute, may be higher for some patients. Lymphwho gave an update on the trial at the edema, for instance, is more common Regional Control, Staging SSO symposium.2 “If we stay at this He described an observational study and severe among overweight patients Proponents of completion lymph pace—and the pace actually seems to suggesting that half of patients with and those who have had lymph nodes node dissection point to its value in rebe picking up—we’ll probably compositive sentinel nodes “will recur taken from the groin. Thus, overall morgional control, regardless of its impact on plete accrual early next year.” Analysis systemically before it makes any difbidity rates after completion lymph node survival. Dr. Balch, who took the pro side of the data, he added, could begin “anference whatsoever what we do in the dissection are 30% to 40%, and even of the debate, cited the Sunbelt Melanoother couple of years after that.” n lymph nodes.” worse (~60%) after groin dissection. Disclosure: Dr. Balch has received speaker’s ma Trial and others showing that among Another argument in favor of compleDr. Coit also cited evidence from honoraria from Merck. Drs. Coit and Faries tion lymph node dissection is its value in reported no potential conflicts of interest. staging, said Dr. Balch. He cited “at least Completion Lymph Node Dissection in Melanoma References five papers” showing that “it’s not just 1. Coit DG, Balch CM: Great debates: the number of nodes but that [nonsenti■ The current standard of care for melanoma patients with positive sentinel Completion axillary node dissection is necesnel] nodes have prognosis, and therefore nodes is completion lymph node dissection. sary in all melanoma patients with a positive there is a staging value in addition to re■ The practice has become controversial, however: proponents argue that it SLN. Society of Surgical Oncology Annual gional control. ” is valuable for staging and regional control, while opponents contend that Cancer Symposium. Presented March 9, 2013. “I wouldn’t argue with that, ” said Dr. it is a morbid and costly test with no proven therapeutic benefits. 2. Faries MB: MSLT 2: An update. SoCoit. The problem is it’s an expensive test ■ It is important to complete the large randomized MSLT-2 trial, which is ciety of Surgical Oncology Annual Cancer with risks of complications and morbiditesting whether completion lymph node dissection improves survival. Symposium. Presented March 7, 2013. ties, he added.

Sentinel Node Biopsy in Melanoma: Essential or Optional? By Caroline McNeil

s sentinel node biopsy in melanoma an essential component of care? Despite a large multinational trial and recently published or updated guidelines, the question is still a thorny one according to experts who debated the issue at the recent meeting of the Society of Surgical Oncology in Washington, DC.1,2

“It’s safe and it’s prognostic,” said Giorgos C. Karakousis, MD, Assistant Professor of Surgery at the University of Pennsylvania’s Perelman School of Medicine in Philadelphia. Moreover, he contended, it facilitates regional control and may play a therapeutic role. On the contrary, said Mary S. Brady, MD, Associate Attending Phy-

sician at Memorial Sloan-Kettering Cancer Center, there is no high-level evidence that sentinel node staging provides better regional control or contributes to survival. There is level 1 medical evidence that the procedure is diagnostic, and not therapeutic. And while sentinel node biopsy is prognostic, the value of staging is questionable

when standard adjuvant therapies have limited effectiveness and are poorly tolerated.

Thin Melanomas Both speakers marshaled their arguments around the different levels of thickness of the primary lesion. For continued on page 8

The ASCO Post | MAY 1, 2013

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Society of Surgical Oncology Annual Cancer Symposium Sentinal Node Biopsy in Melanoma continued from page 7

thin melanomas (Breslow thickness ≤ 1 mm), positive sentinel nodes are uncommon, especially in those with tumors < 0.76 mm. The procedure is not recommended in thin melanomas by either the guidelines published by ASCO and the SSO last year,3 or the latest NCCN guidelines, revised in early 2013.4

Giorgos C. Karakousis, MD

However, Dr. Karakousis noted that it might be warranted for patients whose primary lesion is between 0.76 and 1 mm, and particularly for those who have certain other higher-risk features. “In thin (T1) lesions, the incidence of positive sentinel nodes tends to be very low overall,” he said. “In very thin lesions (< 0.75 mm in depth), the sentinel lymph node positivity rate is even lower and the procedure generally is not recommended in this group, although it may be very selectively considered if other factors such as high mitotic rate, ulceration, lymphovascular invasion, or positive deep margins (of a transected specimen) are present.” “Can we select for patients with thin melanomas that have a higher risk of sentinel node positivity? I think the answer is ultimately yes,” he said. “There is still debate in part about which factors are predictive.” Dr. Brady agreed, cautiously, that sentinel node biopsy could be a “rational option” for higher-risk, thin melanomas. However, she said in an interview, patients offered this option should understand that while it may give them information about prognosis, that is all it will do. “It has nothing to do with therapy,” she said.

Intermediate-risk Melanomas That theme—the possible value or lack of value of sentinel node biopsy for therapy and regional control—continued as the speakers moved to intermediate lesions (1–4 mm Breslow thickness). A major source of data for intermediate melanomas is the first Mul-

ticenter Selective Lymphadenopathy Trial (MSLT-1),5 which compared wide excision with sentinel node biopsy and immediate lymphadenectomy if necessary to wide excision with surveillance and delayed lymphadenectomy if necessary. There was no difference between the two arms in melanoma-specific survival, the primary endpoint of the trial. Dr. Karakousis emphasized that MSLT-1 “validated the tremendous prognostic utility of the [sentinel lymph node] biopsy technique.” He noted that in the sentinel node biopsy group, there was a statistically significant improvement in the estimated 5-year disease-free survival, due in large part to the higher nodal relapse rate in the observation group. Also, he pointed out, in the subgroup of patients with nodal metastases, those who had immediate lymph node dissection had a significantly higher melanoma-specific survival rate than those in the observation group who had delayed lymphadenectomy (72% vs 52%). This suggests that “there may be some therapeutic effect of the sentinel node biopsy procedure in patients with micrometastases,” he said. Dr. Brady argued that subgroup analyses are not high-level evidence. “That’s post hoc analysis,” she said in an interview. And comparing people who got delayed lymphadenectomy (and

clinically apparent nodal metastasis (those in the observation arm for whom treatment failed) have a worse outcome than patients with microscopic nodal disease. These were secondary endpoints of the trial, and rightly so,” Dr. Brady said. “The main reason, in my mind, for doing a sentinel node biopsy is to give patients good news,” she said, adding that good news in itself is clinically valuable. But for those who get bad news—a positive sentinel node—and go on to have a completion lymph node dissection, there is bad news plus the risk of lymphedema and other complications. The need for completion lymph node dissection after a positive sentinel node biopsy, another contentious issue, was the subject of a separate debate at the SSO meeting (see page 1). The ongoing MSLT-2 trial is investigating whether completion lymph node dissection improves survival in this group.

Thick Melanomas Patients with thick melanomas (> 4 mm Breslow thickness) may have > 30% chance of lymph node involvement but are also are at high risk for distant metastases. “So the question is not whether the yield of finding a metastatic event justifies the proce-

Sentinel Node Biopsy in Melanoma ■ Current guidelines suggest sentinel node biopsy should be performed for higher-risk thin melanomas, and all intermediate and thick melanomas, with completion lymph node dissection if the sentinel node is positive. However, much debate surrounds this approach.

■ Proponents emphasize the procedure’s safety and its prognostic and

staging value, as well as evidence suggesting that it facilitates regional control and plays a therapeutic role.

■ Critics argue that there is no high-level evidence that it does either and that staging has little value because current adjuvant therapies have limited effectiveness.

thus had clinically palpable nodes) to those who got immediate lymphadenectomy (with microscopic nodal metastases) “is completely invalid,” she commented. “The primary endpoint of the trial,” she continued, “demonstrated that there was no difference in melanoma-specific survival, indicating that sentinel node biopsy offered no therapeutic advantage to patients with intermediate-risk melanoma. We already knew that the sentinel node biopsy provides prognostic information, and that patients with

dure,” said Dr. Karakousis, “but does it add prognostic information?” There are fewer studies specifically looking at thick melanomas, but most have demonstrated that sentinel node biopsy is prognostic. It also offers important regional control in this group, he said. The ASCO/SSO guidelines recommend the procedure in thick melanomas “for staging purposes and to facilitate regional control.” And the NCCN guidelines say that the “main advantage” in this group of patients is regional control.

Mary S. Brady, MD

Michael S. Sabel, MD

Again, Dr. Brady argued that there is no high-level evidence supporting these guidelines. And although she agreed that sentinel node biopsy and completion lymph node dissection “can very precisely stratify risk in intermediate melanomas,” she questioned that as a rationale for the procedure. Staging, she argued, should help identify patients for adjuvant therapy, but in melanoma, the standard is high-dose interferon, which is a “very toxic therapy of marginal benefit.”

Looking Ahead The value of staging, all agreed, may improve as more systemic therapies prove effective in early melanoma. Ipilimumab (Yervoy), a targeted antibody, and vemurafenib (Zelboraf), a selective BRAF inhibitor, have already been approved for advanced melanoma. Others including MEK inhibitors show promise. In the adjuvant setting, a trial of ipilimumab has been completed but not yet published. Michael S. Sabel, MD, Associate Professor of Surgery at the University of Michigan, Ann Arbor, who moderated the debate, said, “This is a very exciting era in melanoma. But it is a shifting ground on which we stand that we have to continuously reevaluate.” n

Disclosure: Drs. Brady, Karakousis, and Sabel reported no potential conflicts of interest.

References 1. Brady MS: SLN biopsy: An optional diagnostic procedure. SSO Annual Cancer Symposium. Presented March 7, 2013. 2. Karakousis GC: SLN biopsy: An essential component of care. SSO Annual Cancer Symposium. Presented March 7, 2013. 3. Wong SL, Balch CM, Hurley P, et al: Sentinel lymph node biopsy for melanoma: ASCO/SSO joint clinical practice guideline. J Clin Oncol 30:2912-2918, 2012. 4. NCCN Clinical Practice Guidelines in Oncology: Melanoma. Version 2.2013. Available at www.nccn.org. Accessed April 5, 2013. 5. Morton DL, Thompson JF, Cochran AJ, et al: Sentinel-node biopsy or nodal observation in melanoma. N Engl J Med 355:1307-1317, 2006.

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PAGE 10

American Association for Cancer Research Annual Meeting Metastatic Breast Cancer continued from page 1

T-DM1 is a novel antibody-drug conjugate with a mechanism of action that differs from that of classical antiHER2 therapies. The compound attaches the antibody trastuzumab to a toxic chemotherapy called emtansine. Trastuzumab homes in on the HER2 protein in HER2-positive breast cancers and releases emtansine into the tumor cells, thereby killing them. Dr. Baselga pointed out that emtansine is so potent that it cannot be given on its own. “T-DM1 is 10,000 times more potent than vinorelbine, for example,” he noted.

Study Design The pivotal phase III EMILIA trial compared the effectiveness of TDM-1

vs lapatinib and capecitabine (Xeloda) in patients previously treated with trastuzumab plus taxane chemotherapy. In that trial, T-DM1 significantly improved progression-free survival by 35% from a median of 6.4 months with capecitabine plus lapatinib vs 9.6 months for T-DM1 (P < .001). At a median follow-up of 20 months, T-DM1 also improved overall survival by 32%; median overall survival was 30.9 months with T-DM1 vs 25.1 months for capecitabine plus lapatinib. Tumor samples were collected prospectively from patients enrolled in EMILIA for analysis of EGFR, HER2 mRNA, and PIK3CA. Progression-free and overall survival were analyzed for each biomarker subgroup according to amount of HER2 mRNA expression and PIK3CA mutation fre-

First Report of Antibody-Drug Conjugate in Advanced Ovarian Cancer

n a related presentation at the AACR Annual Meeting,1 the antibody-drug conjugate DMUC5754A showed encouraging activity in women with ovarian cancer, particularly those with platinum-resistant disease, which currently lacks effective treatment options. The first-in-human phase I study included 44 patients with advanced, recurrent, platinum-resistant ovarian cancer. Of these difficult-to-treat patients, one achieved a complete response and four achieved partial responses. Joyce F. Liu, MD, MPH Results of the phase I study were reported at a press conference by Joyce F. Liu, MD, MPH, Instructor of Medicine at DanaFarber Cancer Institute and Harvard Medical School in Boston.

Mechanism of Action DMUC5754A consists of an antibody linked to a highly potent antimitotic toxin called MMAE. The antibody is targeted to the MUC16 protein expressed in ovarian cancers and releases the toxin with relative selectivity to the MUC16positive cancer cells, which are expressed in 80% of patients with ovarian cancer. All five confirmed responses occurred in patients with high expression levels of MUC16 in their cancer cells, at the maximum tolerated dose of 2.4 mk/kg. Dr. Liu explained that although chemotherapy and surgery are initially effective in the treatment of ovarian cancer, most patients will experience a recurrence, and platinum-resistant patients are challenging to treat, with limited therapeutic options. The novel agent had tolerable safety, with fatigue as the most common grade 33 adverse event. Peripheral neuropathy was also reported but was manageable and reversible with dose adjustments. “This is the first study of an antibody-drug conjugate in ovarian cancer. If the encouraging activity is confirmed in future studies, this would represent a real step forward in identifying new, effective treatments for a type of ovarian cancer that is difficult to treat,” Dr. Liu told listeners. Further trials evaluating DMUC5754A in advanced ovarian cancer are being planned. n Disclosure: Dr. Liu reported no potential conflicts of interest.

Reference 1. Liu J, Moore K, Birrer M, et al: Targeting MUC16 with the antibody-drug conjugate DMUC5754A in patients with platinum-resistant ovarian cancer: A phase I study of safety and pharmacokinetics. AACR Annual Meeting. Abstract LB-290. Presented April 9, 2013.

Targeted Therapy with Antibody-Drug Conjugates ■ A biomarker analysis of the phase III EMILIA trial found that HER2-positive

breast tumors with the highest expression of HER2 had the best response to the antibody-drug conjugate T-DM1 (also now called ado-trastuzumab emtansine).

■ While the presence of PIK3CA mutations leads to a worse response to

HER2-directed therapies, including trastuzumab and lapatinib, it does not affect response to T-DM1.

quency. Median HER2 mRNA concentration ratios and PIK3CA mutation frequencies were similar across all treatment arms. In all biomarker subgroups, T-DM1 achieved superior progression-free and overall survival. However, patients with tumors that expressed high HER2 mRNA levels derived even more benefit from T-DM1 than those with lower levels of expression. In the high expressors, median progression-free survival was 34.1 months on T-DM1 vs 24.8 months on capecitabine/lapatinib. Patients in the capecitabine/lapatinib arm with PIK3CA mutations had worse outcomes than those with wild-type PIK3CA, but the presence of PIK3CA mutations did not have any effect on progression-free or overall survival in patients treated with T-DM1.

Not Yet Practice-changing “We had known that PIK3CA mutations downstream from HER2 induce resistance to HER2 therapies that inhibit HER2 signalling. Patients [with these mutations] do worse on lapatinib, but that does not happen with T-DM1….

T-DM1 is PIK3CA mutation-neutral in this regard,” Dr. Baselga said. “Our results are not practice-changing at this point,” he commented at an official press conference during the AACR meeting. “In HER2-positive breast cancer, we will begin to sequence patients and test for PIK3CA mutations. Compounds that are targeted to PIK3CA could be given to patients with mutations. We need to study the importance of the PIK3CA pathway further. These data will allow us to characterize HER2positive patients in greater detail.” T-DM1 is currently being studied earlier in the course of disease as adjuvant therapy and also as first-line therapy for metastatic disease. n Disclosure: Dr. Baselga has received honoraria from Roche.

Reference 1. Baselga J, Verma S, Ro J, et al: Relationship between tumor biomarkers and efficacy in EMILIA, a phase III study of trastuzumab emtansine (T-DM1) in HER2positive metastatic breast cancer. AACR Annual Meeting. Abstract LB-63. Presented April 7, 2013.

EXPERT POINT OF VIEW

ommenting on both Dr. Baselga’s study in breast cancer and Dr. Liu’s study in ovarian cancer at the AACR press conference, Louis M. Weiner, MD, Director of the Georgetown University Lombardi Comprehensive Cancer Center, Washington, DC, said that antibody-drug conjugates “represent the fulfillment of the century-long dream of Paul Ehrlich—that of magic bullets for the treatment of cancer.” “One of the main takeaway messages from Dr. Louis M. Weiner, MD Baselga’s study is that biomarkers no longer matter when you have drugs that work very well and overcome defense mechanisms of the tumor,” Dr. Weiner said. The lessons of T-DM1 are not unique to that agent, but apply to other antibody-drug conjugates as well. “The therapeutic concept of antibody-drug conjugates makes sense. Target the antigen on the cell surface, and deliver powerful cytotoxic chemotherapy. The antibody delivers the potent drug that could not be given otherwise to exactly where it needs to go,” he elaborated. “This is where the field is heading for novel cytotoxics.” n Disclosure: Dr. Weiner reported no potential conflicts of interest.

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Journal Spotlight Gastrointestinal Oncology

Benefit of Continued Antiangiogenic Treatment with Bevacizumab after Progression in Metastatic Colorectal Cancer By Matthew Stenger

s reported recently in Lancet Oncology by Jaafar Bennouna, MD, of Institut de Cancérologie de l’Ouest, Nantes, France, and colleagues, the phase III ML18147 trial showed a survival benefit with continued bevacizumab (Avastin) treatment after

Jaafar Bennouna, MD

first progression in metastatic colorectal cancer.1 The trial formed the basis of bevacizumab’s recent approval for use in combination with fluoropyrimidine/irinotecan– or fluoropyrimidine/oxaliplatin–based chemotherapy in the treatment of patients with metastatic colorectal cancer whose disease has progressed on a first-line bevacizumab-containing regimen.

Study Details This open-label trial, performed in 220 centers in 15 countries, enrolled patients aged 18 years or older with unresectable metastatic colorectal cancer progressing up to 3 months after discontinuing firstline bevacizumab plus chemotherapy. Patients were randomly assigned to receive second-line therapy with (n = 409) or without (n = 411) bevacizumab at 2.5 mg/kg per week (either 5 mg/kg every 2 weeks or 7.5 mg/kg every 3 weeks). For second-line chemotherapy, patients were switched to irinotecan-based treatment if their first-line regimen was oxaliplatin-based and vice versa. Treatment continued until progressive disease, unacceptable toxicity, or patient refusal. The primary endpoint was overall survival. Patients in the bevacizumab and chemotherapy-alone groups were well matched for sex (65% vs 63% male), age (median 63 years in both), ECOG

performance status (0 and 1 in 44% and 55% vs 43% and 52%), and proportions of patients who had progression within 9 months on first-line treatment (54% vs 56%), liver metastasis only (27% vs 29%), metastasis to more than one organ (64% vs 61%), received their last bevacizumab dose greater than 42 days prior to the study (23% in both), and received irinotecan-based (59% vs 58%) or oxaliplatin-based (41% vs 42%) first-line therapy. Patients were well matched for type of chemotherapy in second-line treatment. For irinotecan-based regimens, 16% of the bevacizumab group vs 14%

Bevacizumab and Metastatic Colorectal Cancer ■ Continuation of bevacizumab as part of second-line treatment with

irinotecan- or oxaliplatin-based regimens improved survival in metastatic colorectal cancer.

■ Maintenance of VEGF inhibition beyond disease progression has benefits in metastatic colorectal cancer and is being investigated in metastatic breast and non–small cell lung cancers.

of the chemotherapy-alone group received sFOLFIRI (simplified leucovorin, fluorouracil [5-FU], irinotecan); 7% vs 7% received the hybrid regimen LV5FU2 CPT11 (irinotecan plus bolus and infusion 5-FU with high-dose

Prolonged VEGF Inhibition By Axel Grothey, MD

he so-called TML (Treatment across Multiple Lines) study reported by Bennouna and colleagues investigated the efficacy of bevacizumab (Avastin) beyond progression from first- to secondline therapy in advanced colorectal cancer, a strategy that was supported by data from observational cohort studies and that about one-third of U.S. oncologists had already used in clinical practice. The results of the study confirm that prolonged inhibition of the vascular endothelial growth factor Axel Grothey, MD (VEGF) system is beneficial for patients in terms of improved overall survival with relatively mild toxicity. The efficacy of prolonged VEGF inhibition was confirmed by the results of the VELOUR trial, which demonstrated a survival benefit for the use of ziv-aflibercept (Zaltrap), another VEGF inhibitor, even in patients who had been pretreated with bevacizumab. The magnitude of benefit, an approximately 20% reduction of death events on the study (expressed by a hazard ratio of 0.81) and a median gain in overall survival of 1.4 months might not satisfy everyone, but it is a proof of concept that also challenges our traditional understanding of resistance mechanisms and will impact the design of future trials in colorectal cancer.

Insight into Subpopulations The publication of detailed study results now also allows us further insight into subpopulations in the trial. At first glance, it appears that patients with KRAS wild-type cancers derive more benefit from the use of bevacizumab beyond progression than patients with KRAS mutant tumors. Although the definitive statistical analysis, the test of interaction, did not demonstrate any difference between these groups, it needs to be noted that KRAS wild-type tumors have commonly been reported to show a trend toward better response to treatment interventions, including in the most recent phase III regorafenib (Stivarga) last-line trial. This observation makes the upcoming results of trials that compare bevacizumab and cetuximab (Erbitux) head to head in frontline therapy even more interesting. n Disclosure: Dr. Grothey reported no potential conflicts of interest.

Dr. Grothey is Professor of Oncology at the Mayo Clinic, Rochester, Minnesota.

leucovorin); and 12% vs 12% received XELIRI (capecitabine [Xeloda] plus irinotecan). For oxaliplatin-based therapy, 9% of the bevacizumab group vs 9% of the chemotherapy-alone group received FOLFOX4 (leucovorin, 5-FU, oxaliplatin); 9% vs 9% received sFOLFOX4 (simplified FOLFOX); 16% vs 13% received FOLFOX6; 6% vs 9% received FUFOX (another combination of 5-FU, leucovorin, oxaliplatin); and 14% vs 11% received XELOX (capecitabine plus oxaliplatin). Other regimens were received by 12% of the bevacizumab group vs 16% of the chemotherapy-alone group.

Improved Overall Survival Median follow-up was 11.1 months in the bevacizumab group and 9.6 months in the chemotherapy-alone group; median treatment exposure was 4.2 months and 3.2 months, respectively. Median overall survival was 11.2 months in the bevacizumab group vs 9.8 months in the chemotherapyalone group, representing a significant 19% reduction in risk of death with bevacizumab treatment (hazard ratio [HR] = 0.81, 95% confidence interval [CI] = 0.69-0.94, P = .0062). From the start of first-line treatment, median overall survival was 23.9 months in the bevacizumab group and 22.5 months in the chemotherapyalone group (HR = 0.90, P = .17). After completion of study treatment, 69% of the bevacizumab group and 68% of the chemotherapy-alone group received additional treatment, including bevacizumab in 11% and 12% and anti-EGFR treatment in 39% and 41%. Of patients with known KRAS status (n = 616), EGFR inhibitors were given to 70% and 69% of those with KRAS wild-type tumors and to 7% and 9% of those with KRAS mutant tucontinued on page 14

For chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab

EXPAND YOUR OPTIONS A study population in need of additional treatment options1,2

median prior therapies

59%

of patients received prior rituximab

93%

of patients received prior alkylating agents

100%

of patients received prior fludarabine and alemtuzumab

The following serious adverse events (AEs) are discussed in greater detail below: Infusion reactions, cytopenias, progressive multifocal leukoencephalopathy, hepatitis B infection and reactivation, and intestinal obstruction.

To learn more, please visit www.ARZERRA.com. Indication ARZERRA (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. Important Safety Information Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions. Premedicate with acetaminophen, an antihistamine, and a corticosteroid. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina, or other signs and symptoms of myocardial ischemia. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. Infusion reactions occurred in 44% of patients on the day of the first infusion

(300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers

When treated with ARZERRA monotherapy, 42% of patients with CLL refractory to fludarabine and alemtuzumab achieved a partial response1 Patients had received a median of 5 prior therapies

Overall response rate with ARZERRA 60 50 40

42%

The investigator-determined overall response rate in patients with CLL refractory to fludarabine and alemtuzumab was 42% (99% CI: 26, 60) There were no complete responses The eﬀectiveness of ARZERRA is based on the demonstration of durable objective responses

30 20 10

FLUDARABINE AND ALEMTUZUMAB REFRACTORY (n=59)

of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insuﬃcient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. Most Common Adverse Reactions In the pivotal study (total population, n=154) the most common adverse reactions (≥10%, all grades) were neutropenia, followed by pneumonia (23%), pyrexia (20%), cough (19%), diarrhea (18%), anemia (16%), fatigue (15%), dyspnea (14%), rash (14%), nausea (11%), bronchitis (11%), and upper respiratory tract infections (11%).

No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA 6.5 months—median duration of response (95% CI: 5.8, 8.3)

Most Common Serious Adverse Reactions In the pivotal study (total population, n=154), where ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses, the most common serious adverse reactions were infections (including pneumonia and sepsis), neutropenia, and pyrexia. A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Please see Brief Summary of Prescribing Information on adjacent pages. How Supplied: Available as 2 different single-use glass vials for dilution and intravenous administration. Each vial contains either 100 mg ofatumumab in 5 mL of solution or 1,000 mg ofatumumab in 50 mL of solution. References: 1. ARZERRA (ofatumumab) [package insert]. Research Triangle Park, NC: GlaxoSmithKline; 2011. 2. Tam CS, O’Brien S, Lerner S, et al. Leuk Lymph. 2007;48(10):1931-1939.

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PAGE 14

Journal Spotlight

Prolonged Antiangiogenic Treatment continued from page 11

mors; further bevacizumab was given to 17% and 22% of those with KRAS mutant tumors and to 8% and 8% of those with wild-type tumors. A prespecified subgroup analysis showed fairly consistent overall

survival benefits with bevacizumab treatment according to age, ECOG performance status, duration of progression-free survival on first-line treatment, oxaliplatin- or irinotecan-based first-line treatment, time since last bevacizumab dose prior to the study, presence of liver metastasis only, and number of organs with

metastasis. The hazard ratio for male patients was 0.73, whereas that for female patients was 0.99; however, there was no significant treatment by sex interaction on regression analysis. Median progression-free survival was 5.7 months in the bevacizumab group vs 4.1 months in the chemotherapy-alone group, representing a

BRIEF SUMMARY ARZERRA® (ofatumumab) Injection, for intravenous infusion The following is a brief summary only; see full prescribing information for complete product information. 1 INDICATIONS AND USAGE ARZERRA® (ofatumumab) is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL) refractory to fludarabine and alemtuzumab. The effectiveness of ARZERRA is based on the demonstration of durable objective responses [see Clinical Studies (14) of full prescribing information]. No data demonstrate an improvement in disease-related symptoms or increased survival with ARZERRA. 4 CONTRAINDICATIONS None. 5 WARNINGS AND PRECAUTIONS 5.1 Infusion Reactions ARZERRA can cause serious infusion reactions manifesting as bronchospasm, dyspnea, laryngeal edema, pulmonary edema, flushing, hypertension, hypotension, syncope, cardiac ischemia/infarction, back pain, abdominal pain, pyrexia, rash, urticaria, and angioedema. Infusion reactions occur more frequently with the first 2 infusions [see Adverse Reactions (6.1)]. Premedicate with acetaminophen, an antihistamine, and a corticosteroid [see Dosage and Administration (2.1, 2.4) of full prescribing information]. Interrupt infusion for infusion reactions of any severity. Institute medical management for severe infusion reactions including angina or other signs and symptoms of myocardial ischemia [see Dosage and Administration (2.3) of full prescribing information]. In a study of patients with moderate to severe chronic obstructive pulmonary disease, an indication for which ARZERRA is not approved, 2 of 5 patients developed Grade 3 bronchospasm during infusion. 5.2 Cytopenias Prolonged (≥1 week) severe neutropenia and thrombocytopenia can occur with ARZERRA. Monitor complete blood counts (CBC) and platelet counts at regular intervals during therapy, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. 5.3 Progressive Multifocal Leukoencephalopathy Progressive multifocal leukoencephalopathy (PML), including fatal PML, can occur with ARZERRA. Consider PML in any patient with new onset of or changes in pre-existing neurological signs or symptoms. Discontinue ARZERRA if PML is suspected, and initiate evaluation for PML including consultation with a neurologist, brain MRI, and lumbar puncture. 5.4 Hepatitis B Infection and Reactivation Fulminant and fatal hepatitis B virus (HBV) infection and reactivation can occur in patients following treatment with ARZERRA. Screen patients at high risk of HBV infection before initiation of ARZERRA. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection during treatment with ARZERRA and for 6 to 12 months following the last infusion of ARZERRA. Discontinue ARZERRA in patients who develop viral hepatitis or reactivation of viral hepatitis, and institute appropriate treatment. Insufficient data exist regarding the safety of administration of ARZERRA in patients with active hepatitis. 5.5 Intestinal Obstruction Obstruction of the small intestine can occur in patients receiving ARZERRA. Perform a diagnostic evaluation if obstruction is suspected. 5.6 Immunizations The safety of immunization with live viral vaccines during or following administration of ARZERRA has not been studied. Do not administer live viral vaccines to patients who have recently received ARZERRA. The ability to generate an immune response to any vaccine following administration of ARZERRA has not been studied. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the labeling: • Infusion Reactions [see Warnings and Precautions (5.1)] • Cytopenias [see Warnings and Precautions (5.2)] • Progressive Multifocal Leukoencephalopathy [see Warnings and Precautions (5.3)] • Hepatitis B Reactivation [see Warnings and Precautions (5.4)] • Intestinal Obstruction [see Warnings and Precautions (5.5)] The most common adverse reactions (≥10%) in Study 1 were neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections. The most common serious adverse reactions in Study 1 were infections (including pneumonia and sepsis), neutropenia, and pyrexia. Infections were the most common adverse reactions leading to drug discontinuation in Study 1. 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 practice. The safety of monotherapy with ARZERRA was evaluated in 181 patients with relapsed or refractory CLL in 2 open-label, non-randomized, single-arm studies. In these studies, ARZERRA was administered at 2,000 mg beginning with the second dose for 11 doses (Study 1 [n = 154]) or 3 doses (Study 2 [n = 27]). The data described in Table 1 and other sections below are derived from 154 patients in Study 1. All patients received 2,000 mg weekly from the second dose onward. Ninety percent of patients received at least 8 infusions of ARZERRA and 55% received all 12 infusions. The median age was 63 years (range: 41 to 86 years), 72% were male, and 97% were White.

32% reduction in risk of progression with bevacizumab treatment (HR = 0.68, P < .0001). Confirmed response occurred in 5% of the bevacizumab group (including complete response in one patient) and 4% of the chemotherapy-alone group (complete response in two patients). A post hoc analysis showed an improved disease control

Table 1. Incidence of All Adverse Reactions Occurring in ≥5% of Patients in Study 1 and in the Fludarabine- and Alemtuzumab-Refractory Subset of Study 1 (MedDRA 9.0) Total Population (n = 154)

Fludarabine- and AlemtuzumabRefractory (n = 59) Grade All ≥3 Grades % %

Grade All ≥3 Grades Body System/ % % Adverse Event Infections and infestations Pneumoniaa 23 14 25 15 Upper respiratory tract 11 0 3 0 infection Bronchitis 11 <1 19 2 Sepsisb 8 8 10 10 Nasopharyngitis 8 0 8 0 Herpes zoster 6 1 7 2 Sinusitis 5 2 3 2 Blood and lymphatic system disorders Anemia 16 5 17 8 Psychiatric disorders Insomnia 7 0 10 0 Nervous system disorders Headache 6 0 7 0 Cardiovascular disorders Hypertension 5 0 8 0 Hypotension 5 0 3 0 Tachycardia 5 <1 7 2 Respiratory, thoracic, and mediastinal disorders Cough 19 0 19 0 Dyspnea 14 2 19 5 Gastrointestinal disorders Diarrhea 18 0 19 0 Nausea 11 0 12 0 Skin and subcutaneous tissue disorders Rashc 14 <1 17 2 Urticaria 8 0 5 0 Hyperhidrosis 5 0 5 0 Musculoskeletal and connective tissue disorders Back pain 8 1 12 2 Muscle spasms 5 0 3 0 General disorders and administration site conditions Pyrexia 20 3 25 5 Fatigue 15 0 15 0 Edema peripheral 9 <1 8 2 Chills 8 0 10 0 a Pneumonia includes pneumonia, lung infection, lobar pneumonia, and bronchopneumonia. b Sepsis includes sepsis, neutropenic sepsis, bacteremia, and septic shock. c Rash includes rash, rash macular, and rash vesicular.

Infusion Reactions: Infusion reactions occurred in 44% of patients on the day of the first infusion (300 mg), 29% on the day of the second infusion (2,000 mg), and less frequently during subsequent infusions. Infections: A total of 108 patients (70%) experienced bacterial, viral, or fungal infections. A total of 45 patients (29%) experienced ≥Grade 3 infections, of which 19 (12%) were fatal. The proportion of fatal infections in the fludarabine- and alemtuzumab-refractory group was 17%. Neutropenia: Of 108 patients with normal neutrophil counts at baseline, 45 (42%) developed ≥Grade 3 neutropenia. Nineteen (18%) developed Grade 4 neutropenia. Some patients experienced new onset Grade 4 neutropenia >2 weeks in duration. 6.2 Immunogenicity There is a potential for immunogenicity with therapeutic proteins such as ofatumumab. Serum samples from patients with CLL in Study 1 were tested by enzyme-linked immunosorbent assay (ELISA) for anti-ofatumumab antibodies during and after the 24-week treatment period. Results were negative in 46 patients after the 8th infusion and in 33 patients after the 12th infusion. Immunogenicity assay results are highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of incidence of antibodies to ARZERRA with the incidence of antibodies to other products may be misleading.

ASCOPost.com | MAY 1, 2013

PAGE 15

Journal Spotlight

rate with bevacizumab treatment (68% vs 54%, P < .0001).

Outcome by KRAS status Subgroup analysis according to KRAS status showed progression-free survival benefits of bevacizumab in both patients with wild-type KRAS (HR = 0.61, P < .0001) and those with

mutant KRAS (HR = 0.70, P = .003). Bevacizumab treatment was associated with a significant Overall survival benefit in patients with wild-type KRAS (HR = 0.69, P = .005) but not in those with mutant KRAS (HR = 0.92, P = .50). However, there was no significant treatment by KRAS interaction for either progression-free survival or overall

7 DRUG INTERACTIONS No formal drug-drug interaction studies have been conducted with ARZERRA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category C: There are no adequate or well-controlled studies of ofatumumab in pregnant women. A reproductive study in pregnant cynomolgus monkeys that received ofatumumab at doses up to 3.5 times the recommended human dose of ofatumumab did not demonstrate maternal toxicity or teratogenicity. Ofatumumab crossed the placental barrier, and fetuses exhibited depletion of peripheral B cells and decreased spleen and placental weights. ARZERRA should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. There are no human or animal data on the potential short- and long-term effects of perinatal B-cell depletion in offspring following in utero exposure to ofatumumab. Ofatumumab does not bind normal human tissues other than B lymphocytes. It is not known if binding occurs to unique embryonic or fetal tissue targets. In addition, the kinetics of B-lymphocyte recovery are unknown in offspring with B-cell depletion [see Nonclinical Toxicology (13.3)]. 8.3 Nursing Mothers It is not known whether ofatumumab is secreted in human milk; however, human IgG is secreted in human milk. Published data suggest that neonatal and infant consumption of breast milk does not result in substantial absorption of these maternal antibodies into circulation. Because the effects of local gastrointestinal and limited systemic exposure to ofatumumab are unknown, caution should be exercised when ARZERRA is administered to a nursing woman. 8.4 Pediatric Use Safety and effectiveness of ARZERRA have not been established in children. 8.5 Geriatric Use Clinical studies of ARZERRA did not include sufficient numbers of subjects aged 65 and over to determine whether they respond differently from younger subjects [see Clinical Pharmacology (12.3) of full prescribing information]. 8.6 Renal Impairment No formal studies of ARZERRA in patients with renal impairment have been conducted [see Clinical Pharmacology (12.3) of full prescribing information]. 8.7 Hepatic Impairment No formal studies of ARZERRA in patients with hepatic impairment have been conducted. 10 OVERDOSAGE No data are available regarding overdosage with ARZERRA.

Adverse Events Grade 3 to 5 adverse events occurred in 64% of the bevacizumab group and 57% of the chemotherapyalone group, with the most common being neutropenia (16% and 13%), diarrhea (10% and 8%), and asthe-

Fetuses from treated dams exhibiting anti-ofatumumab antibody responses had higher B cell counts and higher spleen weights compared to the fetuses from other treated dams, indicating partial recovery in those animals developing anti-ofatumumab antibodies. When compared to control animals, fetuses from treated dams in both dose groups had a 10% decrease in mean placental weights. A 15% decrease in mean thymus weight compared to the controls was also observed in fetuses from dams treated with 3.5 times the human dose of ofatumumab. The biological significance of decreased placental and thymic weights is unknown. The kinetics of B-lymphocyte recovery and the potential long-term effects of perinatal B-cell depletion in offspring from ofatumumab-treated dams have not been studied in animals. 17 PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Signs and symptoms of infusion reactions including fever, chills, rash, or breathing problems within 24 hours of infusion [see Warnings and Precautions (5.1) and Adverse Reactions (6.1)] • Bleeding, easy bruising, petechiae, pallor, worsening weakness, or fatigue [see Warnings and Precautions (5.2)] • Signs of infections including fever and cough [see Warnings and Precautions (5.2) and Adverse Reactions (6.1)] • New neurological symptoms such as confusion, dizziness or loss of balance, difficulty talking or walking, or vision problems [see Warnings and Precautions (5.3)] • Symptoms of hepatitis including worsening fatigue or yellow discoloration of skin or eyes [see Warnings and Precautions (5.4)] • New or worsening abdominal pain or nausea [see Warnings and Precautions (5.5)] • Pregnancy or nursing [see Use in Specific Populations (8.1, 8.3)] Advise patients of the need for: • Periodic monitoring for blood counts [see Warnings and Precautions (5.2)] • Avoiding vaccination with live viral vaccines [see Warnings and Precautions (5.6)] Manufactured by: GLAXO GROUP LIMITED Greenford, Middlesex, UB6 0NN, United Kingdom U.S. Lic. 1809 Distributed by:

GlaxoSmithKline Research Triangle Park, NC 27709 ©2011, GlaxoSmithKline. All rights reserved. September 2011 ARZ:6BRS ©2011 The GlaxoSmithKline Group of Companies All rights reserved. Printed in USA. AZA295R0 September 2011

nia (6% and 4%). Notable grade 3 to 5 adverse events that occurred more frequently in the bevacizumab group were bleeding or hemorrhage (2% vs < 1%), gastrointestinal (GI) perforation (2% vs < 1%), and venous thromboembolic events (5% vs 3%). Eleven adverse events resulted in death in each group. Those considered related to study treatment consisted of upper GI hemorrhage, cerebrovascular accident, sudden death, and neutropenia in one patient each in the bevacizumab group, and intestinal perforation, general physical health deterioration, and acute prerenal failure in one patient each in the chemotherapy-alone group. Overall, death not related to progressive disease occurred in 6% of patients in the bevacizumab group and 5% of patients in the chemotherapy-alone group. Serious adverse events occurred in 32% of the bevacizumab group and in 33% of the chemotherapy-alone group; the most common were diarrhea (3% and 4%), pyrexia (2% and 3%), and neutropenia (2% and 2%). Treatment was discontinued due to adverse events in 16% of the bevacizumab group, including discontinuation of bevacizumab alone in 2%, and in 9% of the chemotherapy-alone group. The authors concluded, “The findings in our study challenge the conventional definition of treatment resistance and lend support to the hypothesis that continued VEGF inhibition throughout the growth and metastasis of tumors is beneficial for patients with metastatic [colorectal cancer]….The results…could serve as proof of principle that maintaining angiogenesis inhibition while switching chemotherapy from the first and second lines in [colorectal cancer] has clinical benefits in patients. This approach is also being investigated in studies of other tumor types, including metastatic breast and non–small-cell lung cancers.” The study was sponsored by Hoffmann-La Roche. n

B:15.125” T:14” S:12”

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity or mutagenicity studies of ofatumumab have been conducted. In a repeat-dose toxicity study, no tumorigenic or unexpected mitogenic responses were noted in cynomolgus monkeys treated for 7 months with up to 3.5 times the human dose of ofatumumab. Effects on male and female fertility have not been evaluated in animal studies. 13.3 Reproductive and Developmental Toxicology Pregnant cynomolgus monkeys dosed with 0.7 or 3.5 times the human dose of ofatumumab weekly during the period of organogenesis (gestation days 20 to 50) had no maternal toxicity or teratogenicity. Both dose levels of ofatumumab depleted circulating B cells in the dams, with signs of initial B cell recovery 50 days after the final dose. Following Caesarean section at gestational day 100, fetuses from ofatumumab-treated dams exhibited decreases in mean peripheral B-cell counts (decreased to approximately 10% of control values), splenic B-cell counts (decreased to approximately 15 to 20% of control values), and spleen weights (decreased by 15% for the low-dose and by 30% for the high-dose group, compared to control values).

survival on regression analysis.

Full disclosure information can be found online at ASCOPost.com. Reference 1. Bennouna J, Sastre J, Arnold D, et al: Continuation of bevacizumab after first progression in metastatic colorectal cancer (ML18147): A randomized phase III trial. Lancet Oncol 14:29-37, 2013.

The ASCO Post | MAY 1, 2013

PAGE 16

JCO Spotlight Gastrointestinal Oncology

More Recreational Physical Activity Associated with Reduced All-cause Mortality in Patients with Colorectal Cancer By Matthew Stenger

n a study recently reported in Journal of Clinical Oncology, Peter T. Campbell, PhD, and colleagues from the Epidemiology Research Program of the American Cancer Society, Atlanta, found that more recreational physical activity before and after a diagnosis of colorectal cancer was associated with lower all-cause mortality, whereas longer leisure time spent sitting was associated with higher mortality.

Study Details The study involved 2,293 patients from the Cancer Prevention Study-II Nutrition Cohort who did not have colorectal cancer at baseline in 1992– 1993 but were diagnosed with invasive nonmetastatic colorectal cancer up through mid-2007. Participants completed detailed questionnaires including information about recreational physical activity and leisure time spent sitting at baseline and again after diagnosis of colorectal cancer. During a maximum follow up of 16.1 years (mean, 6.8 years) after colorectal cancer diagnosis, 846 patients with colorectal cancer died, 379 of them from colorectal cancer, 152 from cardiovascular disease, 127 from other cancers, and 139 from other causes. All-cause, colorectal cancer– specific, and cardiovascular disease–

specific mortality risks and risk from all other causes were analyzed according to recreational activity categories of < 3.5 (n = 255), 3.5 to < 8.75 (n = 943), and ≥ 8.75 (n = 1,064) metabolic equivalent (MET) hours per week and according to < 3 hours (n = 946), 3 to < 6 hours (n = 976), and ≥ 66 hours (n = 283) = 283) 283) per day of leisure time sitting. A level of 8.75 MET h/wk corresponds to approximately 150 minutes of walking per week. At baseline, there were significant differences across recreational activity MET categories for sex, education level, smoking, red meat intake,

Physical Activity and Colorectal Cancer Survival ■ Increased physical activity before and increased physical activity after colorectal cancer diagnosis were each associated with significantly reduced all-cause mortality.

■ Greater leisure time spent sitting prior to colorectal cancer diagnosis was

associated with significantly increased all-cause mortality; greater time sitting postdiagnosis was associated with a nonsignificant increase in all-cause mortality and a significant increase in colorectal cancer–specific mortality.

tion therapy as first-line treatment. For all comparisons, relative risks (RRs) were the adjusted values from multivariable analysis adjusting for

Physicians should consider counseling colorectal cancer survivors to adopt a more physically active lifestyle. —Peter T. Campbell, PhD

and body mass index, and no significant differences for age at colorectal cancer diagnosis, race, family history of colorectal cancer, leisure time spent sitting, hypertension, diabetes, colorectal cancer location, Surveillance, Epidemiology, and End Results (SEER) stage, tumor grade, or receipt of surgery, chemotherapy, or radia-

Take-home Message By Peter T. Campbell, PhD

erhaps the most important take-home point of our study is that physicians should consider counseling colorectal cancer survivors to adopt a more physically active lifestyle that is consistent with a patient’s abilities and overall medical condition. Physicians should be reminded that most patients with colorectal cancer do not engage in any activity, and that any activity is better than none. In our study, even 60 minutes of activity per week was associated with lower risk of all-cause mortality in patients with colorectal cancer. Moreover, the type of activity here isn’t marathon running or a triathlon—most of the activities reported by these participants were lighter, less intense activities, like walking. n Disclosure: Dr. Campbell reported no potential conflicts of interest.

Dr. Campbell is Director of the Tumor Repository at American Cancer Society, Atlanta. He was the principal investigator in the study.

age at diagnosis, sex, smoking status, body mass index, red meat intake, SEER stage, leisure time spent sitting, and education. The postdiagnosis analyses excluded all patients dying within 6 months of reporting their postdiagnosis physical activity level.

Prediagnosis Activity and Leisure Time Sitting For prediagnosis activity levels, patients in the middle activity category (3.5 to < 8.75 8.75 MET h/wk) h/wk) had a significant 31% reduction in risk for allcause mortality (RR = = 0.69, 95% conconfidence interval [CI] = 0.55–0.85) and those in the highest category (≥ 8.75 MET h/wk) had a significant 27% reduction (RR = 0.72, 95% CI = 0.58–0.89) compared with those in the lowest category (< 3.5 MET h/ wk). The multivariable adjusted relative risks were consistently lower for the middle and highest physical activity categories vs the lowest category for colorectal cancer–specific mortality, cardiovascular disease–specific mortality, and mortality from all other causes. The only other statistically significant difference was a 32%

reduction in risk for colorectal cancer–specific mortality in the middle activity category compared with the lowest activity category (RR = 0.32, 95% CI = 0.49–0.95). For prediagnosis leisure time spent sitting, patients in the highest category (≥ 6 h/d) had a 36% increased risk of all-cause mortality (multivariable adjusted RR = 1.36, 95% CI = 1.10–1.68) compared with those in the lowest category (< 3 h/d). Those in the middle category had a nonsignificant 13% increased risk for allcause mortality compared with those in the lowest category. Relative risks were consistently higher for patients in the middle and highest categories for colorectal cancer–specific mortality, cardiovascular disease–specific mortality, and mortality from all other causes. The only other statistically significant difference was a 48% increased risk for mortality from all other causes among patients in the highest category (RR = 1.48, 95% CI = 1.05–2.08).

Postdiagnosis Activity and Leisure Time Sitting For postdiagnosis activity levels, patients in the highest group had a significant 42% reduced risk of all-cause mortality compared with those in the lowest group (RR = 0.58, 95% CI = 0.47–0.71). Patients in the middle group had a nonsignificant 22% reduction in risk. Relative risks for colorectal cancer–specific mortality were lower for the middle and highest groups, but the differences were not significant. Risk of cardiovascular disease–specific mortality was significantly reduced by 64% (RR = 0.36, 95% CI = 0.20–0.67) in the middle group and 64% in the highest group (RR = 0.36, 95% CI = 0.24–0.55).

ASCOPost.com | MAY 1, 2013

PAGE 17

JCO Spotlight

Risk of mortality from all other causes was significantly reduced by 50% in the highest group (RR = 0.50, 95% CI = 0.36–0.69). Relative risks for all other comparisons favored the middle and highest activity groups (except for a relative risk of 1.00 for colorectal cancer–specific mortality in the middle category). For postdiagnosis leisure time spent sitting, the only significant effect observed was a 62% increased risk of colorectal cancer–specific mortality in patients in the highest category compared with those in the lowest (RR = 1.62, 95% CI = 1.07–2.44). Risk for all-cause mortality was nonsignificantly increased by 27% in the highest category. For all other comparisons, relative risks indicated nonsignificantly increased risk in the middle and highest categories (except for a relative risk of 1.00 for cardiovascular disease–specific mortality in the middle category. The authors noted that limitations of the study include lack of data on cancer recurrence, tumor molecular phenotype, and details of treatment beyond identification of first-line treatment. They stated, “Because all of the studies on this topic to date are observational, we cannot rule out the possibility that other factors associated with both physical activity and mortality and not assessed in these studies may be driving these apparent

Contact

The ASCO Post 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

associations.” The authors concluded, “[T]his study supports public health recommendations for recreational physical activity and the avoidance of sedentary time among colorectal cancer survivors. Clinically, physical activity recommendations should be based on the abilities and overall medical

condition of a patient with cancer. Our results add to mounting evidence that physicians should consider counseling colorectal cancer survivors to adopt a physically active lifestyle aiming to achieve 150 minutes per week or more of moderate intensity activity, such as walking, and to avoid prolonged sitting.” n

Disclosure: The authors reported no potential conflicts of interest.

Reference 1. Campbell PT, Patel AV, Newton CC, et al: Associations of recreational physical activity and leisure time spent sitting with colorectal cancer survival. J Clin Oncol 31:876-885, 2013.

Connect with Leading Employers and Advance Your Career At the ASCO 2013 A nnual Meeting Career Fair Be sure to visit the Career Fair—participating employers include many of the nation’s most prestigious hospitals, health care systems, academic institutions, pharmaceutical companies, and practice groups.

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The ASCO Post | MAY 1, 2013

PAGE 18

Journal Spotlight Treatment Disparities

Access to Care: Who Gets Referred to a Medical Oncologist and/or Another Cancer Specialist and Who Receives Treatment for Advanced Cancer? By Charlotte Bath

hat factors determine who is referred to a medical oncologist and receives treatment for advanced cancers? Several articles in the Journal of Oncology Practice suggest that factors influencing referral and treatment go beyond the patient’s medical condition and preference and include such details as where patients live and receive care, where oncologists practice, and whether guidelines are followed. Racial and income disparities still present barriers for some patients.

Advanced Age and Stage Patients who are older, have advancedstage disease, or have cancers that are either difficult to treat or for which active surveillance may be recommended are less likely to receive treatment, according to a study based on data from 113,885 patient cases with invasive cancer diagnoses.1 “Surgery and chemotherapy were the recommended treatment modalities that were most commonly refused,” reported Marcia M. Ward, PhD, of the University of Iowa, Iowa City, and colleagues from Beth Israel Deaconess Medical Center, Boston; Memorial Sloan-Kettering Cancer Center, New York; and the American Society of Clinical Oncology, Alexandria, Virginia. Patients with lung/bronchial cancer, low-grade non-Hodgkin lymphoma, and prostate cancer were significantly more likely to not be treated. “In contrast, patients with breast, cervical, colon, melanoma, and rectal cancers were significantly less likely to not be treated,” Dr. Ward and colleagues reported. “Not receiving treatment was significantly more common in rural residents than in urban residents,” the investigators added. “Not receiving treatment increased significantly with age and cancer stage. In fact, patients with stage II or III disease were twice as likely to not receive treatment as those with early-stage disease (stage I), and dramatically, stage IV cancers were six times more likely to not be treated.” Most patients with invasive cancer received treatment, but 12.3% of cases had documentation that patients did not receive a first course of treatment. This nontreatment rate, based on data from the Iowa Cancer Registry, is 48% higher

than the rate reported by the National Cancer Data Base (NCDB), which compiles data from cancer program registries accredited by the Commission on Cancer (COC), “but lacks data from the 30% of patient cases that are not represented by COC-accredited cancer programs,” the study authors noted. “This difference in rates suggests that nontreatment is less common in patients seen in COC-accredited cancer programs and that nontreatment for cancer is more common than the NCDB data indicate.” Nontreatment was also less common for patients who saw an oncologist, radiation therapist, or surgeon. The study grew out of the larger ASCO Study of Geographic Access to Oncology Care, which was designed to determine

referred to medical oncologists for treatment and to receive chemotherapy, even though the NCCN guidelines recommend colectomy followed by 6 months of adjuvant chemotherapy for patients with stage III colon cancer, and chemotherapy after colon resection has been shown to improve survival in younger and older patients. Katherine S. Virgo, PhD, MBA

study using the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked database identified 9,262 patients who were aged ≥ 66 years and underwent colectomy for stage III colon cancer diagnosed from 2000 to 2005. Chun Chieh Lin, PhD, MBA, and Katherine S. Virgo, PhD, MBA, of the American

This difference in rates suggests that nontreatment is less common in patients seen in Commission on Cancer–accredited cancer programs and that nontreatment for cancer is more common than the [National Cancer Data Base] data indicate.

Racial and Income Disparities Persist Patients with stage III/IV non–small cell lung cancer (NSCLC) who were older, black, lived in lower-income areas, had higher comorbidities, and were initially seen by a family practice physician vs a general internist, were less likely to be referred to medical oncologists, according to a study of 28,977 patients in the SEER-Medicare database.3 Patient data was linked to data about the patients’ physicians in the American Medical Association Masterfile database to identify physician factors associated with referrals to cancer specialists (medical oncologists, radiation oncologists, and surgeons) and how seeing these can-

—Marcia M. Ward, PhD, and colleagues

if there are gaps in the geographic distribution of physicians and patient access to treatment sites that may contribute to disparities in cancer care. Findings from that study are expected later this year.

Where Patients Live and Oncologists Practice Where patients live can increase or decrease the chances that they will receive chemotherapy following surgery for stage III colon cancer, as recom-

Chun Chieh Lin, PhD, MBA

mended by National Comprehensive Cancer Network (NCCN) guidelines. A

Cancer Society and Emory University, Atlanta, found that the likelihood of initiating chemotherapy following colon resection surgery was approximately 1.5 times higher for patients residing in a hospital service area with one or more medical oncologists than with no medical oncologists.2 In addition, Drs. Lin and Virgo reported that the following factors were associated with a decreased likelihood of initiating chemotherapy within 3 months after colectomy: age > 70 years (P < .001), African American ethnicity (P < .01), current unmarried status or unknown marital status (P < .001), comorbidity score ≥ 1 (P < .001), dual eligibility for Medicare and Medicaid (P < .001), and more recent diagnosis (ie, 2005; P < .05). Overall, only 60.19% of patients in the study initiated chemotherapy with 3 months of surgery, which the authors noted, is “consistent with previous studies.” Previous studies have also shown that older patients are less likely to be

Bernardo H.L. Goulart, MD, MS

cer specialists correlated with delivery of guideline-based therapies, as defined by current versions of the NCCN practice guidelines. The results were reported by Bernardo H.L. Goulart, MD, MS, and colleagues from Fred Hutchinson Cancer Research Center and University of Washington, Seattle; Genentech, San Francisco; and Q.D. Research, Granite Bay, California. “Seeing the three types of cancer specialists predicted higher likelihood of [guideline-based therapies] (stage IIIA: odds ratio [OR] = 20.6; P < .001; IIIB: OR = 77.2; P < .001; and IV: OR = 1.2; P = .011), compared with seeing a medical oncologist only. Use of [guidelinebased therapies] increased over the study continued on page 23

After progression following antiestrogen therapy in postmenopausal women with hormone receptor-positive (HR+) metastatic breast cancer…

The FASLODEX Story Continues… Overall Survival Update Important Safety Information About FASLODEX • FASLODEX is contraindicated in patients with known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema have been reported in association with FASLODEX • Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or in patients on anticoagulants Please see additional Important Safety Information for FASLODEX on the subsequent pages and adjacent brief summary of full Prescribing Information.

After progression following antiestrogen therapy in postmenopausal women with HR+ metastatic breast cancer…

FASLODEX 500 MG STRENGTH Prolonged Progression-Free Survival (PFS)1,* †

With FASLODEX 500 mg vs 250 mg in CONFIRM

FASLODEX 500 mg showed a

20% reduction

in relative risk of progression vs 250 mg2

Median 6.5 months with FASLODEX 500 mg vs

5.4 months with 250 mg

At minimum 18-month follow-up, HR=0.80 (95% CI: 0.68-0.94) (P=0.006)2 • PFS was the primary endpoint 1

• FASLODEX 500 mg signifcantly increased PFS (P=0.006): median PFS 6.5 months vs 5.4 months with FASLODEX 250 mg2 • Objective response rates (ORRs)‡ were not signifcantly different between FASLODEX 500 mg (13.8%) and 250 mg (14.6%) (OR=0.94; 95% CI: 0.57-1.55) (P=0.795)1,2 — Only patients with measurable disease at baseline were analyzed (FASLODEX 500 mg: n=240; FASLODEX 250 mg: n=261) 2 — ORRs in the full patient population were 9.1% and 10.2% for the FASLODEX 500 mg and 250 mg arms, respectively1

Additional Important Safety Information About FASLODEX • FASLODEX is metabolized primarily in the liver. A 250-mg dose is recommended in patients with moderate hepatic impairment. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh Class C) • Fetal harm can occur when administered to a pregnant woman. Women should be advised of the potential hazard to the fetus and to avoid becoming pregnant while receiving FASLODEX • The most common, clinically signifcant adverse reactions occurring in ≥5% of patients receiving FASLODEX were: injection site pain, nausea, bone pain, arthralgia, headache, back pain, fatigue, pain in extremity, hot fash, vomiting, anorexia, asthenia, musculoskeletal pain, cough, dyspnea, and constipation * PFS is defned as the time between randomization and the earliest evidence of progression or death from any cause.2 † The CONFIRM (COmparisoN of FASLODEX In Recurrent or Metastatic Breast Cancer) trial was a randomized, double-blind, controlled phase III study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 ‡ ORR is defned as the number of patients with complete response or partial response.2

Updat

Overaed Surviv ll Analy al s

THE FASLODEX STORY CONTINUES

Overall Survival (OS)

With FASLODEX 500 mg vs 250 mg in updated analysis in CONFIRM M22,*

FASLODEX 500 mg showed a

19% reduction

in relative risk of death vs 250 mg2

Median 26.4 months with FASLODEX 500 mg vs

22.3 months with 250 mg

At minimum 50-month follow-up, HR=0.81 (95% CI: 0.69-0.96)2,† • OS was a secondary endpoint 1 • No statistically signifcant difference in OS after a minimum duration of 50 months as no adjustments were made for multiplicity2 • In the initial OS analysis after a minimum duration of 18 months, there was no statistically signifcant difference in OS between the 2 treatment groups2

Learn more at www.FASLODEXStoryContinues.com

Additional Important Safety Information About FASLODEX • Increased hepatic enzymes (ALT, AST, ALP) occurred in >15% of FASLODEX users and were non dose-dependent

Indication For FASLODEX • FASLODEX is indicated for the treatment of hormone receptor-positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy Please read adjacent brief summary of full Prescribing Information. * The CONFIRM trial was a randomized, double-blind, controlled phase III study of 736 postmenopausal women with advanced breast cancer who had disease recurrence on or after adjuvant endocrine therapy or progression following endocrine therapy for advanced disease.1 † No statistically signifcant difference in OS as no adjustments were made for multiplicity.2

References: 1. Di Leo A, Jerusalem G, Petruzelka L, et al. Results of the CONFIRM phase III trial comparing fulvestrant 250 mg with fulvestrant 500 mg in postmenopausal women with estrogen receptor-positive advanced breast cancer. J Clin Oncol. 2010;28(30):4594-4600. 2. Full Prescribing Information for FASLODEX. AstraZeneca Pharmaceuticals LP, Wilmington, DE.

FASLODEX® (fulvestrant) Injection BRIEF SUMMARY For full Prescribing Information, see package insert. INDICATIONS AND USAGE FASLODEX is indicated for the treatment of hormone receptor positive metastatic breast cancer in postmenopausal women with disease progression following antiestrogen therapy. DOSAGE AND ADMINISTRATION Recommended Dose The recommended dose is 500 mg to be administered intramuscularly into the buttocks slowly (1 - 2 minutes per injection) as two 5 mL injections, one in each buttock, on days 1, 15, 29 and once monthly thereafter [see Clinical Studies (14) in full Prescribing Information]. Dose Modification Hepatic Impairment: A dose of 250 mg is recommended for patients with moderate hepatic impairment (Child-Pugh class B) to be administered intramuscularly into the buttock slowly (1 - 2 minutes) as one 5 mL injection on days 1, 15, 29 and once monthly thereafter. FASLODEX has not been evaluated in patients with severe hepatic impairment (Child-Pugh class C) [see Warnings and Precautions and Use in Specific Populations]. Administration Technique The proper method of administration of FASLODEX for intramuscular use is described in the instructions that follow: 1. Remove glass syringe barrel from tray and check that it is not damaged. 2. Remove perforated patient record label from syringe. 3. Peel open the safety needle (SafetyGlide™) outer packaging. For complete SafetyGlide™ instructions refer below to the “Directions for Use of SafetyGlide™.” 4. Break the seal of the white plastic cover on the syringe luer connector to remove the cover with the attached rubber tip cap. 5. Twist to lock the needle to the luer connector. 6. Remove needle sheath. 7. Remove excess gas from the syringe (a small gas bubble may remain). 8. Administer intramuscularly slowly in the buttock. 9. Immediately activate needle protection device upon withdrawal from patient by pushing lever arm completely forward until needle tip is fully covered. 10. Visually confirm that the lever arm has fully advanced and the needle tip is covered. If unable to activate, discard immediately into an approved sharps collector. 11. Repeat steps 1 through 10 for second syringe. For additional directions for use, see Administration Technique (2.3) in full Prescribing Information. CONTRAINDICATIONS FASLODEX is contraindicated in patients with a known hypersensitivity to the drug or to any of its components. Hypersensitivity reactions, including urticaria and angioedema, have been reported in association with FASLODEX. WARNINGS AND PRECAUTIONS Blood Disorders Because FASLODEX is administered intramuscularly, it should be used with caution in patients with bleeding diatheses, thrombocytopenia, or anticoagulant use. Hepatic Impairment The safety and pharmacokinetics of FASLODEX were evaluated in a study in seven subjects with moderate hepatic impairment (Child-Pugh class B) and seven subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose of 250 mg is recommended [see Dosage and Administration]. FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C) [see Use in Specific Populations]. Use in Pregnancy Based on its mechanism of action and findings in animals, FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area. There are no adequate and well-controlled studies in pregnant women using FASLODEX. Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus [see Use in Specific Populations]. ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice. Comparison of FASLODEX 500 mg and FASLODEX 250 mg The following frequency categories for adverse reactions (ARs) were calculated based on the safety analysis of Study 1 that compared FASLODEX 500 mg with FASLODEX 250 mg. The most frequently reported adverse reactions in the fulvestrant 500 mg group were injection site pain (11.6% of patients), nausea (9.7% of patients) and bone pain (9.4% of patients); the most frequently reported adverse reactions in the fulvestrant 250 mg group were nausea (13.6% of patients), back pain (10.7% of patients) and injection site pain (9.1% of patients). Table 1 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the controlled clinical trial Study 1 comparing the administration of FASLODEX 500 mg intramuscularly once a month with FASLODEX 250 mg intramuscularly once a month. Table 1: Summary of Most Commonly Reported Adverse Reactions in Study 1 (≥5% in either treatment group): Safety Population Body System Number (%) of Patients and Adverse Reaction Fulvestrant 500 mg Fulvestrant 250 mg N=361 N=374 Body as a Whole Injection Site Pain 42 (11.6) 34 (9.1) Headache 28 (7.8) 25 (6.7) Back Pain 27 (7.5) 40 (10.7) Fatigue 27 (7.5) 24 (6.4) Pain in Extremity 25 (6.9) 26 (7.0) Asthenia 21 (5.8) 23 (6.1) Vascular System Hot Flash 24 (6.6) 22 (5.9) Digestive System Nausea 35 (9.7) 51 (13.6) Vomiting 22 (6.1) 21 (5.6) Anorexia 22 (6.1) 14 (3.7) Constipation 18 (5.0) 13 (3.5) Musculoskeletal System Bone Pain 34 (9.4) 28 (7.5) Arthralgia 29 (8.0) 29 (7.8) Musculoskeletal Pain 20 (5.5) 12 (3.2) Respiratory System Cough 19 (5.3) 20 (5.3) Dyspnea 16 (4.4) 19 (5.1)

In the pooled safety population (N=1127) from clinical trials comparing FASLODEX 500 mg to FASLODEX 250 mg, post-baseline increases of ≥1 CTC grade in either AST, ALT, or alkaline phosphatase were observed in >15% of patients receiving FASLODEX. Grade 3-4 increases were observed in 1-2% of patients. The incidence and severity of increased hepatic enzymes (ALT, AST, ALP) did not differ between the 250 mg and the 500 mg FASLODEX arms. Comparison of FASLODEX 250 mg and Anastrozole 1 mg in Combined Trials (Studies 2 and 3) The most commonly reported adverse reactions in the FASLODEX and anastrozole treatment groups, regardless of the investigator’s assessment of causality, were gastrointestinal symptoms (including nausea, vomiting, constipation, diarrhea and abdominal pain), headache, back pain, vasodilatation (hot flashes), and pharyngitis. Injection site reactions with mild transient pain and inflammation were seen with FASLODEX and occurred in 7% of patients (1% of treatments) given the single 5 mL injection (predominantly European Trial Study 3) and in 27% of patients (4.6% of treatments) given the 2 x 2.5 mL injections (North American Trial Study 2). Table 2 lists adverse reactions reported with an incidence of 5% or greater, regardless of assessed causality, from the two controlled clinical trials comparing the administration of FASLODEX 250 mg intramuscularly once a month with anastrozole 1 mg orally once a day. Table 2: Combined Data from Studies 2 and 3, Adverse Reactions ≥ 5% Body System FASLODEX 250 mg Anastrozole 1 mg and Adverse Reactiona N=423 N=423 (%) (%) Body as a Whole Asthenia Pain Headache Back Pain Abdominal Pain Injection Site Painb Pelvic Pain Chest Pain Flu Syndrome Fever Accidental Injury Cardiovascular System Vasodilatation Digestive System Nausea Vomiting Constipation Diarrhea Anorexia Hemic and Lymphatic Systems Anemia Metabolic and Nutritional Disorders Peripheral Edema Musculoskeletal System Bone Pain Arthritis Nervous System Dizziness Insomnia Paresthesia Depression Anxiety Respiratory System Pharyngitis Dyspnea Cough Increased Skin and Appendages Rash Sweating Urogenital System Urinary Tract Infection

68.3 22.7 18.9 15.4 14.4 11.8 10.9 9.9 7.1 7.1 6.4 4.5 30.3 17.7 51.5 26.0 13.0 12.5 12.3 9.0 13.7 4.5 18.2 9.0 25.5 15.8 2.8 34.3 6.9 6.9 6.4 5.7 5.0 38.5 16.1 14.9 10.4 22.2 7.3 5.0 18.2 6.1

67.6 27.0 20.3 16.8 13.2 11.6 6.6 9.0 5.0 6.4 6.4 5.7 27.9 17.3 48.0 25.3 11.8 10.6 12.8 10.9 13.5 5.0 17.7 10.2 27.9 13.7 6.1 33.8 6.6 8.5 7.6 6.9 3.8 33.6 11.6 12.3 10.4 23.4 8.0 5.2 14.9 3.5

a A patient may have more than one adverse reaction. b All patients on FASLODEX received injections, but only those anastrozole patients who were in the North American Study 2 received placebo injections.

Post-Marketing Experience For FASLODEX 250 mg, other adverse reactions reported as drug-related and seen infrequently (<1%) include thromboembolic phenomena, myalgia, vertigo, leukopenia, and hypersensitivity reactions including angioedema and urticaria. Vaginal bleeding has been reported infrequently (<1%), mainly in patients during the first 6 weeks after changing from existing hormonal therapy to treatment with FASLODEX. If bleeding persists, further evaluation should be considered. Elevation of bilirubin, elevation of gamma GT, hepatitis, and liver failure have been reported infrequently (<1%). DRUG INTERACTIONS There are no known drug-drug interactions. Although, fulvestrant is metabolized by CYP 3A4 in vitro, drug interactions studies with ketoconazole or rifampin did not alter fulvestrant pharmacokinetics. Dose adjustment is not needed in patients co-prescribed CYP3A4 inhibitors or inducers [see Clinical Pharmacology (12.3) in full Prescribing Information]. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D [see Warnings and Precautions] FASLODEX can cause fetal harm when administered to a pregnant woman. Fulvestrant caused fetal loss or abnormalities in animals when administered during the period of organogenesis at doses significantly smaller than the maximum recommended human dose based on the body surface area (BSA). Women of childbearing potential should be advised not to become pregnant while receiving FASLODEX. If FASLODEX is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. In studies in female rats at intramuscular doses ≥0.01 mg/kg/day (0.6% of the human recommended dose based on BSA), fulvestrant caused a reversible reduction in female fertility, as well as effects on embryo-fetal development consistent with its antiestrogenic activity. Fulvestrant caused an increased incidence of fetal abnormalities in rats (tarsal flexure of the hind paw at 2 mg/kg/day; equivalent to the human dose based on BSA) and non-ossification of the odontoid and ventral tubercle of the first cervical vertebra at doses ≥0.1 mg/kg/day (6% the human dose based on BSA) when administered during the period of organogenesis. Rabbits failed to maintain pregnancy when dosed intramuscularly with 1 mg/kg/day fulvestrant (equivalent to the human dose based on BSA) during the period of organogenesis. Further, in rabbits dosed at 0.25 mg/kg/day (30% the human dose based on BSA), increases in placental weight and post-implantation loss were observed. Fulvestrant was associated with an increased incidence of fetal variations in rabbits (backwards displacement of the pelvic

girdle, and 27 pre-sacral vertebrae at 0.25 mg/kg/day; 30% the human dose based on BSA) when administered during the period of organogenesis. Because pregnancy could not be maintained in the rabbit following doses of fulvestrant of 1 mg/kg/day and above, this study was inadequate to fully define the possible adverse effects on fetal development at clinically relevant exposures. Nursing Mothers It is not known if fulvestrant is excreted in human milk. Fulvestrant is found in rat milk at levels significantly higher (approximately 12-fold) than plasma after administration of 2 mg/kg. Drug exposure in rodent pups from fulvestrant-treated lactating dams was estimated as 10% of the administered dose. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from FASLODEX, 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. Pediatric Use A multi-center, single-arm, open-label, study of fulvestrant was conducted in 30 girls with McCune-Albright Syndrome (MAS) associated with progressive precocious puberty (PPP). The median age at informed consent was 6 years old (range: 1 to 8). The first 10 patients initially received fulvestrant 2 mg/kg. Based on PK data from the first 6 patients, all 10 patients receiving 2 mg/kg were escalated to a dose of 4 mg/kg and all other patients received 4 mg/kg from study entry. Baseline measurements for vaginal bleeding days, bone age, growth velocity, and Tanner staging for at least 6 months prior to study entry were provided retrospectively by the parent, guardian or local consultant. All measurements during the study period were collected prospectively. Patients’ baseline characteristics included the following: a mean ± SD chronological age of 5.9 ± 1.8 years; a mean rate of bone age advancement (change in bone age in years divided by change in chronological age in years) of 2.0 ± 1.03; and a mean growth velocity z-score of 2.4 ± 3.26. Twenty-nine of 30 patients completed the 12-month study period. The following results were observed: 35% (95% CI: 16%, 57%) of the 23 patients with baseline vaginal bleeding experienced a complete cessation of vaginal bleeding on-treatment (month 0 to 12); a reduction in the rate of bone age advancement during the 12-month study period compared to baseline (mean change = -0.9 [95% CI = -1.4, -0.4]); and a reduction in mean growth velocity Z-score on-treatment compared to baseline (mean change = -1.1 [95% CI = -2.7, 0.4]). There were no clinically meaningful changes in median Tanner stage (breast or pubic), mean uterine volume, or mean ovarian volume, or predicted adult height (PAH) on-treatment compared to baseline. The effect of FASLODEX on bone mineral density in children has not been studied and is not known. Eight patients (27%) experienced adverse reactions that were considered possibly related to FASLODEX. These included injection site reactions (inflammation, pain, hematoma, pruritis, rash), abdominal pain, contusion, tachycardia, hot flush, extremity pain, and vomiting. Nine (30.0%) patients reported an SAE, none of which were considered related to FASLODEX. No patients discontinued study treatment due to an AE and no patients died. Pharmacokinetics The pharmacokinetics of fulvestrant was characterized using a population pharmacokinetic analysis with sparse samples per patient obtained from 30 female pediatric patients aged 1 to 8 years with PPP associated with MAS. Pharmacokinetic data from 294 postmenopausal women with breast cancer who received 125 or 250 mg monthly dosing regimen were also included in the analysis. In these pediatric patients receiving 4 mg/kg monthly intramuscular dose of fulvestrant, the geometric mean (SD) CL/F was 444 (165) mL/min which was 32% lower than adults. The geometric mean (SD) steady state trough concentration (Cmin,ss) and AUCss was 4.19 (0. 87) ng/mL and 3680 (1020) ng*hr/mL, respectively. Geriatric Use For FASLODEX 250 mg, when tumor response was considered by age, objective responses were seen in 22% and 24% of patients under 65 years of age and in 11% and 16% of patients 65 years of age and older, who were treated with FASLODEX in Study 2 and Study 3, respectively. Hepatic Impairment FASLODEX is metabolized primarily in the liver. The pharmacokinetics of fulvestrant were evaluated after a single dose of 100 mg in subjects with mild and moderate hepatic impairment and normal hepatic function (n = 7 subjects/group), using a shorter-acting intramuscular injection formulation. Subjects with mild hepatic impairment (Child-Pugh class A) had comparable mean AUC and clearance values to those with normal hepatic function. In subjects with moderate hepatic impairment (Child-Pugh class B) the average AUC of fulvestrant increased by 70% compared to patients with normal hepatic function. AUC was positively correlated with total bilirubin concentration (p = 0.012). FASLODEX has not been studied in patients with severe hepatic impairment (Child-Pugh class C). A dose of FASLODEX 250 mg is recommended in patients with moderate hepatic impairment (Child-Pugh class B) [see Dosage and Administration and Warnings and Precautions]. Renal Impairment Negligible amounts of fulvestrant are eliminated in urine; therefore, a study in patients with renal impairment was not conducted. In the advanced breast cancer trials, fulvestrant concentrations in women with estimated creatinine clearance as low as 30 mL/min were similar to women with normal creatinine. OVERDOSAGE Animal studies have shown no effects other than those related directly or indirectly to antiestrogen activity with intramuscular doses of fulvestrant higher than the recommended human dose. There is no clinical experience with overdosage in humans. No adverse reactions were seen in healthy male and female volunteers who received intravenous fulvestrant, which resulted in peak plasma concentrations at the end of the infusion, that were approximately 10 to 15 times those seen after intramuscular injection.

SafetyGlide™ is a trademark of Becton Dickinson and Company. FASLODEX is a trademark of the AstraZeneca group of companies. © AstraZeneca 2013 Distributed by: AstraZeneca Pharmaceuticals LP, Wilmington, DE 19850 Manufactured for: AstraZeneca UK Limited, Macclesfield, Cheshire, England By: Vetter Pharma-Fertigung GMBH & Co. KG, Ravensburg, Germany Rev. 11/12 2543202 4/13

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Journal Spotlight

Access to Care continued from page 18

period (42% to 48% from 2000 to 2005; P < .001),” results showed. “Within 6 months from diagnosis, 24,462 patients (84%) saw at least a medical oncologist, and 9,053 patients (31%) saw all cancer specialists (medical oncologists, radiation oncologists, and thoracic or general surgeons),” the researchers reported. “Although patients with stages IIIA and IIIB were more likely to see all types of cancer specialists than stage IV patients (41% and 32% vs 28%, P < .001), patients with stages IIIA and IIIB were less likely to receive care consistent with guidelines than stage IV patients (45% and 30% vs 54%, P < .001),” the authors noted. Consistent with previous observational studies, the current study found that patients who were older, black, or lived in lower-income areas had a lower likelihood of referrals to medical oncologists, as did patients seen initially by family practice physicians. “These findings indicate that sociodemographic characteristics still represent access barriers to specialty care for NSCLC and that some general practitioners are not fully aware of the role of chemotherapy for stages III and IV NSCLC,” the authors asserted. “Health care systems need to promote efforts that increase access to specialty care so that only medical factors and

patient preferences determine the receipt of cancer therapy modalities.” Dr. Goulart and coauthors did note that patients “diagnosed in more recent years were more likely to see medical oncologists and to receive recommended therapies. This increasing trend in adoption of evidence-based practices suggests improvements in supportive care, lower surgical morbidity, and increased dissemination of guideline recommendations through scientific events and multimedia tools, including Web-enabled electronic health records.”

A 2000 survey included 191 admissions of 151 unique patients, and a 2010 survey assessed 149 admissions of 119 patients. The most common diagnoses

Gabrielle B. Rocque, MD

Missed Opportunities for End-of-life Care? An unscheduled hospitalization for a patient with advanced cancer “strongly predicts survival of fewer than 6 months,” according to survey data, and may represent a missed opportunity to move patients to end-of-life care. This conclusion was based on analysis of data collected on hospital admissions, interventions, and survival, in two separate surveys conducted at the University of Wisconsin Hospital in Madison inpatient oncology service.4 The results were reported by Gabrielle B. Rocque, MD, and colleagues from the University of Wisconsin, Madison; Park Nicollet Methodist Hospital, St. Louis Park, Minnesota; and Bay State Medical Center and Tufts University School of Medicine, Springfield, Massachusetts.

were for lung, gastrointestinal, and breast cancers. Most patients were admitted for uncontrolled symptoms. “The median survival of patients after discharge was 4.7 months in 2000 and 3.4 months in 2010. Despite poor survival in this patient population, hospice was recommended in only 23% and 24% of patients in 2000 and 2010, respectively. Seventy percent of patients were discharged home without additional services,” Dr. Rocque and colleagues stated. “Although the prognosis for patients with metastatic cancer varies widely based on the primary site, patients who are hospitalized have a poor prognosis regardless of cancer type,” the authors noted. “Given the

overall poor survival, any patient with metastatic cancer with an unscheduled hospitalization could be considered hospice eligible and appropriate for end-of-life planning, including discussion of advanced directives. Palliative care consultation would be a potential intervention to better address end-oflife care for these patients.” n

Disclosure: Dr. Carolina M. Reyes has had an employment or leadership position with Genentech and stock ownership in Roche. Dr. Sacha Satram-Hoang has served in a consultant or advisory role for Genentech. Dr. Bernardo H.L. Goulart, Ms. Catherine R. Fedorenko, Mr. David G. Mummy, Ms. Lisel M. Koepl, and Dr. Scott D. Ramsey have received research funding from Genentech (all reference 3). The authors of the other studies discussed in this article reported no potential conflicts of interest.

References 1. Ward MM, Ullrich F, Matthews K, et al: Who does not receive treatment for cancer? J Oncol Pract 9:20-26, 2013. 2. Lin CC, Virgo KS: Association between the availability of medical oncologists and initiation of chemotherapy for patients with stage III colon cancer. J Oncol Pract 9:27-33, 2013. 3. Goulart BHL, Reyes CM, Fedorenko CR, et al: Referral and treatment patterns among patients with stages III and IV non– small-cell lung cancer. J Oncol Pract 9:42-50, 2013. 4. Rocque GB, Barnett AE, Illig LC, et al: Inpatient hospitalization of oncology patients: Are we missing an opportunity for end-of-life care? J Oncol Pract 9:51-54, 2013.

Don’t Miss These Important Reports in This Issue of The ASCO Post Jose Baselga, MD, on T-DM1 in Metastatic Breast Cancer see page 1

Daniel G. Coit, MD, and Charles M. Balch, MD on Completion Lymph Node Dissection in Melanoma see pages 1 and 7

Giorgos C. Karakousis, MD, and Mary S. Brady, MD, on Sentinel Node Biopsy in Melanoma see page 7

Peter T. Campbell, PhD, on Physical Activity and Colorectal Cancer see page 16

Rebecca H. Johnson, MD, on Advanced Breast Cancer in Younger Women see page 40

Michael A. Choti, MD, on Resectability of Liver Metastases see page 3

Susan O’Brien, MD, on Ibrutinib in CLL see pages 1 and 24

Visit The ASCO Post online at ASCOPost.com

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Expert’s Corner Hematology

A Promising New Agent’s Road to Approval in CLL Raises Questions, Stirs Controversy By Ronald Piana

principal investigator in RESONATE, an active phase III trial of single-agent ibrutinib vs ofatumumab (Arzerra) in CLL, also offered her candid opinion about the trial design of the ongoing study, which is causing concern among clinicians and patients. (See Dr. O’Brien’s commentary on page 1.)

Mechanism of Action

Susan M. O’Brien, MD

arly trial results in single-agent therapy with the oral Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib have produced excellent responses in patients with chronic lymphocytic leukemia (CLL). Moreover, ibrutinib is extremely well tolerated, allowing patients to remain on trial and receive the drug’s full benefit. These encouraging responses and solid safety profile have left many in the oncology community anxious for results from phase III III studies of the drug in patients with CLL. In an interview with The ASCO Post, leukemia expert Susan M. O’Brien, MD, Ashbel Smith Professor at The University of Texas MD Anderson Cancer Center, explained ibrutinib’s clinical allure. Dr. O’Brien, who is a

In the simplest terms, how does ibrutinib work? The clinical idea behind ibrutinib is that if you ligate the B-cell receptor on

This is such a challenging disease setting; could you discuss some of the early data of ibrutinib in CLL? The exciting ibrutinib data in CLL presented at the American Society of Hematology (ASH) Annual Meeting and several other conferences are from a phase II trial in two different patient populations: treatment-naive patients aged 65 years and older, and patients with relapsed or refractory disease.1 The study opened with relapsed or refractory patients. However, once the

Based on the ASH meeting presentations, the 26-month progression-free survival rate in the relapsed/ refractory patients is 75%, and in treatment-naive patients, it’s 96%. That kind of durability is part of what’s generating the excitement about ibrutinib. —Susan M. O’Brien, MD

either a normal or malignant B cell, it provides a very strong survival and proliferation signal to the cell. One might then assume that interrupting that survival signal in a malignancy should cause a favorable effect on the disease. That’s the agent’s promise in a nutshell.

Three Breakthrough Therapy Designations for Ibrutinib from the FDA

Phase II Trial

n February 2013, FDA granted Breakthrough Therapy Designations for ibrutinib as a monotherapy for the treatment of patients with relapsed or refractory mantle cell lymphoma and as a monotherapy for the treatment of patients with Waldenström’s macroglobulinemia, both of which are also B-cell malignancies. In April 2013, the FDA granted a third Breakthrough Therapy Designation for the investigational oral agent ibrutinib as monotherapy for the treatment of chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma patients with deletion of the short arm of chromosome 17 (deletion 17p). Patients harboring a deletion within chromosome 17 generally have poor response to chemoimmunotherapy and have limited treatment options. The presence of deletion 17p is one of the worst prognostic factors in patients with CLL. The Breakthrough Therapy Designation is intended to expedite the development and review of a potential new drug for serious or life-threatening diseases where “preliminary clinical evidence indicates that the drug may demonstrate substantial improvement over existing therapies on one or more clinically significant endpoints, such as substantial treatment effects observed early in clinical development.” The designation of a drug as a Breakthrough Therapy was enacted as part of the 2012 FDA Safety and Innovation Act. n

investigators saw how well the drug was tolerated, that led to the enrollment of older, treatment-naive patients, the rationale being that although chemoimmunotherapy is the standard of care in CLL, toxicities such as myelosuppression and infection are more problematic in this older population. Therefore, it’s prudent to give them an investigational agent, if the toxicity is tolerable. The data in the older, treatment-naive patients looked better, which is not surprising in previously untreated patients. But on short-term follow-up, the relapsed/refractory data are actually more clinically impressive, simply because of the heavily pretreated disease in these patients. For example, they had received a median of four prior regimens, and they often had very severe baseline cytopenias. Quite frankly, these cytopenic patients rarely get enrolled in clinical trials, but they tolerated ibrutinib, which is one of the very encouraging properties of this drug.

Pattern of Response What have we learned so far about ibrutinib’s “personality”? Ibrutinib and other drugs that target these B-cell tumors have a very interesting response pattern. When we first give ibrutinib to a patient, there’s a

dramatic shrinkage in the lymph nodes, but at the same time, the lymphocyte count goes up. In fact, some patients were taken off the phase I study early on, because the rise in lymphocytes was interpreted as disease progression. But something more complicated was happening: True, the lymphocyte count went up, but a week later, the nodes had shrunk demonstrably. This unique pattern of response began to be recognized and addressed. The good news is that CLL patients can walk around with very high lymphocyte counts without being symptomatic, probably because the cells are so small and soft that they pass through the vasculature without creating the hyperviscosity we see in other diseases. And over time, those high lymphocyte numbers come down.

Interpreting the Data Please describe the drug’s response data so far? Using the International Workshop on Chronic Lymphocytic Leukemia (IWCLL) criteria for response in CLL, a partial remission indicates not only a 50% reduction in tumor bulk in the lymph nodes, liver, and spleen, but also a 50% reduction in the lymphocyte count. At about 3 months into therapy, some patients with an 80% reduction in their lymph nodes were not qualifying as a partial remission because their baseline lymphocyte counts were actually higher than the 50% cutoff. This is important because when you look at responses over time, the response profile changes with longer follow-up, which has been made clear by presentations at the ASCO Annual Meetings. So, in effect, this changed the established terminology. In other words, you may now see a patient who achieves a partial remission with lymphocytosis or a partial remission with nodal responses. These terms were not part of the original IWCLL criteria, but they are now fairly well recognized to indicate patients who have dramatic lymph node shrinkage, and yet, because of their lymphocyte count, they are not qualifying as having a partial remission. The latest ASH data in relapsed/refractory patients are impressive. If you add the different responses—71%

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Expert’s Corner

had a partial remission using standard IWCLL criteria, and 18% had the newer classification of partial remission with lymphocytosis—89% of these patients on trial had at least 50% shrinkage in their tumor bulk, which is very impressive.

Further Considerations Would you discuss the drug’s safety profile? Ibrutinib is not myelosuppressive, so we don’t see an increased rate of in-

Ibrutinib CLL Trial continued from page 1

endpoint has been met, not allowing crossover has caused considerable dismay in the oncology community, not to mention among patients. It is my understanding that the FDA strongly opposed allowing crossover. I presume that is because the FDA also wants to see if there is a survival advantage.

fection, which is the biggest complication in treating CLL. Some infections are seen since these patients are already immunocompromised by the disease itself and prior treatment. Moreover, the side effects of ibrutinib are almost negligible; the most common is diarrhea, which is self-limiting. In fact, I have never seen a patient come off study because of diarrhea. This is probably the easiest hematologic drug for patients to handle that I’ve ever seen. And last, the durability is another

plus. Sure, it’s nice to have a 70% response rate in a refractory population, but if it only lasts 3 months, the value is limited. Based on the ASH meeting presentations, the 26-month progression-free survival rate in the relapsed/refractory patients is 75%, and in treatment-naive patients, it’s 96%. That kind of durability is part of what’s generating the excitement about ibrutinib. n

Reference 1. Byrd JC, Furman RR, Coutre S, et al: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve and relapsed or refractory chronic lymphocytic leukemia or small lymphocytic leukemia patients including patients with high-risk disease: New and updated results of 116 patients in a phase Ib/II study. 2012 ASH Annual Meeting. Abstract 189. Presented December 9, 2012.

In my opinion that’s wrong—the magnitude of benefit of ibrutinib over ofatumumab is going to be spectacular. Where is the equipoise?

FDA approval for chronic myeloid leukemia patients after failure of interferon, which was the standard frontline therapy at the time. Then the IRIS trial compared front-line treatment with interferon to imatinib in randomized fashion. In retrospect, that trial was not reasonable. The data clearly showed that imatinib was an order of magnitude superior to interferon, not

to mention significantly less toxic, yet there were very strict crossover criteria that resulted in little crossover. When that trial ended, imatinib received immediate approval in the front-line setting, and patients on the interferon arm instantly went on imatinib. Thus, there was no improvement in survival with imatinib, but does anyone really think that without a randomized trial you can’t show survival benefit? Just look at published data for survival curves in imatinib compared to any historical control data as well as SEER data. Imatinib has dramatically improved survival for the population at large. We knew that going into the trial. Here’s the harsh reality: There are people on the control arm of RESONATE who will probably have disease progression and die. Presumably, that is what FDA believes is necessary to document improved survival. As I’ve pointed out, the magnitude of ibrutinib’s benefit obviates the need for this. I think it’s unfortunate, and most people in the CLL community feel the same way. This is an important issue that needs open discussion. n

Similar Situation Look back several years, and you’ll find a glaring example of what’s now happening with RESONATE. Imatinib (Gleevec) received accelerated

Disclosure: Dr. O’Brien receives research support from Pharmacyclics.

The Ethical Imperative of Clinical Equipoise By Stephen J. Schuster, MD

n her editorial about the RESONATE trial (page 1), Dr. O’Brien raises the issue of equipoise in this phase III clinical trial that compares the efficacy of ibrutinib and ofatumumab (Arzerra) in patients with relapsed or refractory

Stephen J. Schuster, MD

chronic lymphocytic leukemia (CLL) who are not appropriate candidates for treatment or retreatment with purine analog-based therapy. In the latest update of a phase Ib/II study of ibrutinib in 116 patients presented in December 2012, Byrd et al reported that 85 patents with relapsed or refractory CLL had a 71% overall response rate (or 89% if patients with a partial response with lymphocytosis are included) and a progression-free survival rate of 75% at 26 months.1 In 31 elderly, treatment-naive patients, overall response rate was 68% (or 81% if patients with a partial response with lymphocy-

tosis are included) with a progressionfree survival rate of 96% at 26 months.1 In contrast, Wierda et al had previously reported overall response rates for ofatumumab of 58% with median progression-free survival of 5.7 months in fludarabine- and alemtuzumab (Campath)-refractory CLL patients and 47% with median progression-free survival of 5.9 months in fludarabine-refractory CLL patients with bulky lymphadenopathy.2 Thus, as Dr. O’Brien notes, the phase II data for ibrutinib presented at the American Society of Hematology Annual Meeting appear spectacular, especially with respect to progression-free survival, and the magnitude of benefit of ibrutinib over ofatumumab should be impressive.

Interim Results Due in 2014 The phase III RESONATE trial should provide the “substantial evidence” required by the FDA to establish the effectiveness of ibrutinib. On April 3, 2013, the enrollment target of 350 patients for the RESONATE trial was achieved. Based on estimates of progression-free survival events for each arm, we should expect the results of the planned interim analysis in the first quarter of 2014. If what we expect is confirmed—ie, the interim analysis shows sufficient evidence of benefit in progression-free sur-

vival for patients receiving ibrutinib—we are obligated to uphold the ethical imperative of clinical equipoise. All patients who participated in the study should be allowed early access to ibrutinib. We will watch closely to see that this responsibility to our patients is fulfilled. n Disclosure: Dr. Schuster receives research support from Pharmacyclics.

References 1. Byrd JC, Furman RR, Coutre S, et al: The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib (PCI-32765) promotes high response rate, durable remissions, and is tolerable in treatment naïve (TN) and relapsed or refractory (RR) chronic lymphocytic leukemia (CLL) or small lymphocytic lymphoma (SLL) patients including patients with highrisk (HR) disease: New and updated results of 116 Patients in a phase Ib/II study. 2012 ASH Annual Meeting. Abstract 189. Presented December 9, 2012. 2. Wierda WG, Kipps TJ, Mayer J, et al: Ofatumumab as single-agent CD20 immunotherapy in fludarabine-refractory chronic lymphocytic leukemia. J Clin Oncol 28:1749-1755, 2010. Dr. Schuster is Robert and Margarita LouisDreyfus Associate Professor in Chronic Lymphocytic Leukemia and Lymphoma Clinical Care and Research and Director, Lymphoma Program, Abramson Cancer Center of the University of Pennsylvania, Philadelphia.

Disclosure: Dr. O’Brien receives research support from Pharmacyclics.

Editor’s note: Ibrutinib is currently being studied in a randomized phase III trial called RESONATE [A Randomized, Multicenter, Open-label, Phase III Study of the Bruton’s Tyrosine Kinase Inhibitor Ibrutinib vs Ofatumumab in Relapsed or Refractory CLL/SLL]. There is no crossover for patients who show disease progression on treatment. The ASCO Post invited leukemia experts Susan O’Brien, MD, and Stephen J. Schuster, MD, to share their opinions on the issue. We invite you to share your opinions on this subject. Write to editor@ASCOPost.com.

Can you tell which patient has ALK-positive NSCLC? Molecular testing is increasingly important in lung cancer In a study of 420 patients with adenocarcinoma non-small cell lung cancer (NSCLC), more than 50% of tumors tested positive for a predictive biomarker.1 About 3% to 5% of patients with advanced NSCLC harbor a genetic alteration known as the anaplastic lymphoma kinase (ALK) fusion gene.2-9 The ALK fusion gene (a fusion between ALK and other genes such as EML4) is believed to be a key oncogenic driver that contributes to cell proliferation and tumor survival.6,10-12

Approval of the first ALK inhibitor is a compelling reason to test patients for the ALK fusion gene XALKORI® (crizotinib)—the first ALK inhibitor—may offer antitumor activity for patients with locally advanced or metastatic ALK-positive NSCLC. As an inhibitor of the ALK receptor tyrosine kinase, XALKORI is believed to block growth and survival mechanisms in tumor cell lines, potentially leading to regression or stabilization of tumors.7 Testing is necessary to identify patients for whom XALKORI may be appropriate. An FDA-approved test must be used to determine which patients have ALK-positive NSCLC.

Clinical characteristics should not be used to determine which patients to test13 In XALKORI registration studies, the ALK fusion gene was identified in patients who varied by age, race, gender, and performance status. While the ALK fusion gene was identified more frequently in never-smokers, it was also seen in former and current smokers. In addition, the ALK fusion gene was identified more frequently in patients with adenocarcinoma but occurred in all histologic types. Thus, simultaneous testing for all clinically relevant biomarkers—including ALK—prior to treatment initiation may help guide

therapeutic decisions.14

References: 1. Johnson BE, Kris MG, Kwiatkowski D, et al. Clinical characteristics of planned 1000 patients with adenocarcinoma of lung (ACL) undergoing genomic characterization in the US Lung Cancer Mutation Consortium (LCMC). 14th World Conference on Lung Cancer. July 3-7, 2011; Amsterdam, the Netherlands. Abstract O16.01. 2. Garber K. ALK, lung cancer, and personalized therapy: portent of the future? J Natl Cancer Inst. 2010;102:672-675. 3. Takeuchi K, Choi YL, Soda M, et al. Multiplex reverse transcription-PCR screening for EML4-ALK fusion transcripts. Clin Cancer Res. 2008;14:6618-6624. 4. Soda M, Choi YL, Enomoto M, et al. Identification of the transforming EML4-ALK fusion gene in non-small-cell lung cancer. Nature. 2007;448:561-567. 5. Palmer RH, Vernersson E, Grabbe C, Hallberg B. Anaplastic lymphoma kinase: signalling in development and disease. Biochem J. 2009;420:345-361. 6. Mossé YP, Wood A, Maris JM. Inhibition of ALK signaling for cancer therapy. Clin Cancer Res. 2009;15:5609-5614. 7. Sasaki T, Rodig SJ, Chirieac LR, Jänne PA. The biology and treatment of EML4-ALK non-small cell lung cancer. Eur J Cancer. 2010;46:1773-1780. 8. Koivunen JP, Mermel C, Zejnullahu K, et al. EML4-ALK fusion gene and efficacy of an ALK kinase inhibitor in lung cancer. Clin Cancer Res. 2008;14:4275-4283. 9. Wong DW, Leung EL, So KK, et al. The EML4-ALK fusion gene is involved in various histologic types of lung cancers from nonsmokers with wild-type EGFR and KRAS. Cancer. 2009;115:1723-1733. 10. Shaw AT, Yeap BY, Mino-Kenudson M, et al. Clinical features and outcome of patients with non–small-cell lung cancer who harbor EML4-ALK. J Clin Oncol. 2009;27:4247-4253. 11. Chiarle R, Voena C, Ambrogio C, Piva R, Inghirami G. The anaplastic lymphoma kinase in the pathogenesis of cancer. Nat Rev Cancer. 2008;8:11-23. 12. Soda M, Takada S, Takeuchi K, et al. A mouse model for EML4-ALK-positive lung cancer. Proc Natl Acad Sci U S A. 2008;105:19893-19897. 13. Referenced with permission from The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) Non-Small Cell Lung Cancer V.2.2013. © 2013 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed January 22, 2013. To view the most recent and complete version of the guideline, go online to http://www.nccn.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES®, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc. 14. Pérez-Soler R. Individualized therapy in non-small cell lung cancer: future versus current clinical practice. Oncogene. 2009;28(suppl 1):S38-S45.

Not without testing. The National Comprehensive Cancer Network® (NCCN®) recommends that all patients with advanced or metastatic NSCLC determined by histology to be nonsquamous or NOS undergo EGFR and ALK testing13 • EGFR and ALK testing is also recommended in patients with squamous cell carcinoma if they never smoked and if small biopsy specimens were used to assess histology

XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

SELECTED SAFETY INFORMATION Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. XALKORI has been associated with severe, life-threatening or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatment-related pneumonitis. Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI.

Please see additional Important Safety Information on the next page and accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

XALKORI® (crizotinib) is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI.

IMPORTANT SAFETY INFORMATION Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Temporarily suspend, dose reduce, or permanently discontinue XALKORI as indicated. Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes and permanently discontinue XALKORI in patients with treatmentrelated pneumonitis. QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI for grade 4 QTc prolongation. XALKORI should be withheld for grade 3 QTc prolongation until recovery to ≤ grade 1. Permanently discontinue XALKORI if grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. Women of childbearing potential should be advised to avoid becoming pregnant while receiving XALKORI. If the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to the fetus. Adverse Reactions: Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). The most common adverse reactions (≥25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. • Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia were reported in 159 (62%) patients in clinical trials. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder. • Neuropathy attributed to study drug was reported in 34 (13%) patients. Grade 2 motor neuropathy and grade 3 peripheral neuropathy were reported in 1 patient each. • Bradycardia was reported in 12 (5%) patients treated with XALKORI. All of these cases were grade 1 or 2 in severity. • Complex renal cysts were reported in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Grade 3 or 4 laboratory abnormalities of neutropenia, thrombocytopenia, and lymphopenia were observed in 5.2%, 0.4%, and 11.4% of patients, respectively. Drug Interactions: Exercise caution with concomitant use of moderate CYP3A inhibitors. Avoid grapefruit or grapefruit juice which may increase plasma concentrations of crizotinib. Avoid concomitant use of strong CYP3A inducers and inhibitors. Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Nursing Mothers: Given the potential for serious adverse reactions in nursing infants, consider whether to discontinue nursing or discontinue XALKORI. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Use caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild and moderate renal impairment. No data are available for patients with end-stage renal disease. Use caution in patients with severe renal impairment or patients with end-stage renal disease. XALKORI is a registered trademark of Pfizer Inc.

Please see accompanying brief summary of Prescribing Information. For more information, please visit www.xalkorihcp.com.

CRI550916-01

Printed in USA/March 2013

ASCOPost.com | MAY 1, 2013

PAGE 29

Announcements

AACR Elects Carlos L. Arteaga, MD, as President-elect 2013-2014

he members of the American Association for Cancer Research (AACR) have elected Carlos L. Arteaga, MD, as their President-elect for 2013-2014. Dr. Arteaga is Professor of Medicine and Cancer Biology at

Vanderbilt University School of Medicine where he holds the Donna S. Hall Chair in Breast Cancer Research. He also serves as Associate Director for Clinical Research and Director of the Breast Cancer Research Program at

XALKORI® (crizotinib) capsules Brief Summary of Prescribing Information

ADVERSE REACTIONS Safety of XALKORI was evaluated in 255 patients with locally advanced or metastatic ALK-positive NSCLC in 2 single-arm clinical trials (Studies A and B). Among the 255 patients for whom data on Grade 1-4 adverse reactions are available, median exposure to study drug was 5.1 months in Study A and 7.8 months in Study B. Dosing interruptions occurred in 36% and 45% of patients in Studies A and B, and lasted >2 weeks in 13% and 19% of all patients. Dose reductions occurred in 44% and 29% of patients. The rates of treatment-related adverse events resulting in permanent discontinuation were 6% in Study A and 3% in Study B. The most common adverse reactions (≥ 25%) across both studies were vision disorder, nausea, diarrhea, vomiting, edema, and constipation. Grade 3-4 adverse reactions in ≥4% of patients in both studies included ALT increased and neutropenia. Among the 397 patients for whom information on deaths and serious adverse reactions is available, deaths within 28 days of the last dose of study drug occurred in 45 patients. Ten (2.5%) patients died within 28 days of their first dose of study drug. Causes of death included disease progression (32 patients), respiratory events (9), and other (4). Respiratory causes of death included pneumonia (2), hypoxia (2), ARDS (1), dyspnea (1), pneumonitis (1), empyema (1), and pulmonary hemorrhage (1). Other causes of deaths included septic shock, DIC, cardiovascular event, and death due to unknown cause (1 each). Serious adverse events in ≥2% of patients included pneumonia, dyspnea, and pulmonary embolism. Table 3 lists the common adverse reactions on Studies A and B in patients receiving XALKORI. Table 3: Adverse Reactions in ≥ 10% of Patients with Locally Advanced or Metastatic ALK-Positive NSCLC on Studies A and B1

Vision Disorder2

Treatment Emergent (N=255) All Grades Grades 3/4 n (%) n (%)

Treatment Related (N=255) All Grades Grades 3/4 n (%) n (%)

163 (64%)

0 (0)

159 (62%)

0 (0)

145 (57%) 124 (49%) 116 (45%) 98 (38%) 51 (20%) 40 (16%) 27 (11%)

2 (<1%) 1 (<1%) 3 (1%) 2 (<1%) 3 (1%) 1 (<1%) 1 (<1%)

136 (53%) 109 (43%) 101 (40%) 69 (27%) 29 (11%) 20 (8%) 15 (6%)

0 0 0 1 (<1%) 0 0 1 (<1%)

97 (38%) 80 (31%) 30 (12%) 30 (12%)

2 (<1%) 6 (2%) 1 (<1%) 1 (<1%)

72 (28%) 51 (20%) 3 (1%) 2 (<1%)

0 4 (2%) 0 0

GASTROINTESTINAL DISORDERS

Nausea Diarrhea Vomiting Constipation Esophageal Disorder3 Abdominal Pain4 Stomatitis5 GENERAL DISORDERS

Edema6 Fatigue Chest Pain/Discomfort7 Fever INFECTIONS AND INFESTATIONS

Upper Respiratory Infection8 INVESTIGATIONS

Alanine Aminotransferase Increased Aspartate Aminotransferase Increased METABOLISM AND NUTRITION

Decreased Appetite MUSCULOSKELETAL

Arthralgia Back Pain

50 (20%)

1 (<1%)

4 (2%)

38 (15%) 29 (11%)

17 (7%) 7 (3%)

34 (13%) 24 (9%)

14 (5%) 5 (2%)

69 (27%)

3 (1%)

49 (19%)

29 (11%) 28 (11%)

3 (1%) 0

4 (2%) 2 (<1%)

0 0

60 (24%) 58 (23%) 34 (13%) 33 (13%)

0 1 (<1%) 1 (<1%) 0

42 (16%) 34 (13%) 10 (4%) 30 (12%)

0 1 (<1%) 0 0

NERVOUS SYSTEM DISORDERS

Dizziness9 Neuropathy10 Headache Dysgeusia PSYCHIATRIC DISORDERS

Insomnia

RESPIRATORY DISORDERS

Dyspnea Cough

SKIN DISORDERS

Rash

Study A used CTCAE v4.0, and Study B used CTCAE v3.0. Includes diplopia, photopsia, photophobia, vision blurred, visual field defect, visual impairment, vitreous floaters, visual brightness, and visual acuity reduced. Includes dyspepsia, dysphagia, epigastric discomfort/pain/burning, esophagitis, esophageal obstruction/pain/spasm/ulcer, gastroesophageal reflux, odynophagia, and reflux esophagitis. 4 Includes abdominal discomfort, abdominal pain, abdominal pain upper, and abdominal tenderness. 5 Includes mouth ulceration, glossodynia, glossitis, cheilitis, mucosal inflammation, oropharyngeal pain/discomfort, oral pain, and stomatitis. 6 Includes edema, edema localized, and peripheral edema. 7 Includes chest pain, chest discomfort, and musculoskeletal chest pain. 8 Includes nasopharyngitis, rhinitis, pharyngitis, and upper respiratory tract infection. 9 Includes balance disorder, dizziness, and presyncope. 10 Includes burning sensation, dysesthesia, hyperesthesia, hypoesthesia, neuralgia, paresthesia, peripheral neuropathy, peripheral motor neuropathy, and peripheral sensory neuropathy. 2

CONTRAINDICATIONS None. WARNINGS AND PRECAUTIONS Hepatotoxicity: Drug-induced hepatotoxicity with fatal outcome has occurred. These cases have occurred during XALKORI treatment in <1% of patients in clinical trials. Concurrent elevations in ALT >3 times the upper limit of normal and total bilirubin >2 times the upper limit of normal, with normal alkaline phosphatase, occurred in <1% of patients in clinical trials. Elevation in ALT >5 times the upper limit of normal occurred in 7% of patients in Study A and in 4% of patients in Study B. These laboratory findings were generally asymptomatic and reversible upon dosing interruption. Patients usually resumed treatment at a lower dose without recurrence; however, 3 patients from Study A (2%) and 1 patient from Study B (<1%) required permanent discontinuation from treatment. Transaminase elevations generally occurred within the first 2 months of treatment. Monitor with liver function tests including ALT and total bilirubin once a month and as clinically indicated, with more frequent repeat testing for increased liver transaminases, alkaline phosphatase, or total bilirubin in patients who develop transaminase elevations. Pneumonitis: XALKORI has been associated with severe, life-threatening, or fatal treatment-related pneumonitis in clinical trials with a frequency of 4 in 255 (1.6%) patients across Studies A and B. All of these cases occurred within 2 months after the initiation of treatment. Monitor patients for pulmonary symptoms indicative of pneumonitis. Exclude other causes of pneumonitis, and permanently discontinue XALKORI in patients diagnosed with treatment-related pneumonitis. QT Interval Prolongation: QTc prolongation has been observed. Avoid use of XALKORI in patients with congenital long QT syndrome. Consider periodic monitoring with electrocardiograms (ECGs) and electrolytes in patients with congestive heart failure, bradyarrhythmias, electrolyte abnormalities, or who are taking medications that are known to prolong the QT interval. Permanently discontinue XALKORI in patients who develop Grade 4 QTc prolongation. Withhold XALKORI in patients who develop Grade 3 QTc prolongation until recovery to ≤ Grade 1, then resume XALKORI at 200 mg twice daily. In case of recurrence of Grade 3 QTc prolongation, withhold XALKORI until recovery to ≤ Grade 1, then resume XALKORI at 250 mg once daily. Permanently discontinue XALKORI if Grade 3 QTc prolongation recurs. ALK Testing: Detection of ALK-positive NSCLC using an FDA-approved test, indicated for this use, is necessary for selection of patients for treatment with XALKORI. Assessment for ALK-positive NSCLC should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance can lead to unreliable test results. Refer to an FDA-approved test’s package insert for instructions on the identification of patients eligible for treatment with XALKORI. Pregnancy: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies in pregnant women using XALKORI. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus.

EYE DISORDERS

to prevent and cure cancer through research, education, communication

INDICATIONS AND USAGE XALKORI is indicated for the treatment of patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) that is anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test. This indication is based on response rate. There are no data available demonstrating improvement in patient reported outcomes or survival with XALKORI. DOSAGE AND ADMINISTRATION Recommended Dosing: The recommended dose and schedule of XALKORI is 250 mg taken orally twice daily. Continue treatment as long as the patient is deriving clinical benefit from therapy. XALKORI may be taken with or without food. Swallow capsules whole. If a dose of XALKORI is missed, make up that dose unless the next dose is due within 6 hours. Dose Modification: Dosing interruption and/or dose reduction may be required based on individual safety and tolerability. If dose reduction is necessary, then reduce the dose of XALKORI to 200 mg taken orally twice daily. If further dose reduction is necessary, then reduce the dosage to 250 mg taken orally once daily based on individual safety and tolerability.

Adverse Event

Vanderbilt-Ingram Cancer Center in Nashville, Tennessee. In his new role, Dr. Arteaga will work collaboratively with the AACR Board of Directors and the 34,000-plus membership to further the AACR’s mission

30 (12%)

8 (3%)

57 (22%) 54 (21%)

16 (6%) 3 (1%)

5 (2%) 9 (4%)

3 (1%) 0

41 (16%)

25 (10%)

Vision disorders including visual impairment, photopsia, vision blurred, vitreous floaters, photophobia, and diplopia, were reported in 159 (62%) patients in clinical trials. These events generally started within two weeks of drug administration. Consider ophthalmological evaluation, particularly if patients experience photopsia or experience new or increased vitreous floaters. Severe or worsening vitreous floaters and/or photopsia could also be signs of a retinal hole or pending retinal detachment. Advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder. Neuropathy as defined in Table 3 and attributed to study drug by the investigator was reported in 34 (13%) patients. While most events were Grade 1, Grade 2 motor neuropathy and Grade 3 peripheral neuropathy were reported in 1 patient each. Dizziness and dysgeusia were also very commonly reported in these studies, but were all Grade 1 or 2 in severity. Bradycardia occurred in 12 (5%) patients treated with XALKORI. All of these cases were Grade 1 or 2 in severity. Complex renal cysts occurred in 2 (1%) patients treated with XALKORI. There were no reports of abnormal urinalyses or renal impairment in these cases. Laboratory Abnormalities: Grade 3 or 4 neutropenia, thrombocytopenia, and lymphopenia occurred in 5.2%, 0.4%, and 11.4% of patients, respectively. DRUG INTERACTIONS Drugs That May Increase Crizotinib Plasma Concentrations: Coadministration of crizotinib with strong CYP3A inhibitors increases crizotinib plasma concentrations. Avoid concomitant use of strong CYP3A inhibitors, including but not limited to atazanavir, clarithromycin, indinavir, itraconazole, ketoconazole, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, troleandomycin, and voriconazole. Avoid grapefruit or grapefruit juice which may also increase plasma concentrations of crizotinib. Exercise caution with concomitant use of moderate CYP3A inhibitors. Drugs That May Decrease Crizotinib Plasma Concentrations: Coadministration of crizotinib with strong CYP3A inducers decreases crizotinib plasma concentrations. Avoid concurrent use of strong CYP3A inducers, including but not limited to carbamazepine, phenobarbital phenytoin, rifabutin, rifampin, and St. John’s Wort. Drugs Whose Plasma Concentrations May Be Altered By Crizotinib: Dose reduction may be needed for coadministered drugs that are predominantly metabolized by CYP3A. Avoid coadministration of crizotinib with CYP3A substrates with narrow therapeutic indices, including but not limited to alfentanil, cyclosporine, dihydroergotamine, ergotamine, fentanyl, pimozide, quinidine, sirolimus, and tacrolimus. USE IN SPECIFIC POPULATIONS Pregnancy Category D: XALKORI can cause fetal harm when administered to a pregnant woman based on its mechanism of action. There are no adequate and well-controlled studies of XALKORI in pregnant women. Advise women of childbearing potential to avoid becoming pregnant while receiving XALKORI. Women of childbearing potential who are receiving this drug, or partners of women of childbearing potential receiving this drug, should use adequate contraceptive methods during therapy and for ≥90 days after completing therapy. If this drug is used during pregnancy, or if the patient or their partner becomes pregnant while taking this drug, apprise the patient of the potential hazard to a fetus. Nursing Mothers: It is not known whether XALKORI is 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 XALKORI, consider whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and efficacy of XALKORI in pediatric patients has not been established. Decreased bone formation in growing long bones was observed in immature rats at 150 mg/kg/day following once daily dosing for 28 days (approximately 10 times the AUC in adult patients at the recommended human dose). Other toxicities of potential concern to pediatric patients have not been evaluated in juvenile animals. Geriatic Use: Clinical studies of XALKORI did not include sufficient numbers of patients aged 65 and older to determine whether they respond differently from younger patients. Of the 136 patients in Study A, 19 (14%) were ≥65 years. Of the 119 patients in Study B, 16 (13%) were ≥65 years. Hepatic Impairment: XALKORI has not been studied in patients with hepatic impairment. As crizotinib is extensively metabolized in the liver, hepatic impairment is likely to increase plasma crizotinib concentrations. Clinical studies excluded patients with AST or ALT >2.5 x ULN, or >5 x ULN, if due to liver metastases. Patients with total bilirubin >1.5 x ULN were also excluded. Therefore, use caution in patients with hepatic impairment. Renal Impairment: No starting dose adjustment is needed for patients with mild (creatinine clearance [CLcr] 60 to 90 mL/min) and moderate renal impairment (CLcr 30 to 60 mL/min), as steady-state trough concentrations in these two groups were similar to those in patients with normal renal function (CLcr >90 mL/min) in Study B. The potential need for starting dose adjustment in patients with severe renal impairment cannot be determined, as clinical and pharmacokinetic data were available for only one patient. In addition, no data are available for patients with end-stage renal disease. Therefore, use caution in patients with severe renal impairment (CLcr <30 mL/min) or patients with end-stage renal disease. OVERDOSAGE There have been no known cases of XALKORI overdose. Treatment of overdose with XALKORI should consist of general supportive measures. There is no antidote for XALKORI. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility: Carcinogenicity studies with crizotinib have not been conducted. Crizotinib was genotoxic in an in vitro micronucleus assay in Chinese Hamster Ovary cultures, in an in vitro human lymphocyte chromosome aberration assay, and in in vivo rat bone marrow micronucleus assays. Crizotinib was not mutagenic in vitro in the bacterial reverse mutation (Ames) assay. No specific studies with crizotinib have been conducted function and fertility in humans based on findings in repeat-dose toxicity studies in the rat. Findings observed in the male reproductive tract included testicular pachytene spermatocyte degeneration in rats given ≥50 mg/kg/day for 28 days (>3 times the AUC at the recommended human dose). Findings observed in the female reproductive tract included single-cell necrosis of ovarian follicles of a rat given 500 mg/kg/day (approximately 10 times the recommended human daily dose on a mg/m2 basis) for 3 days. PATIENT COUNSELING INFORMATION Hepatotoxicity: Inform patients that symptoms of weakness, fatigue, anorexia, nausea, vomiting, abdominal pain (especially RUQ abdominal pain), jaundice, dark urine, generalized pruritus, and bleeding diathesis, especially in combination with fever and rash, should be reported immediately. Gastrointestinal Effects: Inform patients that nausea, diarrhea, vomiting, and constipation are the most commonly reported gastrointestinal adverse events occurring in patients who received XALKORI. Supportive care for gastrointestinal adverse events requiring treatment may include standard anti-emetic and/or anti-diarrheal or laxative medications. Visual Effects: Inform patients that visual changes such as perceived flashes of light, blurry vision, light sensitivity, and floaters are commonly reported adverse events. These events began most commonly during the first two weeks of treatment. Advise patients to report flashes or floaters to their physicians. Effects on Ability to Drive and Use Machines: No studies on the effect of XALKORI on the ability to drive and use machines have been performed. However, advise patients to exercise caution when driving or operating machinery due to the risk of developing a vision disorder, dizziness, or fatigue while taking XALKORI. Concomitant Medications: Advise patients to inform their health care providers of all concomitant medications, including prescription medicines, over-the-counter drugs, vitamins, and herbal products. Instructions for Taking XALKORI: Advise patients to take XALKORI exactly as prescribed, not to change their dose or to stop taking XALKORI unless they are told to do so by their doctor. Take XALKORI with or without food. Swallow XALKORI capsules whole. Advise patients to keep XALKORI in the original container. Do not crush, dissolve, or open capsules. Inform patients to avoid grapefruit or grapefruit juice while taking XALKORI. If a patient misses a dose, advise the patient to take it as soon as remembered unless it is less than 6 hours until the next dose, in which case, advise the patient not to take the missed dose. Advise patients not to take two doses at the same time to make up for a missed dose. Pregnancy and Nursing: Inform patients of childbearing potential to use adequate contraceptive methods during therapy and for ≥90 days after completing therapy. Advise patients to inform their doctor if they or their partners are pregnant or think they may be pregnant. Also advise patients not to breastfeed while taking XALKORI. Rx Only April 2012

Carlos L. Arteaga, MD

and collaboration. He will assume the AACR presidency in April 2014. “I am very grateful to the AACR and its members for this honor and opportunity,” said Dr. Arteaga. “I look forward to working with the association and meaningfully contributing to its leadership role and progress in the fight against cancer in these difficult but also exciting times.” “Dr. Arteaga’s contributions to breast cancer research have had a major impact on the lives of breast cancer patients,” said Margaret Foti, PhD, MD (hc), Chief Executive Officer of the AACR. “We are thrilled that an esteemed expert in translational and clinical research has been elected to serve as the next AACR President-elect. Dr. Arteaga shares in the AACR’s mission to prevent and cure cancer, and we know that he will lead the association with much vigor and commitment to ensure that we continue to accelerate progress against this insidious disease.” Dr. Arteaga’s research interests include oncogene signaling and molecular therapeutics in breast cancer with an emphasis on targeted therapies, mechanisms of drug resistance, translational research and investigatorinitiated clinical trials. He has received many honors and awards, including the AACR-Richard and Hinda Rosenthal Award. Dr. Arteaga received his medical degree in 1980 from the Facultad de Ciencias Médicas at the Universidad de Guayaquil in Ecuador. Following internal medicine residency at Emory University in Atlanta, Georgia. Dr. Arteaga completed a fellowship in medical oncology at The University of Texas Health Science Center at San Antonio. He joined the faculty at Vanderbilt University in 1989. n See page 42 in this issue of The ASCO Post for news of awards presented at the recent AACR Annual Meeting.

The ASCO Post | MAY 1, 2013

PAGE 30

Direct from ASCO

New ASCO/AAHPM Project Will Harness Technology to Foster Improved Palliative Care in Oncology

SCO and the American Academy of Hospice and Palliative Care Medicine (AAHPM) recently announced a joint initiative to support delivery of high-quality palliative care in medical oncology. The initiative is funded by ASCO’s first-ever grant from the Agency for Health Care Research Quality. The project aims to address the complex care needs of

Nationwide Initiative Twenty oncology practices from around the country will be recruited to participate in a structured

Never before has technology been leveraged to quickly spread practice-changing research and to connect oncologists allowing them to share best practices in palliative care. —Sandra M. Swain, MD, FACP

ceptions of the VLC; assess the impact of the VLC on performance related to primary palliative care, and inform additional refinements to the platform and the toolbox of content and resources. Ultimately, project leaders aim to provide a

Volume 29, Issue 15

May 20, 2011

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

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

patients with advanced cancer, including relief or prevention of symptoms, one goal of palliative care in oncology practice.

Virtual Learning Collaborative The 3-year project will create a virtual learning collaborative (VLC), a web-based technology platform, to efficiently and broadly disseminate evidence-based palliative care approaches in oncology. The VLC will include coordinated, customized learning modules, social networking capabilities, and a toolbox of evidence-based resources to help translate the latest research into practice. “We recognize that palliative care is an essential component of care for patients with cancer. This partnership will help get the latest palliative care evidence directly into the hands of oncologists so that palliative care can be provided as early as possible,” said ASCO President Sandra M. Swain, MD, FACP. “Never before has technology been leveraged to quickly spread practice-changing research and to connect oncologists allowing them to share best practices in palliative care.”

practice improvement pilot project, enabled by the VLC. Pilot practices will report data on palliative care quality using ASCO’s Quality Oncology Practice Initiative®. “The oncologist or treating specialist could manage many palliative care problems, initiating a specialist palliative care consultation for more complex situations. The VLC moves this goal from concept to practical reality,” said AAHPM President-elect Amy P. Abernethy, MD, FACP, principle investigator of the VLC project.

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 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

proven palliative care toolbox to all ASCO members for use in their practices, and to leverage the VLC platform to address other targets for practice improvement. n © 2013. American Society of Clinical Oncology. All rights reserved.

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

What’s Hot in

JCO

JCO.org Randomized Phase III Trial of ABVD Versus Stanford V With or Without Radiation Therapy in Locally Extensive and AdvancedStage Hodgkin Lymphoma: An Intergroup Study Coordinated by the Eastern Cooperative Oncology Group (E2496) by Leo I. Gordon, et al

Systematic Review of Acupuncture in Cancer Care: A Synthesis of the Evidence by M. Kay Garcia, et al

Randomized Phase III Trial of Induction Chemotherapy With Docetaxel, Cisplatin, and Fluorouracil Followed by Surgery Versus Up-Front Surgery in Locally Advanced Resectable Oral Squamous Cell Carcinoma by Lai-ping Zhong, et al

Amy P. Abernethy, MD, FACP

Providers will share best practices and resources through the VLC, and benefit from expert and peer guidance as they implement local improvements. Qualitative and quantitative evaluation will assess oncology practitioners’ per-

Phase III Randomized Clinical Trial Comparing Tremelimumab With Standard-of-Care Chemotherapy in Patients With Advanced Melanoma by Antoni Ribas, et al

Breast Cancer Follow-Up and Management After Primary Treatment: American Society of Clinical Oncology Clinical Practice Guideline Update by James L. Khatcheressian, et al

ASCOPost.com | MAY 1, 2013

PAGE 31

Direct from ASCO

ASCO’s Pre–Annual Meeting Seminar Series to Offer a New, Fourth Focus: Genetics and Genomics

SCO’s pre–Annual Meeting seminar series continues this year, offering intimate, discussionbased seminars just before the start of the Annual Meeting in late May. The seminars are an excellent educational opportunity for health providers who are attending the Annual Meeting but would like to drill down further into specific areas of interest. The seminars are also useful to those who are unable to attend the Annual Meeting or for whom the Annual Meeting’s topics aren’t closely targeted to their areas of focus.

• New Drugs in Oncology • Contemporary Designs for Early-phase Clinical Trials • Clinical Care in Oncology for the Advanced Practice Provider

erful new information is already changing oncology care for them, their patients, and—because some of the information goes beyond tumor genetics—their patients’ families,” says Judy E. Garber, MD,

This seminar will introduce many clinicians to the remarkable progress being made in cancer genetics and genomics. —Judy E. Garber, MD, MPH

Seminars Held Just Prior to the Annual Meeting The seminars will take place at the same location as the Annual Meeting: Chicago’s McCormick Place, starting at 1 PM on Thursday, May 30, and continuing through 11 AM on Friday, May 31, the first day of the Annual Meeting. ASCO has expanded the program from three to four sessions. The following three seminars, which are part of the series, will expand upon topics discussed last year:

And this year, ASCO has added a new seminar: • Genetics and Genomics for the Practicing Clinician

Genetics and Genomics: Why Now? “This seminar will introduce many clinicians to the remarkable progress being made in cancer genetics and genomics, and get them thinking about the ways this pow-

MPH, Professor in the Department of Medicine at Harvard Medical School, Director of the Center for Cancer Risk and Prevention at the Dana-Farber Cancer Institute, and Co-chair of the Genetics and Genomics Seminar. William Pao, MD, PhD, Cornelius Abernathy Craig Chair in Medical and Surgical Oncology, Professor of Medicine, and Director of the Division of Hematology/

William Pao, MD, PhD

Oncology and Personalized Cancer Medicine at Vanderbilt-Ingram Cancer Center, is the session’s other co-chair. Explaining the particular relevancy and timeliness of this seminar to practicing clinicians, Dr. Pao says, “Recently, there’s been an explosion in two areas: next-generation sequencing technology that makes it feasible to quickly analyze tumor DNA from patients, and the number of targeted therapies that are most effective in patients whose tumors harbor certain molecular characteristics. The convergence of both areas makes it important for clinicians to know about this now.” continued on page 32

From One to Many, Here and Around the World

he Conquer Cancer Foundation Grants and Awards Program has grown tremendously in 30 years, from supporting just one researcher in the United States to thousands working around the world. These investigators are performing breakthrough research in all aspects of cancer and making discoveries that impact the quality of care of patients on every continent. In addition, the Foundation’s investment in these clinician scientists is further multiplied as they mentor and pass their valuable knowledge on to the bright young researchers who will become the future generation of oncologists.

Addressing the Global Cancer Burden Many Foundation grant and award opportunities are open to interna-

tional applicants, and in 30 years we have broadened our focus and cadre of funding opportunities to include programs that help address the growing global cancer burden, particularly in low- and middle-income countries,

which often lack the resources needed to adequately serve people with cancer. Two programs have previously been designed specifically with this population in mind. Through the In-

ternational Development and Education Awards, the Foundation helps develop future oncology leaders in low- and middle-income countries by pairing recipients with ASCO member mentors who are experts in their field. The Long-term International Fellowship provides early-career oncologists from developing countries with resources to advance their training at a U.S. or Canadian institution with an ASCO member mentor through a 1-year medical fellowship, after which the recipient returns home and disseminates the knowledge gained during the experience.

New International Innovation Grant This year, a third opportunity is being launched: the International continued on page 33

The ASCO Post | MAY 1, 2013

PAGE 32

Direct from ASCO

Pre–Annual Meeting Seminars continued from page 31

Expanding on Last Year’s Topics

The seminar Clinical Care in Oncology for the Advanced Practice Provider, cosponsored with

the Association of Physician Assistants in Oncology and the Oncology Nursing Society, is designed to meet the educational needs of advanced practice providers such as advanced practice nurses and physician assistants. Topics will include trends in oncology care,

standards for cancer screening, and symptom and side-effect management. New Drugs in Oncology will address the theoretical and practical aspects of both recently approved drugs and those on their way to approval. Oncologists who

All of your

Oncology News...

focus in specific disease areas will speak to generalists about the indications and side-effect profiles of the market’s new drugs. Topics will include mechanisms of action, administration, toxicity and sideeffect management, and use in the clinic. The seminar Contemporary Designs for Early-phase Clinical Trials co-sponsored with the Society for Clinical Trials, will bring together statisticians and clinicians to discuss the design, implementation, and analysis of phase I clinical trials. Lectures will be complemented by case studies and panel discussions with audience interaction. To learn more and to register for one of the limited number of seats at the Pre-Annual Meeting Seminars, visit chicago2013.asco.org/ pre-annual-meeting-seminars. n © 2013. American Society of Clinical Oncology. All rights reserved.

Help Your Patients Understand the Latest Research to Be Highlighted at the 2013 ASCO Annual Meeting

...at your

Fingertips Now Available: The ASCO Post iPad App • Complete issues of The ASCO Post • Oncology News Feed – updated throughout the day • Analysis and opinions from the experts you trust

ASCOPost.com

Download The ASCO Post on iTunes

tarting on May 15, direct your patients to Cancer.Net, ASCO’s patient information website, to find easy-to-read summaries of studies released in advance of this year’s Annual Meeting. In addition, encourage them to listen to a panel discussion and Q&A session about these latest advances in a recording of a teleconference for patient advocates. These materials, as well as continuing coverage from the 2013 meeting, can be found at www.cancer.net/ ascoannualmeeting. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCOPost.com | MAY 1, 2013

PAGE 33

Direct from ASCO

Innovation Grant continued from page 31

Innovation Grant. This grant provides research funding in support of novel and innovative projects that can have a significant impact on cancer control in low- and middle-income countries. It will support project proposals that have the potential to reduce the cancer burden in local communities, while also being potentially transferrable to other low- or middle-income settings. The novel approaches and clinical designs proposed for this International Innovation Grant will likely differ from what would be considered stan-

dard practice in high-income settings. This year, as we celebrate the th 30 anniversary of the Foundation’s Grants and Awards Program, it is not without the knowledge that the growth of this program and extension of its impact from local to global simply would not have been possible without the support of our generous donors. Please help us continue to advance progress in all parts of the world by making a gift at www.conquercancerfoundation.org/donate. Together, we can make a global difference. n © 2013. American Society of Clinical Oncology. All rights reserved.

Spotlight on Patient Advocacy Pavilion at the ASCO Annual Meeting

he ASCO-sponsored Patient Advocacy Booth, located near the entrance of the Oncology Professionals Hall at the ASCO Annual Meeting, is designed to give 26 nonprofit patient advocacy organizations an opportunity to promote their programs, services, and resources to the professional oncology community. Established in 1992, this booth serves as a place where participants can display materials and where meeting attendees and patient advocates can network and exchange information.

Valuing Patient Advocacy “The visibility and placement that ASCO offers their nonprofit partners through the Oncology Professionals Hall provides maximum exposure to the thousands of individuals representing oncologists, cancer centers, corporate partners, and other nonprofits,” said Lisa Hughes, Senior Director of Policy and Advocacy for the Prevent Cancer Foundation. “Additionally, ASCO offers advocates several learning and networking opportunities outside of the exhibit

hall, including a Patient Advocate Lounge, Research Review Sessions, and the Conquer Cancer Foundation Patient Advocate Scholarship Program. ASCO illustrates the value they place on patient advocacy— which makes the Annual Meeting a priority for us each year.”

There are also nearly 30 additional patient advocacy organizations that exhibit at the ASCO Annual Meeting. Along with the ASCO-sponsored Patient Advocacy Booth, these exhibits make up the Patient Advocacy Pavilion of the Oncology Professionals Hall. For a list of all exhibit-

ing organizations, visit chicago2013. asco.org/exhibitor-information. To learn more about ASCO programs for patient advocates, visit www.cancer.net/advocacy-andpolicy. n © 2013. American Society of Clinical Oncology. All rights reserved.

ASCO-sponsored Patient Advocacy Booth

he following organizations will exhibit at the 2013 ASCO Annual Meeting as part of the ASCO-sponsored Patient Advocacy Booth: • Alliance for Childhood Cancer • American Brain Tumor Association • BAG IT • Bear Necessities Pediatric Cancer Foundation • Bladder Cancer Advocacy Network • Blood & Marrow Transplant Information Network • Bright Pink • CancerCare • Cancer Support Community • Can’t Stomach Cancer: The Foundation of Debbie’s Dream • Cholangiocarcinoma Foundation • Colon Cancer Alliance • Fight Colorectal Cancer

• First Descents • Imerman Angels • International Brain Tumour Alliance • LUNGevity Foundation • Melanoma International Foundation • MyLifeline.org Cancer Foundation • National Lung Cancer Partnership • Ovarian Cancer National Alliance • Ovarian Cancer Research Fund • Patient Access Network Foundation • Prevent Cancer Foundation • Sharsheret • Support for People with Oral and Head and Neck Cancer

Visit the

Patient Advocacy Pavilion at the ASCO Annual Meeting May 31 - June 4, 2013, Chicago

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ASCOPost.com | MAY 1, 2013

PAGE 35

Health-care Policy

Rally for Medical Research Draws Thousands in Person and on Social Media By Caroline McNeil

n estimated 10,000 demonstrators filled the streets in front of Washington, DC’s historic Carnegie Library on April 8 to protest budget cuts at the National Institutes of Health. The Rally for Medical Research was held to “emphasize to our policymakers that medical research must become a national priority,” said Margaret Foti, PhD, the CEO of the American Association for Cancer Research (AACR), which was the founding organizer of this historic event. A magnified Twitter feed scrolled

$29.1 billion, said Mary Lee Watts, MPH, RD, Director of Government Relations at AACR. Efforts are underway to reverse the trend. In Congress, Representatives David McKinley (R-WV) and Ed Markey (D-MA) are leading a bipartisan effort to get colleagues to sign on to a letter requesting $32 billion for NIH for next year. And Senators Dick Durbin (D-IL), Jerry Moran (R-KS), and Barbara Mikulski (D-MD) have offered an amendment to the 2014 budget resolution to boost funding. Representative

Never before have so many people in the medical research community and the public at large united in such a public way to express their collective support for medical research. —Margaret Foti, PhD, MD(hc)

across large electronic screens set up on the library grounds as emcee Cokie Roberts, of ABC News and National Public Radio, introduced medical researchers, members of Congress, and survivors of cancer and other diseases. En masse, the crowd sent text messages to members of Congress, and the event was live-streamed on YouTube. Shortly after the rally ended, it was the second most popular topic on Twitter. “Never before have so many people in the medical research community and the public at large united in such a public way to express their collective support for medical research,” said Dr. Foti. More than 200 organizations participated in the rally, she said, and several institutions were holding related events in other parts of the country.

Flat Funding The NIH budget doubled between 1998 and 2003, but has been relatively flat since then. Congresswoman Rosa DeLauro (D-CT), an ovarian cancer survivor, told the crowd that this year’s mandatory sequestration took $1.5 billion from the agency and that came on top of caps set in place by the Budget Control Act. The exact budget figure for fiscal year 2013 is still being calculated but is expected to be about

McKinley and Senator Moran sent messages that were read at the rally. Speakers emphasized not only the health benefits but also the economic returns on an investment in medical research. “Every $1 that goes to NIH results in $2 of business activity and economic impact,” said Representative DeLauro. “If we cannot get the naysayers on their humanity, let’s get

Marc Tessier-Lavigne, PhD

Genentech, Dr. Tessier-Lavigne pointed out that the U.S. investment in basic science as a percentage of gross domestic product is now the lowest in 50 years. We can’t expect that private industry will take up the slack in funding, he said. “Return on investment in basic research takes too long from a business perspective…. Only government has the necessary long-term perspective.”

Impact on Research The impact of federal budget cuts on basic research laboratories can be especially serious and long-lasting, said several cancer researchers after the rally. “Even if temporary, the impact can be severe,” said AACR President Frank McCormick, PhD, Director of the University of California, San Francisco Comprehensive Cancer

Sciences, Little Rock. “There’s only so much data you have to work with when applying for grants, and if you can’t do research and get any more data, it’s hard to apply for more grants. It’s a scary time.” Dr. Franco, who is past Chairperson of AACR’s Associate Member Council, said that special career sessions for young investigators at AACR’s Annual Meeting included advice on how to

Aime Franco, PhD

transfer their skills to fields other than research. The AACR meeting was underway at the nearby Washington Convention Center. Another young researcher, Jessica Clague DeHart, PhD, an Assistant Research Professor at City of Hope, Duarte, California, and current Chairperson of the Council, said five or six of her colleagues had left academia and cancer research in the past few years. “If you’re young and have no grants, then you don’t have a job,” she said.

Frank McCormick, PhD

Mary Lee Watts, MPH, RD

them on the economics.” Marc Tessier-Lavigne, PhD, President of Rockefeller University, New York, noted, “last year, we spent $100 per citizen supporting NIH, but we spend $8,000 per citizen per year on medical care.” It will take medical research to bring down “the huge costs of care that otherwise may bankrupt us,” he said. A former Chief Scientific Officer at

Center. Dr. McCormick stressed the importance to a laboratory of steady, continuous funding. “It takes years to establish a sustainable and effective group,” he said in an interview. A cut, though temporary, still means that post-docs and technicians have to leave and that fewer data are generated. In his institution, some faculty are taking voluntary pay cuts, he said, and the leadership is beginning to rethink long-term plans. Young investigators especially are affected by NIH budget cuts. “This is a critical time in our careers,” said Aime Franco, PhD, Assistant Professor at the University of Arkansas for Medical

Jessica Clague DeHart, PhD

Drs. Franco and DeHart served as a youthful, two-woman pep squad, starting off the Rally with group cheers for “more progress, more hope, more life.” They said they turned into advocates when they realized it wasn’t enough to be a good scientist. “Now you need to be two things,” said Dr. DeHart, “a great scientist and a great advocate for funding.” n Disclosure: Drs. Foti, Tessier-Lavigne, McCormick, and Clague DeHart, and Ms. Watts reported no potential conflicts of interest.

The ASCO Post | MAY 1, 2013

PAGE 36

News Technology

CancerLinQ Prototype

Real-time Data Collection

continued from page 2

The prototype contains de-identified data from 100,000 patients with breast cancer, and more are being added. The response from clinicians volunteering to participate in the prototype has been high, demonstrating that the project has the support of the community, noted Dr. Swain. Because the system accepts data from all the widely used electronic health record programs, transferring the records involved minimal effort and time, according to Charles Penley, MD, a medical oncologist at Tennessee Oncology, which participated in creating the prototype. Dr. Penley is also Chair of ASCO’s Conquer Cancer

Rapid Learning System CancerLinQ is a learning health system as described in a series of reports last year from the Institute of Medicine, with best practices seamlessly embedded in the delivery process and new knowledge captured as an integral byproduct of the delivery experience. Also known as rapid learning systems, these knowledge bases are envisioned as bigdata systems that will not only assemble and analyze millions of records (with patient privacy protections), but will also grow “smarter” over time, as more records are added and analyzed.

We are still learning from the prototype and will figure out ways to increase our efficiency as we build out toward the full system. —Clifford A. Hudis, MD

Eventually the system will enable clinical learning from the experience of a wide range of patients, including the 97% who do not participate in cancer clinical trials, said Dr. Swain. The prototype, “in a way confirms our belief that every patient can be … a knowledge donor,” she said. The system has four core functions, most of which were built with opensource software: real-time data collection, clinical decision support, data mining and visualization, and quality feedback.

Foundation, which helped obtain funding for this early phase of development of CancerLinQ.

Clinical Decision Support Using ASCO’s expert breast cancer guidelines, the system can provide individualized guidance on care. And when fully implemented, it will provide guidance based on the collective experiences of other patients with breast cancer. “For instance”, said

When physicians now are puzzled by a case, they may consult the literature, bring it up at a tumor board, and call colleagues. With CancerLinQ, they will also be able to query thousands of oncologists whose experience, collectively, includes millions of patients. —Charles Penley, MD

Dr. Penley, “when physicians now are puzzled by a case, they may consult the literature, bring it up at a tumor board, and call colleagues whom they know personally. With CancerLinQ, they will also be able to query thousands of oncologists whose experience, collectively, includes millions of patients.”

Data Mining and Visualization The system can show trends and associations. For instance a query about the duration of tamoxifen or anastrozole therapy in estrogen receptor– positive breast cancer generates a chart showing that appropriate patients in the prototype database took one of the drugs for up to 10 years. A query about outcomes generates a Kaplan-Meier plot showing that longer duration was associated with better outcomes. This specific example confirms clinical trial results, but it also shows how the system could be used to inform care where no clinical trial data are available, said panel member Clifford A. Hudis, MD, Chief of the Breast

Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center, New York, and ASCO’s President-Elect.

Quality Feedback The prototype can provide immediate feedback on quality of care, using 10 measures from ASCO’s Quality Oncology Practice Initiative (QOPI). That program, now paper-based, allows physicians to measure their performance against established standards of care. CancerLinQ will automate the process and provide feedback in real time. The prototype is “just the first step in what is certain to be a long process,” said Dr. Hudis. The results will be published over the next year as work continues. “We are still learning from the prototype and will figure out ways to increase our efficiency as we build out toward the full system,” he said. That will be created in modular fashion, like the prototype, and will include all types of cancer. n

Disclosure: Drs. Swain, Penley, and Hudis reported no potential conflicts of interest.

Alopecia a Common but Underreported Side Effect of Endocrine Agents By Caroline Helwick

t the recent American Academy of Dermatology Annual Meeting in Miami, researchers presented interesting findings regarding melanoma and other skin cancers, as well as dermatologic effects of cancer agents. The following is a summary of one such study. While alopecia is a common side effect of many cytotoxics, the occurrence of hair loss with endocrine agents has not been established. Investigators undertook a systematic analysis of the literature and found a surprisingly high incidence.1 Vishal Saggar, of New York University School of Medicine, Mario E. Lacouture, MD, of Memorial Sloan-Kettering Cancer Center, New York, and colleagues,

conducted a review of phase II and III clinical trials conducted between 1966 and 2012. Investigators identified 1,429 studies, of which 35 included rates of alopecia without confounding variables. The final analysis included 19,430 patients, in whom alopecia was associated with the use of the aromatase inhibitors anastrozole, letrozole, and exemestane, tamoxifen, leuprolide, fulvestrant, and megestrol. A total of 13,415 patients received endocrine treatments while 6,015 served as controls. The incidence of all-grade alopecia ranged from 0% to 25%, with an

opecia is a “common yet under-reported side effect” secondary to endocrine agents, especially those used for breast and prostate cancer. This underscores the importance of pretherapy counseling and offering patients interventions that may improve alopecia or improve its appearance. n

Vishal Saggar

Mario E. Lacouture, MD

overall incidence of 4.4% (95% CI:3.3% to 5.9%). The highest incidence was observed in patients treated with anastrozole and goserelin. The relative risk in comparison to placebo was 12.88 (P < .001). The investigators concluded that al-

Disclosure: Dr. Lacouture and Vishal Saggar reported no potential conflicts of interest.

Reference 1. Saggar V, Lacouture ME, Dickler M: Incidence of alopecia from endocrine therapies in cancer. Presented at the American Academy of Dermatology 2013 Annual Meeting, March 1-5, 2013. Abstract P6446.

ASCOPost.com | MAY 1, 2013

PAGE 37

FDA Update Radiation Oncology

Elekta Receives FDA 510(k) Clearance Following Launch of New Versa HD Radiation Therapy System

lekta recently received 510(k) clearance from the FDA, allowing the company to begin shipping and installation of all components of the Versa HD system within the United States. The Versa HD radiation system, featuring high-precision beam shaping and tumor targeting, is capable of delivering radiation doses three times faster than previous Elekta linear accelerators.

“We are delighted to receive FDA clearance,” says Jay Hoey, Executive Vice President, Elekta North America. “The potential clinical benefits for patients are significant.”

High Dose Rate Delivery Versa HD is fully integrated with the Agility 160-leaf multileaf collimator and provides high-definition, highspeed beam shaping over a versatile 40�40 �40 40 cm field. field. The The unique combination of fast multileaf collimator leaf speed with the new High Dose Rate

mode allows clinicians to fully exploit high dose rate delivery and take advanced therapies such as volumetric modulated arc therapy, stereotactic ra-

diosurgery, and stereotactic radiotherapy to new levels, without compromising treatment times. Versa HD also features advanced

safety features; customizable, diseasespecific configurations; real-time remote system monitoring; and patientfriendly ergonomics. n

SPECIFIC

IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER Immunotherapy primes T cells and B cells to recognize and target cancer cells expressing specific tumor antigens.1-3

The ASCO Post It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer.

@ASCOPost

For more information go to www.FightCancerWithImmunotherapy.com References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Namm JP, et al. J Surg Oncol. 2012;105:431-435. 3. Sharma P, et al. Nat Rev Cancer. 2011;11:805-812.

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The ASCO Post | MAY 1, 2013

PAGE 38

2013

2013 Oncology Meetings May 2013 Annual Paris Melanoma Conference May 2-3 • Paris, France For more information: www.primeoncology.org/ parismelanoma2013 5th IMPAKT Breast Cancer Conference May 2-4 • Brussels, Belgium For more information: www.esmo.org Florida Society of Clinical Oncology Third Annual AVBCC Conference May 2-5 • Hollywood, Florida For more information: www.flasco.org/ Scientific and Clinical Update in Gynecologic Oncology May 3 • Philadelphia, Pennsylvania For more information: www.kimmelcancercenter.org/ symposium/ Medical Oncology Association of Southern California Spring General Membership Meeting May 9 • Los Angeles, California For more information: www.moasc.org Nevada Oncology Society Spring Membership Conference May 9 • Las Vegas, Nevada For more information: www.nos-nevada.com/ Precision Medicines in Breast Cancer May 9-10 • London, United Kingdom For more information: www.precisionmedicines.com European Multidisciplinary Conference in Thoracic Oncology May 9-11 • Lugano, Switzerland For more information: www.esmo.org The Psychological Impact of Cancer for Patients, Carers, and Families May 15 • Milton Keynes, United Kingdom For more information: www8.open.ac.uk/health-and-socialcare/main/research/research-events/ psychological-impact-of-cancer

Northern New England Clinical Oncology Society Spring Meeting May 17 • Manchester, New Hampshire For more information: www.nnecos.org Iowa Oncology Society Spring Membership Conference May 17-18 • West Des Moines, Iowa For more information: www.ios-iowa.com California Breast Cancer Research Symposium: From Research to Action: Two Decades of Change May 17-18 • Costa Mesa, California For more information: www.cabreastcancer.org/symposium/ Oregon Society of Medical Oncology Spring 2013 Oncology Conference May 17-18 • Ashland, Oregon For more information: www.osmo.org/events/view/18 State of the Art Techniques Symposium May 17-19 • San Antonio, Texas For more information: www.astro.org/ stateofthearttechniques 3rd International Symposium on Lung-Sparing Therapies for Malignant Pleural Mesothelioma May 18, 2013 • Santa Monica, California For more information: www.cme.ucla.edu/courses/ Michigan Society of Hematology and Oncology – Oncology Pharmacists’ Forum May 22 • Novi, Michigan For more information: www.msho.org 5th Symposium on Cancer Metastasis and the Lymphovascular System and the 8th International Sentinel Node Society Congress May 27-29, 2013 • San Francisco, California For more information: www.sn-cancermets.org Targeting Cancer Drug Resistance May 28-30 • Chicago, Illinois For more information: www.cancer-drugresistance.com

The Bone Marrow Niche, Stem Cells, and Leukemia: Impact of Drugs, Chemicals, and the Environment May 29-31 • New York, New York For more information: www.nyas.org/bonemarrow Interventional Oncology Sans Frontières May 29-June 1 • Cernobbio, Italy For more information: www.iosfc2013.org 13th World Congress of the European Association for Palliative Care May 30-June 2 • Prague, Czech Republic For more information: www.eapc-2013.org Ohio Hematology Oncology Society/Kentucky Association of Medical Oncology Spring Meeting May 31 • Cincinnati, Ohio For more information: www.kentuckyoncology.org 2013 ASCO Annual Meeting May 31-June 4 • Chicago, Illinois For more information: www.asco.org

June Molecular and Translational Oncology Workshop June 14-18 • Fort Myers, Florida For more information: www.cancereducationconsortium. org/programs_mtow.html

6th International Nasopharyngeal Carcinoma Symposium June 20-22 • Istanbul, Turkey For more information: www.npc2013.org 2nd International Breakthrough Breast Cancer Conference– Triple Negative Breast Cancer June 26-28 • London, United Kingdom For more information: www.breakthroughconference.org.uk

MASCC/ISOO 2013 International Cancer Care Symposium June 27-29 • Berlin, Germany For more information: mascc.kenes.com

July WIN 2013 Symposium: Personalized Cancer Therapy: From Innovation to Implementation July 10-12 • Paris, France For more information: www.winsymposium.org 12th International Congress on the Future of Breast Cancer July 18-20 • Huntington Beach, California For more information: www.gotoper.com/conferences 14th International Lung Cancer Congress July 25-27 • Huntington Beach, California For more information: www.gotoper.com/conferences

12th International Conference on Malignant Lymphoma June 19-22 • Lugano, Switzerland For more information: www.lymphcon.ch

Up Close and Personalized: The 2nd International Congress on Personalized Medicine July 25-28 • Paris, France For more information: www.upcp.org

British Gynaecological Cancer Society Annual Scientific Meeting June 20-21 • Belfast, Ireland For more information: bgcsconference.com

Multidisciplinary Cancer Management Course July 26-28 • La Paz, Bolivia For more information: www.mdanderson.org/conferences

ASCOPost.com | MAY 1, 2013

PAGE 39

FDA Update Genitourinary Oncology

FDA Approves Assay That May Help Detect the Progression of Testicular Cancer

bbott announced that the ARCHITECT AFP assay, which may help doctors detect the progression of testicular cancer as well as serious birth defects, has received FDA approval. The ARCHITECT AFP assay is a chemiluminescent microparticle immunoassay for the quantitative determination of alpha-fetoprotein (AFP) in human serum or plasma to aid in monitoring disease progres-

sion during the course of disease and treatment of patients with nonseminomatous testicular cancer; and human serum, plasma, and amniotic fluid at 15 to 21 weeks gestation to aid in the detection of fetal open neural tube defects.

AFP and Testicular Cancer Men with nonseminomatous germ cell tumors, have elevated AFP levels present in their bloodstream, and blood tests to measure AFP can be used to evaluate responses to treatment. By monitoring disease progression and seeking treatment when necessary, testicular cancer can be a highly treatable and usually curable cancer. “The ARCHITECT AFP assay is a valuable tool that will help physi-

cians obtain reliable measurements of this protein for use in guiding critical patient treatment decisions,” said Brian Blaser, Executive Vice

President, Diagnostics Products, Abbott. The new assay runs on Abbott’s ARCHITECT i2000, i2000SR,

ci8200, and ci16200 analyzers, and is available in the United States, CEmarked, and nonregulated countries. n

ADAPTABLE IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER As tumor cells mutate, many cancers can become resistant to traditional cancer therapies.1-3 The activated immune system can adapt and recognize new tumor antigens to continue the attack over time.1,4--6

It’s time to consider

IMMUNOTHERAPY

The ASCO Post

as an important treatment in your fight against cancer. For more information go to www.FightCancerWithImmunotherapy.com

Like us on

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References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. DeVita VT, et al, eds. Cancer: Principles & Practice of Oncology. 8th ed. Lippincott, Williams & Wilkins; Philadelphia, PA: 2008. 3. Chabner BA, et al, eds. Cancer Chemotherapy & Biotherapy: Principles & Practices. 4th ed. Lippincott, Williams & Wilkins; Philadelphia, PA: 2006. 4. Ribas A, et al. J Clin Oncol. 2003;21:2415-2432. 5. Namm JP, et al. J Surg Oncol. 2012;105:431-435. 6. Kirkwood JM, et al. CA Cancer J Clin. 2012;62:309-335.

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The ASCO Post | MAY 1, 2013

PAGE 40

In the News Breast Cancer

Increase in Advanced Breast Cancer among Younger Women Is Small but Significant, and Trend Is Likely to Continue By Charlotte Bath

he incidence of advanced breast cancer among women aged 25 to 39 years increased by an average of 2.07% per year from 1976 to 2009

Rebecca H. Johnson, MD

and the trend seems likely to continue, according to an analysis of data for 936,497 women diagnosed with malig-

nant breast cancer. The small but statistically significant increase should serve to alert young women and their physicians that “breast cancer can and does occur” in younger women and that changes in the breast warrant followup, the study’s lead author, Rebecca H. Johnson, MD, said in an interview with The ASCO Post. Dr. Johnson is Medical Director of the Adolescent and Young Adult Oncology Program at Seattle Children’s Hospital and Assistant Professor at the University of Washington in Seattle. Data from the U.S. Surveillance, Epidemiology, and End Results (SEER) program showed “the incidence of breast cancer with distant involvement at diagnosis increased in 25- to 39-year-

old women from 1.53 (95% confidence interval [CI] = 1.01–2.21) per 100,000 in 1976 to 2.90 (95% CI = 2.31–3.59) per 100,000 in 2009. This is an absolute difference of 1.37 per 100,000, representing an average compounded increase of 2.07% per year (95% CI = 1.57%–2.58%; P < .001) over the 34year interval,” according to the study report published in the Journal of the American Medical Association.1 SEER definitions of extent of disease at diagnosis refer to distant disease as involving remote metastases, for example, to the bone, brain, or lung. Similar increases in incidence were not found for localized disease (defined by SEER as confined to the breast) or regional disease (defined as contiguous

and adjacent organ spread, such as to lymph nodes or the chest wall), or for age groups other than those 25 to 39.

Personal Experience with Breast Cancer Dr. Johnson has firsthand knowledge about breast cancer in young women. She discovered a lump in her

Archie Bleyer, MD

Expect Questions from Younger Women about Breast Cancer

“ S

EER data showed a small but statistically significant increase in the incidence of breast cancer with distant involvement for women aged 25 to 39 years,” concluded a study published in the Journal of the American Medical Association.1 “The trajectory of the incidence trend predicts that an increasing number of young women in the United States will present with metastatic breast cancer in an age group that already has the worst prognosis, no recommended routine screening practice, the least health insurance, and the most potential years of life.”

Breast Awareness for Young Women So what can these young women do to protect themselves against advanced breast cancer with distant metastases and poor prognosis? The study’s lead author, Rebecca H. Johnson, MD, supports efforts to teach adolescent girls and young women to be aware of their bodies, including their breasts, because previous research has shown that breast cancer is the most common malignant tumor in women between the ages of 15 and 39. “Young women need to know what is normal for them and understand that they need to go to the doctor if a change in their breasts occurs,” Dr. Johnson told The ASCO Post. “In women under 40, who are obviously not a screened popu-

lation,” she noted, “at least half of the breast cancers are detected by patients themselves.” Dr. Johnson is Medical Director of the Adolescent and Young Adult Oncology Program at Seattle Children’s Hospital and Assistant Professor at the University of Washington in Seattle. It is also important that physicians who care for these young patients realize that “breast cancer can and does occur,” and they should not be dismissive

cancer study. She explained that there is no evidence that screening mammography helps younger women who are at average risk of breast cancer. “Women who have a known breast cancer predisposition syndrome— BRCA1 or BRCA2 mutations—would be an exception to the rule of not being screened, as would women who received chest radiation as young adults or teenagers for lymphomas or for any other reason,” Dr. Johnson stated. “They

Young women need to know what is normal for them and understand that they need to go to the doctor if a change in their breasts occurs. —Rebecca H. Johnson, MD

of breast changes noticed by patients or “blow off new symptoms,” Dr. Johnson added. If changes are noted, physicians “should not watch and wait for a prolonged period of time.”

Not Advocating Screening Mammography “We’re certainly not advocating that young women get mammography at an earlier age than is generally specified,” Dr. Johnson said in an interview with The New York Times,2 one of several national media outlets reporting on the breast

should be screened because they are a very high-risk population, but that’s obviously a small minority of all women under 40.” n Disclosure: Dr. Johnson reported no potential conflicts of interest.

References 1. Johnson RH, Chien FL, Bleyer A: Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA 309:800-805, 2013. 2. Grady D: Advanced breast cancer may be rising among women, study finds. New York Times. February 26, 2013.

breast and was diagnosed with breast cancer when she was 27. “It was a 2-cm tumor, stage I, with negative lymph nodes, 0 out of 26,” she said. “I had a mastectomy and then chemotherapy.” She was a medical resident back then and in reviewing the medical literature found much of it focused on breast cancer as a disease of older women. After being diagnosed, however, “I kept hearing from friends, and friends of friends, and distant relatives about more than a dozen cases of breast cancer in young women,” she said. Two of about 15 other people in a Houston book group that she belonged to while completing fellowships in clinical genetics and pediatric oncology were also diagnosed with breast cancer before age 35. (One was interviewed by National Public Radio as part of the coverage of the study.2) Her personal experience with breast cancer and meeting other young women with breast cancer led her to question whether breast cancer among younger women “is a significant health problem that has always been here, but that we just didn’t talk about. Or is there really some sort of an increase?” She and her colleague and coauthor, Archie Bleyer, MD, of St. Charles Health System, Central Oregon, and Oregon Health and Science University, Portland, started tackling these questions for a research task force on breast cancer organized by the LIVESTRONG Young Adults Alliance to “identify what was different

ASCOPost.com | MAY 1, 2013

PAGE 41

In the News

about the cancers of teens and young adults,” Dr. Johnson explained. “I had a personal interest in breast cancer, even though I don’t see patients with breast cancer,” and Dr. Bleyer had been involved in many SEER data analyses, including one that found breast cancer is the most common cancer of 15- to 39-year-old women, comprising about 25% of all cancers in that age group. Those data were used to answer the question, If you are a woman and you are under 40, what is your chance of getting breast cancer? The results, published in Seminars in Oncology,3 “showed that your chances of getting breast cancer as a woman in the United States by the time you or are 40, is 1 in 173,” Dr. Johnson noted. “So I thought that most women won’t get breast cancer when they are under 40, but most women will know someone who does.”

Tripling of Incidence “The next question, which led to this study that we just published in JAMA, was: What has been the change in incidence over time, and is that actually increasing or is it static? When you look at the whole population by age since the mid-1970s, when the SEER database really got up and running, you

The evidence we observed for the increasing incidence of advanced breast cancer in young women will require corroboration and may be best confirmed by data from other countries. don’t see a change in the rate of young adult breast cancer. But when we broke it down by stage at diagnosis, that was when we identified the increase in metastatic breast cancer.” The 2.07% average compounded increase per year in the incidence of advanced cancer among younger women was somewhat surprising, Dr. Johnson admitted. It was probably not apparent earlier, she added, because the actual number of cases was small compared to the large number of older women with breast cancer and young women

with earlier-stage breast cancer. “If you project out to the population, it translates into an increase from about 275 or so metastatic breast cancers in younger women per year in the mid1970s to about 850 in 2008/2009,” she explained. “So, essentially, it is a tripling of the incidence. On a population basis, it is a small change. But if a pediatric

cancer had tripled from 275 to 850 cases, we would certainly worry about it.”

Reasons Remain Unknown The reasons for the rise in metastatic breast cancer among younger women remain unknown, although some media reports included comments speculating about possible causes. Others ex-

pressed skepticism about an increase. Despite “quite an extensive literature review looking at risk factors and their temporal trends over the past 35 years to see if there was one single thing that really correlated with this increase, I didn’t find anything that by itself was a potential explanation,” Dr. continued on page 42

DURABLE

IMMUNOTHERAPY EMPOWERS THE IMMUNE SYSTEM TO FIGHT CANCER Immunotherapy activates some immune cells to become memory cells.1-4 These memory cells remain primed to rapidly induce another immune response, even after active treatment has ended.1-4

It’s time to consider

IMMUNOTHERAPY

as an important treatment in your fight against cancer. For more information go to www.FightCancerWithImmunotherapy.com References: 1. Murphy K, et al, eds. Janeway’s Immunobiology. 7th ed. Garland Science, Taylor & Francis Group, LLC. New York, NY: 2008. 2. Abbas AK, et al, eds. Basic Immunology. Functions and Disorders of the Immune System. 3rd ed. Saunders Elsevier; Philadelphia, PA: 2011. 3. Atanackovic D, et al. PNAS. 2008;105(5):1650-1655. 4. Perret R, et al. Tissue Antigens. 2008;72:187-194.

Dendreon and the Dendreon logo are registered trademarks of Dendreon Corporation.

The ASCO Post | MAY 1, 2013

PAGE 42

Awards

American Association for Cancer Research Honors Award Recipients at Annual Meeting

he American Association for Cancer Research (AACR) named the following as recipients of awards at the recent Annual Meeting.

Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Cancer Research Hagop Kantarjian, MD, Chair and Professor in The University of Texas MD Anderson Cancer Center’s De-

Hagop Kantarjian, MD

multiple improvements in the treatment of leukemia patients, including the development and testing of firstand second-generation BCR-ABL inhibitors; combination therapies for acute lymphocytic leukemia and the single agent clofarabine, approved for ALL in 2005. Dr. Kantarjian’s work also contributed to FDA approval of ruxolitinib for myelofibrosis, the first approved treatment for the disease and the first to target the JAK2 protein. All clinical trials for the drug were led at MD Anderson. “As with many individual awards, this honor reflects the efforts and accomplishments of MD Anderson’s Department of Leukemia, which includes outstanding investigators across the full spectrum of leukemia,” Dr. Kantarjian said.

Jane Cooke Wright Lectureship

partment of Leukemia, was honored for clinical research excellence at the AACR Annual Meeting. Dr. Kantarjian was presented the 18th Annual AACR Joseph H. Burchenal Memorial Award for Outstanding Achievement in Clinical Cancer Research “I am truly honored and humbled to be in the company of great men and women who, by their dedication to clinical research, have made seminal discoveries that have led to seismic changes in our understanding of cancer biology and therapeutics,” Dr. Kantarjian said. As a clinician and clinical researcher, Dr. Kantarjian has contributed to

Gabriel Hortobagyi, MD, Professor in the Department of Breast Medical Oncology at The University of Texas MD Anderson Cancer Center, received the Jane Cooke Wright Lectureship from AACR and its Minorities in Cancer Research membership group. Dr. Hortobagyi is internationally recognized for his clinical and translational contributions to the field of breast cancer research. “I’m humbled by the AACR and their Minorities in Cancer Research colleagues. To be recognized for furthering the advancement of minority investigators in cancer research is truly an honor -all of us share a mutual dedication to breast cancer care and feel that there

Cancer in Younger Women

example, the three of those together do predict an increased risk of premenopausal breast cancer,” Dr. Johnson said. “Whatever the causes—and likely there are more than one—the evidence we observed for the increasing incidence of advanced breast cancer in young women will require corroboration and may be best confirmed by data from other countries,” the authors concluded. Because the SEER database includes such a large sample of patients with breast cancer from the United States, and the findings were significant, “we think that the best thing to

continued from page 41

Johnson said. While the rise in obesity has raised health concerns, “in terms of breast cancer incidence, obesity or being overweight is actually protective against getting breast cancer as a young adult. That has been shown in really large prospective studies,” she noted. “However, being obese is a risk factor for dying from breast cancer,” she continued. In addition, “some smaller studies suggest that if you take several risk factors at a time, like obesity, sedentary lifestyle, and high caloric intake, for

has never been a more exciting time for the field,” Dr. Hortobagyi said. “I had the distinct pleasure of knowing Jane Cooke Wright. Her myriad scientific contributions and unwavering commitment to mentoring young scientists, especially African American women, are still impactful in cancer research and the community at large.” Dr. Hortobagyi, who holds the Nellie B. Connally Chair in Breast Cancer, is the past-chair of the Department of Breast Medical Oncology and has been a member of MD Anderson’s faculty since 1976. He is widely recognized for developing combined therapies for previously inoperable breast tumors,

Gabriel Hortobagyi, MD

improving multidisciplinary treatment for patients with all stages of the disease and conducting clinical trials to develop treatment regimens that have become standard practices for managing breast cancer.

Women in Cancer Research Charlotte Friend Memorial Lectureship AACR named Guillermina “Gigi” Lozano, PhD, as recipient of the 16th annual Women in Cancer Research do would be to look at other very large samples—in Canada, in Australia, in Europe—in order to get enough patients to confirm the results,” Dr. Johnson explained. Other experts commenting to the media also called for confirmation of the results, including ASCO President Sandra M. Swain, MD, FACP, Medical Director of the Washington Cancer Institute at the MedStar Washington Hospital Center in Washington, DC, who was interviewed by NBC News.4 n

Disclosure: Drs. Johnson and Bleyer reported no potential conflicts of interest.

Guillermina “Gigi” Lozano, PhD

Charlotte Friend Memorial Lectureship, recognizing her contributions to the field of cancer research and the advancement of women in science. Dr. Lozano is Chair and Professor in the Department of Genetics at The University of Texas MD Anderson Cancer Center. Dr. Lozano is a pioneer in understanding the p53 tumor suppressor pathway. Her lab at MD Anderson was the first to establish p53 as a transcriptional activator of other genes. Their landmark study published in Science in 1989 identified a p53 transactivation domain and showed that p53 mutants failed to activate transcription, paving the way for important discoveries regarding its mechanism in the development of numerous cancers including breast, colon, lung and ovarian cancer. Dr. Lozano credits the mentorship of Arnold Levine, PhD, her postgraduate advisor at Princeton University and the discoverer of p53, and Peter Mueller of the Max Planck Institute for their guidance early in and throughout her career. “Their invaluable perspective has driven me to reach for goals I might never have dreamed of,” Dr. Lozano said. n References 1. Johnson RH, Chien FL, Bleyer A: Incidence of breast cancer with distant involvement among women in the United States, 1976 to 2009. JAMA 309:800-805, 2013. 2. Knox R: Younger women have rising rate of advanced breast cancer, study says. National Public Radio, February 27, 2013. Available at npr.org/blogs/health. 3. Anders CK, Johnson R, Litton J, et al: Breast cancer before age 40 years. Semin Oncol 36:237-249, 2009. 4. Fox M: Aggressive breast cancer in more young women, study finds. NBC News Vitals, February 26, 2013. Available at vitals.nbcnews.com.

When hemoglobin fallsâ&#x20AC;Ś

For chemotherapy-induced anemia (CIA) in metastatic patients with Hb < 10 g/dL

Catch hemoglobin levels before they fall too far Reduce RBC transfusions and achieve a gradual and steady Hb rise with Aranesp

®1-4

• In untreated patients whose Hb fell below 10 g/dL, 1 in 3 required an RBC transfusion within 6 weeks*5 • Aranesp® significantly reduced the need for RBC transfusions by 48% compared to placebo†2,3 • Aranesp® can be synchronized with the majority of chemotherapy regimens, including Q3W6 * Data from an exploratory, pooled analysis performed on a subset of placebo-treated patients (N = 411) from 6 randomized darbepoetin alfa CIA trials. Patients had baseline Hb ≥ 10 g/dL and decline to Hb < 10 g/dL at least once during the study-treatment period. Kaplan-Meier (K-M) estimates were calculated for the incidence of patients with transfusions by Weeks 0, 3, 6, and 9 after Hb < 10 g/dL was reached. Seventy-two percent of patients had lung cancer.5 †Data from a randomized, double-blind, placebo-controlled trial of 314 anemic (Hb ≤ 11 g/dL) patients with lung cancer receiving platinum-containing chemotherapy. Patients received once-weekly treatment with either Aranesp® (2.25 mcg/kg) or placebo, administered by subcutaneous injection, for up to 12 weeks. Per the pivotal trial protocol, doses were withheld if Hb exceeded 14 g/dL for women or 15 g/dL for men.3

INDICATION and LIMITATIONS OF USE Aranesp® (darbepoetin alfa) is for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Aranesp® is not for use: • In patients receiving hormonal agents, biologic products, or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy • In patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • As a substitute for RBC transfusions in patients requiring immediate correction of anemia Aranesp® has not been shown to improve quality of life, fatigue, or patient well-being.

References: 1. Vansteenkiste J, Hedenus M, Gascon P, et al. BMC Cancer. 2009;9:311. doi:10.1186/1471-2407-9-311. 2. Aranesp® (darbepoetin alfa) Prescribing Information, Amgen. 3. Vansteenkiste J, Pirker R, Massuti B, et al. J Natl Cancer Inst. 2002;94:1211-1220. 4. Canon JL, Vansteenkiste J, Bodoky G, et al. J Natl Cancer Inst. 2006;98:273-284. 5. Pirker R, Collins H, Legg J, et al. J Clin Oncol. 2011;29(suppl). Abstract e19637. 6. Data on file, Amgen; [Tandem Anti-cancer and Tumor Audit].

Amgen One Amgen Center Drive Thousand Oaks, CA 91320-1799

RBC = red blood cell

Hb = hemoglobin

Q3W = once every three weeks

Important Safety Information including Boxed WARNINGS for Aranesp® (darbepoetin alfa) WARNING: ESAs Increase the Risk of Death, Myocardial Infarction, Stroke, Venous Thromboembolism, Thrombosis of Vascular Access and Tumor Progression or Recurrence Chronic Kidney Disease: • In controlled trials, patients experienced greater risks for death, serious adverse cardiovascular reactions, and stroke when administered erythropoiesis-stimulating agents (ESAs) to target a hemoglobin level of greater than 11 g/dL • No trial has identified a hemoglobin target level, Aranesp® dose, or dosing strategy that does not increase these risks • Use the lowest Aranesp® dose sufficient to reduce the need for red blood cell (RBC) transfusions Cancer: • ESAs shortened overall survival and/or increased the risk of tumor progression or recurrence in clinical studies of patients with breast, non-small cell lung, head and neck, lymphoid, and cervical cancers • To decrease these risks, as well as the risk of serious cardiovascular and thromboembolic reactions, use the lowest dose needed to avoid RBC transfusions • Use ESAs only for anemia from myelosuppressive chemotherapy, and discontinue upon completion of a chemotherapy course

• ESAs are not indicated for patients receiving myelosuppressive chemotherapy when the anticipated outcome is cure • Prescribers and hospitals must enroll in the ESA APPRISE Oncology Program to prescribe or dispense Aranesp® to patients with cancer; to enroll, visit www.esa-apprise.com or call 1-866-284-8089 for assistance Do not use Aranesp® in patients with uncontrolled hypertension; control blood pressure prior to and during treatment. Do not use Aranesp® in patients with pure red cell aplasia (PRCA) that begins after treatment with Aranesp® or other erythropoietin protein drugs. If severe anemia and low reticulocyte count develop during treatment, withhold Aranesp® and evaluate for PRCA. Do not use Aranesp® in patients with history of serious allergic reactions to the product, which may include anaphylaxis, angioedema, bronchospasm, skin rash, and urticaria. Immediately discontinue Aranesp® if such a reaction occurs. Adverse reactions in ≥ 1% of patients treated with Aranesp® in clinical studies were abdominal pain, edema, and thrombovascular events. Please see Aranesp® brief summary on following page for additional safety information, including Boxed WARNINGS. Visit Aranesp.com for more information.

BRIEF SUMMARY: Consult package insert for complete prescribing information. Aranesp┬о (darbepoetin alfa) Injection, for intravenous or subcutaneous use WARNING: ESAs INCREASE THE RISK OF DEATH, MYOCARDIAL INFARCTION, STROKE, VENOUS THROMBOEMBOLISM, THROMBOSIS OF VASCULAR ACCESS AND TUMOR PROGRESSION OR RECURRENCE Chronic Kidney Disease: t *O DPOUSPMMFE USJBMT QBUJFOUT FYQFSJFODFE HSFBUFS SJTLT GPS EFBUI TFSJPVT BEWFSTF DBSEJPWBTDVMBS SFBDUJPOT BOE TUSPLF XIFO BENJOJTUFSFE FSZUISPQPJFTJT TUJNVMBUJOH BHFOUT &4"T UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- t /P USJBM IBT JEFOUJmFE B IFNPHMPCJO UBSHFU MFWFM "SBOFTQ EPTF PS EPTJOH TUSBUFHZ UIBU EPFT OPU JODSFBTF UIFTF SJTLT t 6TF UIF MPXFTU "SBOFTQ EPTF TVGmDJFOU UP SFEVDF UIF OFFE GPS SFE CMPPE cell (RBC) transfusions. Cancer: t &4"T TIPSUFOFE PWFSBMM TVSWJWBM BOE PS JODSFBTFE UIF SJTL PG UVNPS QSPHSFTTJPO PS SFDVSSFODF JO DMJOJDBM TUVEJFT PG QBUJFOUT XJUI CSFBTU OPO TNBMM DFMM MVOH IFBE BOE OFDL MZNQIPJE BOE DFSWJDBM DBODFST t #FDBVTF PG UIFTF SJTLT QSFTDSJCFST BOE IPTQJUBMT NVTU FOSPMM JO BOE DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS 5P FOSPMM JO UIF &4" "113*4& 0ODPMPHZ 1SPHSBN WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF t 5P EFDSFBTF UIFTF SJTLT BT XFMM BT UIF SJTL PG TFSJPVT DBSEJPWBTDVMBS BOE UISPNCPFNCPMJD SFBDUJPOT VTF UIF MPXFTU EPTF OFFEFE UP BWPJE RBC transfusions. t 6TF &4"T POMZ GPS BOFNJB GSPN NZFMPTVQQSFTTJWF DIFNPUIFSBQZ t &4"T BSF OPU JOEJDBUFE GPS QBUJFOUT SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF BOUJDJQBUFE PVUDPNF JT DVSF t %JTDPOUJOVF GPMMPXJOH UIF DPNQMFUJPO PG B DIFNPUIFSBQZ DPVSTF

INDICATION AND USAGE "OFNJB %VF UP $IFNPUIFSBQZ JO 1BUJFOUT 8JUI $BODFS Aranesp is indicated for the treatment of anemia in patients with non-myeloid malignancies where anemia is due to the effect of concomitant myelosuppressive chemotherapy, and upon initiation, there is a minimum of two additional months of planned chemotherapy. Limitations of Use Aranesp has not been shown to improve quality of life, fatigue, or patient well-being. Aranesp is not indicated for use: t *O QBUJFOUT XJUI DBODFS SFDFJWJOH IPSNPOBM BHFOUT CJPMPHJD QSPEVDUT or radiotherapy, unless also receiving concomitant myelosuppressive chemotherapy. t *O QBUJFOUT XJUI DBODFS SFDFJWJOH NZFMPTVQQSFTTJWF DIFNPUIFSBQZ XIFO UIF anticipated outcome is cure. t "T B TVCTUJUVUF GPS 3#$ USBOTGVTJPOT JO QBUJFOUT XIP SFRVJSF JNNFEJBUF correction of anemia.

CONTRAINDICATIONS

Aranesp is contraindicated in patients with: t 6ODPOUSPMMFE IZQFSUFOTJPO t 1VSF SFE DFMM BQMBTJB 13$" UIBU CFHJOT BGUFS USFBUNFOU XJUI "SBOFTQ PS PUIFS erythropoietin protein drugs. t 4FSJPVT BMMFSHJD SFBDUJPOT UP "SBOFTQ

WARNINGS AND PRECAUTIONS *ODSFBTFE .PSUBMJUZ .ZPDBSEJBM *OGBSDUJPO 4USPLF BOE 5ISPNCPFNCPMJTN *O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI $,% DPNQBSJOH IJHIFS IFNPHMPCJO UBSHFUT H E- UP MPXFS UBSHFUT H E- "SBOFTQ BOE PUIFS &4"T increased the risk of death, myocardial infarction, stroke, congestive heart failure, thrombosis of hemodialysis vascular access, and other thromboembolic events in the higher target groups. 6TJOH "SBOFTQ UP UBSHFU B IFNPHMPCJO MFWFM PG HSFBUFS UIBO H E- JODSFBTFT UIF SJTL of serious adverse cardiovascular reactions and has not been shown to provide BEEJUJPOBM CFOFmU 6TF DBVUJPO JO QBUJFOUT XJUI DPFYJTUFOU DBSEJPWBTDVMBS EJTFBTF BOE TUSPLF 1BUJFOUT XJUI $,% BOE BO JOTVGmDJFOU IFNPHMPCJO SFTQPOTF UP &4" UIFSBQZ may be at even greater risk for cardiovascular reactions and mortality than other QBUJFOUT " SBUF PG IFNPHMPCJO SJTF PG HSFBUFS UIBO H E- PWFS XFFLT NBZ DPOUSJCVUF to these risks. * O DPOUSPMMFE DMJOJDBM USJBMT PG QBUJFOUT XJUI DBODFS "SBOFTQ BOE PUIFS &4"T increased the risks for death and serious adverse cardiovascular reactions. These adverse reactions included myocardial infarction and stroke. *O DPOUSPMMFE DMJOJDBM USJBMT &4"T JODSFBTFE UIF SJTL PG EFBUI JO QBUJFOUT VOEFSHPJOH DPSPOBSZ BSUFSZ CZQBTT HSBGU TVSHFSZ $"#( BOE UIF SJTL PG EFFQ WFOPVT UISPNCPTJT %75 JO QBUJFOUT VOEFSHPJOH PSUIPQFEJD QSPDFEVSFT 1BUJFOUT XJUI $BODFS An increased incidence of thromboembolic reactions, some serious and lifeUISFBUFOJOH PDDVSSFE JO QBUJFOUT XJUI DBODFS USFBUFE XJUI &4"T *O B SBOEPNJ[FE QMBDFCP DPOUSPMMFE TUVEZ TFF 4UVEZ JO 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO PG XPNFO XJUI NFUBTUBUJD CSFBTU DBODFS SFDFJWJOH DIFNPUIFSBQZ patients received either weekly epoetin alfa or placebo for up to a year. This study was designed to show that survival was superior when epoetin alfa was administered UP QSFWFOU BOFNJB NBJOUBJO IFNPHMPCJO MFWFMT CFUXFFO BOE H E- PS IFNBUPDSJU CFUXFFO BOE 5IJT TUVEZ XBT UFSNJOBUFE QSFNBUVSFMZ XIFO JOUFSJN SFTVMUT EFNPOTUSBUFE B IJHIFS NPSUBMJUZ BU NPOUIT WT BOE B IJHIFS SBUF PG GBUBM UISPNCPUJD SFBDUJPOT WT JO UIF mSTU NPOUIT PG UIF TUVEZ BNPOH QBUJFOUT USFBUFE XJUI FQPFUJO BMGB #BTFE PO ,BQMBO .FJFS FTUJNBUFT BU UIF UJNF PG TUVEZ UFSNJOBUJPO UIF NPOUI TVSWJWBM XBT MPXFS JO UIF FQPFUJO BMGB HSPVQ UIBO JO UIF QMBDFCP HSPVQ WT )3 $* Q 1SFTDSJCJOH BOE %JTUSJCVUJPO 1SPHSBN GPS "SBOFTQ JO 1BUJFOUT 8JUI $BODFS *O PSEFS UP QSFTDSJCF BOE PS EJTQFOTF "SBOFTQ UP QBUJFOUT XJUI DBODFS BOE BOFNJB due to myelosuppressive chemotherapy, prescribers and hospitals must enroll in and DPNQMZ XJUI UIF &4" "113*4& 0ODPMPHZ 1SPHSBN SFRVJSFNFOUT 5P FOSPMM WJTJU XXX FTB BQQSJTF DPN PS DBMM GPS GVSUIFS BTTJTUBODF "EEJUJPOBMMZ QSJPS UP each new course of Aranesp in patients with cancer, prescribers and patients must provide written acknowledgment of a discussion of the risks of Aranesp.

*ODSFBTFE .PSUBMJUZ BOE PS *ODSFBTFE 3JTL PG 5VNPS 1SPHSFTTJPO PS 3FDVSSFODF JO 1BUJFOUT 8JUI $BODFS &4"T SFTVMUFE JO EFDSFBTFE MPDPSFHJPOBM DPOUSPM QSPHSFTTJPO GSFF TVSWJWBM BOE PS PWFSBMM TVSWJWBM 4FF 5BCMF JO 1SFTDSJCJOH *OGPSNBUJPO 5IFTF mOEJOHT XFSF observed in studies of patients with advanced head and neck cancer receiving SBEJBUJPO UIFSBQZ 4UVEJFT BOE JO QBUJFOUT SFDFJWJOH DIFNPUIFSBQZ GPS NFUBTUBUJD CSFBTU DBODFS 4UVEZ PS MZNQIPJE NBMJHOBODZ 4UVEZ BOE JO QBUJFOUT XJUI OPO small cell lung cancer or various malignancies who were not receiving chemotherapy PS SBEJPUIFSBQZ 4UVEJFT BOE Hypertension "SBOFTQ JT DPOUSBJOEJDBUFE JO QBUJFOUT XJUI VODPOUSPMMFE IZQFSUFOTJPO *O "SBOFTQ DMJOJDBM TUVEJFT BQQSPYJNBUFMZ PG QBUJFOUT XJUI $,% SFRVJSFE JOJUJBUJPO PS intensiямБcation of antihypertensive therapy during the early phase of treatment. )ZQFSUFOTJWF FODFQIBMPQBUIZ BOE TFJ[VSFT IBWF CFFO SFQPSUFE JO QBUJFOUT XJUI $,% receiving Aranesp. Appropriately control hypertension prior to initiation of and during treatment with "SBOFTQ 3FEVDF PS XJUIIPME "SBOFTQ JG CMPPE QSFTTVSF CFDPNFT EJGmDVMU UP DPOUSPM Advise patients of the importance of compliance with antihypertensive therapy and dietary restrictions. Seizures "SBOFTQ JODSFBTFT UIF SJTL PG TFJ[VSFT JO QBUJFOUT XJUI $,% %VSJOH UIF mSTU TFWFSBM months following initiation of Aranesp, monitor patients closely for premonitory neurologic symptoms. Advise patients to contact their healthcare practitioner for OFX POTFU TFJ[VSFT QSFNPOJUPSZ TZNQUPNT PS DIBOHF JO TFJ[VSF GSFRVFODZ Lack or Loss of Hemoglobin Response to Aranesp For lack or loss of hemoglobin response to Aranesp, initiate a search for causative GBDUPST F H JSPO EFmDJFODZ JOGFDUJPO JOnBNNBUJPO CMFFEJOH *G UZQJDBM DBVTFT PG MBDL PS MPTT PG IFNPHMPCJO SFTQPOTF BSF FYDMVEFE FWBMVBUF GPS 13$" *O UIF BCTFODF PG 13$" GPMMPX EPTJOH SFDPNNFOEBUJPOT GPS NBOBHFNFOU PG QBUJFOUT XJUI BO insufямБcient hemoglobin response to Aranesp therapy. Pure Red Cell Aplasia $BTFT PG 13$" BOE PG TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT UIBU BSJTF GPMMPXJOH UIF EFWFMPQNFOU PG OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO IBWF CFFO reported in patients treated with Aranesp. This has been reported predominantly in QBUJFOUT XJUI $,% SFDFJWJOH &4"T CZ TVCDVUBOFPVT BENJOJTUSBUJPO 13$" IBT BMTP CFFO SFQPSUFE JO QBUJFOUT SFDFJWJOH &4"T GPS BOFNJB SFMBUFE UP IFQBUJUJT $ USFBUNFOU BO JOEJDBUJPO GPS XIJDI "SBOFTQ JT OPU BQQSPWFE *G TFWFSF BOFNJB BOE MPX SFUJDVMPDZUF DPVOU EFWFMPQ EVSJOH USFBUNFOU XJUI "SBOFTQ XJUIIPME "SBOFTQ BOE FWBMVBUF QBUJFOUT GPS OFVUSBMJ[JOH BOUJCPEJFT UP FSZUISPQPJFUJO $POUBDU "NHFO ".(&/ UP QFSGPSN BTTBZT GPS CJOEJOH BOE OFVUSBMJ[JOH BOUJCPEJFT 1FSNBOFOUMZ EJTDPOUJOVF "SBOFTQ JO QBUJFOUT XIP EFWFMPQ 13$" GPMMPXJOH USFBUNFOU XJUI "SBOFTQ PS PUIFS FSZUISPQPJFUJO QSPUFJO ESVHT %P OPU TXJUDI QBUJFOUT UP PUIFS &4"T Serious Allergic Reactions 4FSJPVT BMMFSHJD SFBDUJPOT JODMVEJOH BOBQIZMBDUJD SFBDUJPOT BOHJPFEFNB CSPODIPTQBTN TLJO SBTI BOE VSUJDBSJB NBZ PDDVS XJUI "SBOFTQ *NNFEJBUFMZ BOE permanently discontinue Aranesp and administer appropriate therapy if a serious allergic or anaphylactic reaction occurs. Dialysis Management 1BUJFOUT NBZ SFRVJSF BEKVTUNFOUT JO UIFJS EJBMZTJT QSFTDSJQUJPOT BGUFS JOJUJBUJPO PG "SBOFTQ 1BUJFOUT SFDFJWJOH "SBOFTQ NBZ SFRVJSF JODSFBTFE BOUJDPBHVMBUJPO XJUI IFQBSJO UP QSFWFOU DMPUUJOH PG UIF FYUSBDPSQPSFBM DJSDVJU EVSJOH IFNPEJBMZTJT Laboratory Monitoring &WBMVBUF USBOTGFSSJO TBUVSBUJPO BOE TFSVN GFSSJUJO QSJPS UP BOE EVSJOH "SBOFTQ treatment. Administer supplemental iron therapy when serum ferritin is less than NDH - PS XIFO TFSVN USBOTGFSSJO TBUVSBUJPO JT MFTT UIBO 5IF NBKPSJUZ PG QBUJFOUT XJUI $,% XJMM SFRVJSF TVQQMFNFOUBM JSPO EVSJOH UIF DPVSTF PG &4" UIFSBQZ 'PMMPXJOH JOJUJBUJPO PG UIFSBQZ BOE BGUFS FBDI EPTF BEKVTUNFOU NPOJUPS IFNPHMPCJO XFFLMZ VOUJM UIF IFNPHMPCJO JT TUBCMF BOE TVGmDJFOU UP NJOJNJ[F UIF OFFE GPS 3#$ transfusion. Thereafter, hemoglobin may be monitored less frequently provided hemoglobin levels remain stable.

ADVERSE REACTIONS $MJOJDBM 5SJBM &YQFSJFODF #FDBVTF DMJOJDBM USJBMT BSF DPOEVDUFE VOEFS XJEFMZ WBSZJOH DPOEJUJPOT BEWFSTF reaction rates observed in the clinical trials of a drug cannot be directly compared UP SBUFT JO UIF DMJOJDBM USJBMT PG PUIFS ESVHT BOE NBZ OPU SFnFDU UIF SBUFT PCTFSWFE in practice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tudy Adverse Reaction 5ISPNCPFNCPMJD "EWFSTF 3FBDUJPOT O

Arterial .ZPDBSEJBM JOGBSDUJPO 7FOPVT 1VMNPOBSZ FNCPMJTN $FSFCSPWBTDVMBS EJTPSEFST

"MM 1MBDFCP controlled Studies

*O BEEJUJPO UP UIF UISPNCPWBTDVMBS BEWFSTF SFBDUJPOT BCEPNJOBM QBJO BOE FEFNB occurred at a higher incidence in patients taking Aranesp compared to patients on QMBDFCP "NPOH BMM QMBDFCP DPOUSPMMFE TUVEJFT BCEPNJOBM QBJO WT BOE FEFNB WT XFSF SFQPSUFE NPSF GSFRVFOUMZ JO QBUJFOUT SFDFJWJOH "SBOFTQ DPNQBSFE UP UIF QMBDFCP HSPVQ *O UIF 4$-$ TUVEZ UIF JODJEFODF PG BCEPNJOBM QBJO WT BOE FEFNB WT JO UIF "SBOFTQ USFBUFE QBUJFOUT compared to those receiving placebo. 1PTUNBSLFUJOH &YQFSJFODF #FDBVTF QPTUNBSLFUJOH SFQPSUJOH PG BEWFSTF SFBDUJPOT JT WPMVOUBSZ BOE GSPN B QPQVMBUJPO PG VODFSUBJO TJ[F JU JT OPU BMXBZT QPTTJCMF UP SFMJBCMZ FTUJNBUF UIFJS GSFRVFODZ PS FTUBCMJTI B DBVTBM SFMBUJPOTIJQ UP ESVH FYQPTVSF The following adverse reactions have been identiямБed during postmarketing use of Aranesp: t 4FJ[VSFT t 13$" t 4FSJPVT BMMFSHJD SFBDUJPOT Immunogenicity "T XJUI BMM UIFSBQFVUJD QSPUFJOT UIFSF JT B QPUFOUJBM GPS JNNVOPHFOJDJUZ /FVUSBMJ[JOH antibodies to darbepoetin alfa that cross-react with endogenous erythropoietin and PUIFS &4"T DBO SFTVMU JO 13$" PS TFWFSF BOFNJB XJUI PS XJUIPVU PUIFS DZUPQFOJBT *O DMJOJDBM TUVEJFT UIF QFSDFOUBHF PG QBUJFOUT XJUI BOUJCPEJFT UP "SBOFTQ XBT FYBNJOFE VTJOH UIF #JBDPSF┬о BTTBZ 4FSB GSPN QBUJFOUT XJUI $,% BOE cancer patients were tested. At baseline, prior to Aranesp treatment, binding BOUJCPEJFT XFSF EFUFDUFE JO QBUJFOUT XJUI $,% BOE DBODFS QBUJFOUT %VSJOH "SBOFTQ UIFSBQZ SBOHF UP XFFLT B GPMMPX VQ TBNQMF XBT UBLFO 0OF BEEJUJPOBM QBUJFOU XJUI $,% BOE BEEJUJPOBM DBODFS QBUJFOUT EFWFMPQFE BOUJCPEJFT DBQBCMF PG CJOEJOH "SBOFTQ /POF PG UIF QBUJFOUT IBE BOUJCPEJFT DBQBCMF PG OFVUSBMJ[JOH UIF BDUJWJUZ PG "SBOFTQ PS FOEPHFOPVT FSZUISPQPJFUJO BU CBTFMJOF PS BU FOE PG TUVEZ /P DMJOJDBM TFRVFMBF DPOTJTUFOU XJUI 13$" XFSF BTTPDJBUFE XJUI UIF presence of these antibodies. The incidence of antibody formation is highly dependent on the sensitivity and TQFDJmDJUZ PG UIF BTTBZ "EEJUJPOBMMZ UIF PCTFSWFE JODJEFODF PG BOUJCPEZ JODMVEJOH OFVUSBMJ[JOH BOUJCPEZ QPTJUJWJUZ JO BO BTTBZ NBZ CF JOnVFODFE CZ TFWFSBM GBDUPST including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Aranesp with the incidence of antibodies to other products may be misleading.

DRUG INTERACTIONS

/P GPSNBM ESVH JOUFSBDUJPO TUVEJFT IBWF CFFO DPOEVDUFE XJUI "SBOFTQ

USE IN SPECIFIC POPULATIONS Pregnancy 1SFHOBODZ $BUFHPSZ $ There are no adequate and well-controlled studies of Aranesp use in pregnant women. *O BOJNBM SFQSPEVDUJPO BOE EFWFMPQNFOUBM UPYJDJUZ TUVEJFT "SBOFTQ JODSFBTFE FBSMZ QPTU JNQMBOUBUJPO MPTT 6TF "SBOFTQ EVSJOH QSFHOBODZ POMZ JG UIF QPUFOUJBM CFOFmU KVTUJmFT UIF QPUFOUJBM SJTL UP UIF GFUVT 8IFO "SBOFTQ XBT BENJOJTUFSFE JOUSBWFOPVTMZ to healthy pregnant rats and rabbits, there was no evidence of embryofetal UPYJDJUZ PS PUIFS BEWFSTF PVUDPNFT BU UIF JOUSBWFOPVT EPTFT UFTUFE VQ UP NDH LH EBZ 5IJT BOJNBM EPTF MFWFM PG NDH LH EBZ JT BQQSPYJNBUFMZ GPME IJHIFS UIBO UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF EFQFOEJOH PO UIF QBUJFOU T USFBUNFOU JOEJDBUJPO 4MJHIUMZ SFEVDFE GFUBM XFJHIUT XFSF PCTFSWFE XIFO IFBMUIZ SBU BOE SBCCJU NPUIFST SFDFJWFE EPTFT PG NDH LH PS NPSF 5IJT EPTF PG NDH LH JT OFBS UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF 8IJMF OP BEWFSTF FGGFDUT on uterine implantation occurred in animals, there was an increase in early postJNQMBOUBUJPO MPTT JO BOJNBM GFSUJMJUZ TUVEJFT *U JT OPU DMFBS XIFUIFS UIF JODSFBTFE QPTU JNQMBOUBUJPO MPTT SFnFDUT B ESVH FGGFDU PO UIF VUFSJOF FOWJSPONFOU PS PO UIF DPODFQUVT /P TJHOJmDBOU QMBDFOUBM USBOTGFS PG "SBOFTQ XBT EFUFDUFE *O B QFSJ QPTUOBUBM EFWFMPQNFOU TUVEZ QSFHOBOU GFNBMF SBUT SFDFJWFE "SBOFTQ intravenously every other day from implantation throughout pregnancy and MBDUBUJPO 5IF MPXFTU EPTF UFTUFE NDH LH EJE OPU DBVTF GFUBM UPYJDJUZ UIJT EPTF JT BQQSPYJNBUFMZ FRVJWBMFOU UP UIF DMJOJDBM SFDPNNFOEFE TUBSUJOH EPTF "U NBUFSOBM EPTFT PG NDH LH BOE IJHIFS QVQT IBE EFDSFBTFE GFUBM CPEZ XFJHIUT which correlated with a slight increase in the incidence of fetal deaths, as well as delayed eye opening and delayed preputial separation. 8PNFO XIP CFDPNF QSFHOBOU EVSJOH "SBOFTQ USFBUNFOU BSF FODPVSBHFE UP FOSPMM JO "NHFO T 1SFHOBODZ 4VSWFJMMBODF 1SPHSBN 1BUJFOUT PS UIFJS QIZTJDJBOT TIPVME DBMM ".(&/ UP FOSPMM /VSTJOH .PUIFST *U JT OPU LOPXO XIFUIFS "SBOFTQ JT FYDSFUFE JO IVNBO NJML #FDBVTF NBOZ ESVHT BSF FYDSFUFE JO IVNBO NJML DBVUJPO TIPVME CF FYFSDJTFE XIFO "SBOFTQ JT BENJOJTUFSFE to a nursing woman. Pediatric Use The safety and efямБcacy of Aranesp in pediatric cancer patients have not been established. Geriatric Use 0G UIF QBUJFOUT XJUI $,% JO DMJOJDBM TUVEJFT PG "SBOFTQ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS 0G UIF QBUJFOUT JO DMJOJDBM TUVEJFT SFDFJWJOH "SBOFTQ BOE DPODPNJUBOU DBODFS DIFNPUIFSBQZ XFSF BHF BOE PWFS XIJMF XFSF BHF BOE PWFS /P EJGGFSFODFT JO TBGFUZ PS FGmDBDZ XFSF PCTFSWFE between older and younger patients.

OVERDOSAGE

Aranesp overdosage can cause hemoglobin levels above the desired level, which TIPVME CF NBOBHFE XJUI EJTDPOUJOVBUJPO PS SFEVDUJPO PG "SBOFTQ EPTBHF BOE PS XJUI QIMFCPUPNZ BT DMJOJDBMMZ JOEJDBUFE $BTFT PG TFWFSF IZQFSUFOTJPO IBWF CFFO PCTFSWFE GPMMPXJOH PWFSEPTF XJUI &4"T

Aranesp Placebo Aranesp Placebo O O O O

i$FSFCSPWBTDVMBS EJTPSEFSTw FODPNQBTTFT $F/4 IFNPSSIBHFT BOE DFSFCSPWBTDVMBS BDDJEFOUT JTDIFNJD BOE IFNPSSIBHJD &WFOUT JO UIJT DBUFHPSZ NBZ BMTP CF JODMVEFE VOEFS iUISPNCPFNCPMJD BEWFSTF SFBDUJPOT w

Aranesp┬о EBSCFQPFUJO BMGB

Manufactured by: "NHFO .BOVGBDUVSJOH -JNJUFE B TVCTJEJBSZ PG "NHFO *OD 0OF "NHFO $FOUFS %SJWF 5IPVTBOE 0BLT $" This product, the process of its manufacture, or its use, may be covered by one or NPSF 6 4 1BUFOUT JODMVEJOH 6 4 1BUFOU /P ┬к "NHFO *OD "MM SJHIUT SFTFSWFE 3 7

ASCOPost.com | MAY 1, 2013

PAGE 47

Patient’s Corner Breast Cancer

Acts of Kindness Were Key to My Survival

We may look strong on the outside, but on the inside, many cancer survivors are fragile. By Karey Edele, as told to Jo Cavallo

ust 1 month after undergoing a mammogram that was deemed normal with some dense tissue in my left breast, my gynecologist felt a mass in that breast about the size of a cherry tomato during a routine well visit. After watching the lump for a month to see if it was cyclical, she sent me for another mammogram and then an ultrasound. The results were so suspicious, my doctor scheduled an appointment the next day with a surgeon for a biopsy of the mass. But even before the surgeon got back the biopsy results, she said she could tell by looking at the ultrasound that I had breast cancer. The biopsy report showed the cancer was stage IIB ductal carcinoma.

going through treatment—a lumpectomy, four rounds of combination chemotherapy of cyclophosphamide and docetaxel, and 28 radiation treatments—was no easy feat, especially for my daughters. I think it was my

Cancer Is a Family Disease

hair loss that was most frightening for them because it is such a hallmark of having a life-threatening disease.

T:14”

B:14.25”

S:13”

All along the way to the diagnosis, I wasn’t expecting to hear that I had breast cancer. My family and I had just moved to Vermont and were just becoming established in the community when I got the news. The diagnosis was especially daunting because I home school my three daughters, ages 14, 12, and 8, and now I had to adapt their curriculum and lesson schedule around my cancer treatment. Although my oncologist assured me that my prognosis was excellent,

radiotherapy, showed me such caring, it made all the difference in how well I coped with having breast cancer. I often think we cancer survivors put on a brave face, but on the inside we are so fragile, we can break apart at any

The experience of having cancer has made us aware of the difficulties other people may be facing behind their brave smiles and has taught us to return the kindness we were shown to everyone we meet. —Karey Edele

Putting on a Brave Face What helped us get through the last year and a half is our close-knit community and the incredible kindness of my medical team. Everyone, from my oncologist (who told me I was in a place of healing and that I would be fine) to the nurses who administered my chemotherapy and the radiation therapists who directed my

moment. At my first radiation appointment, I started to shake so uncontrollably—either from fear or being cold, I’m not sure which—several radiation therapists rushed over to reassure me that I would be okay and that what I was experiencing was normal. They covered me in warm blankets, talked about their families, and asked me about mine. They even let my daughters visit the radiation therapy room so they could see the machine that was helping to cure me. On the day of my last treatment, the

therapists presented me with a photo a friend had taken of them and me after one of my treatments, which they had signed with well-wishes. It was those many acts of kindness that made my experience with cancer less frightening for my family and for me.

Life Lessons Learned To give back to the community that has given so much to us, last spring my husband, daughters, and I participated in a Breast Cancer Walkathon, the American Cancer Society’s Relay for Life, and the Komen Race for the Cure to raise awareness and funds for breast cancer research. Being involved in these events was comforting to my children, to see so many people thriving after cancer, and it was empowering for them to see how their efforts were making a difference in the lives of cancer survivors, including their mother’s. The experience of having cancer has also made us aware of the difficulties other people may be facing behind their brave smiles and has taught us to return the kindness we were shown to everyone we meet. Having cancer has been an important life lesson for all of us. n Karey Edele lives in Franklin, Vermont.

Fred Hutchinson Cancer Research Center Survivorship Program to Lead New Study on Cancer In Young Adults

he Fred Hutchinson Cancer Research Center Survivorship Program and its Directors, K. Scott Baker, MD, and Karen Syrjala, PhD, have been selected to lead a nationwide study that aims to improve long-term health outcomes for cancer survivors between the ages of 18 and 39 years. Underway this spring, the study will involve the Livestrong Survivorship Center of Excellence Network, a collaborative research group of seven National Cancer Institute-designated comprehensive cancer centers, including the Fred Hutchinson/University of Washington Cancer Consortium. The Livestrong Foundation awarded the group $1.2 million for the initial study start-up to learn more about its young-

adult cancer survivors with four goals in mind: testing the impact of providing essential elements of survivorship care, including a treatment summary and a survivorship care plan with recommendations for ongoing health monitoring, strategies for improving health, and future cancer screenings; providing evidence to support long-term follow-up recommendations for these these hese adult survivors; determining effective methods of communication for survivors in this age group; and testing treatments that could improve survivors’ health and well-being. “There’s a compelling need for this work, as young adults fall into the gap between studies of childhood cancer patients and those in mid to late life, who more commonly have cancer,” Dr. Baker

said. “Young people with cancer are impacted at a very formative, critical time of life, and we must put more effort into learning how we can help them thrive in the years following treatment.”

NCI-designated Sites Participating in Study Collaborating sites include The Abramson Cancer Center at the University of Pennsylvania, Dana-Farber Cancer Institute, Jonsson Comprehensive Cancer Center at UCLA, Memorial Sloan-Kettering Cancer Center, University of Colorado Cancer Center and University of North Carolina Lineberger Comprehensive Cancer Center.

K. Scott Baker, MD

Karen Syrjala, PhD

The study goal is to recruit a total of 3,000 former patients from across the network of cancer centers. The survivors in the study are a year or more out from cancer treatment, and they will be followed for at least 3 years. For more information visit www. fhcrc.org/survivorship. n

INNOVATION AT WORK

JOURNAL OF CLINICAL ONCOLOGY

Journal of Clinical Oncology (JCO) is uncompromising in providing comprehensive information and dedicated to producing innovative formats for faster delivery and access.

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High-caliber content including new article types such as Oncology Grand Rounds, Rapid Communications, and Understanding the Pathway

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JCO iPad Edition offers an enhanced reading experience bringing together the best of print and digital content

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Translating research into practice with podcasts providing commentary on selected JCO articles

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JCO Essential Reading. Influential Information.

To submit your manuscript, please visit http://submit.jco.org. Or e-mail the JCO Editorial Office at jco@asco.org Subscribe by calling 888-273-3508 or 703-519-1430

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PAGE 49

Announcements

Neurosurgeon Eric Holland, MD, PhD, joins Fred Hutchinson and University of Washington Medicine; Plans to Develop Brain Cancer Program

eurosurgeon and brain cancer researcher Eric Holland, MD, PhD, will be joining Fred Hutchinson Cancer

ing with the world’s leading experts in genome sciences, computational biology, and those involved in the development of novel platforms for delivering innovative therapies to cancer patients,”

Dr. Holland said. “The highly collaborative, multidisciplinary nature of cancer research at Fred Hutchinson and University of Washington Medicine provides a solid foundation to build on.”

Dr. Holland is currently the Emily Tow Jackson Chair in Oncology and the founding director of the Brain Tumor Center at Memorial Sloan-Kettering Cancer Center in New York. n

Read the Expert’s Guide to the

Eric Holland, MD, PhD

Research Center and the University of Washington in summer 2013. Dr. Holland will be Senior Vice President and Director of the Human Biology Division at Fred Hutchinson Cancer Research Center, where his lab will be based. Larry Corey, MD, President and Director of Fred Hutchinson said “I am confident that Eric will help us apply the strategies he has developed and used so successfully for brain tumors to many other types of solid-tumor cancers. His recruitment will catalyze numerous opportunities of this kind for our institutions,” he said. With advances in genomics increasingly playing an important role in solid-tumor oncology, Dr. Holland’s expertise will provide strong leadership in this area. Dr. Holland will oversee the recruitment of new laboratory-based investigators at Fred Hutchinson. At University of Washington Medicine, Dr. Holland will be a Professor of Neurological Surgery, hold the Chap and Eve Alvord and Elias Alvord Chair in Neuro-oncology and direct the Nancy and Buster Alvord Brain Tumor Center. The Alvord Center was established in 2009 to promote, develop and coordinate outstanding interdisciplinary brain tumor care and research among physicians and scientists in a variety of fields ranging from neurology to radiation oncology. Dr. Holland said he is looking forward to the challenge of developing a world-class brain cancer and solid-tumor program in Seattle to build on the Hutchinson Center’s pioneering, Nobel Prize-winning work in bone-marrow transplantation to treat leukemia and other blood cancers and to collaborate with the outstanding genome scientists at UW Medicine. “I am thrilled at the prospect of work-

Skin Effects of Cancer For Your

Patients

More people than ever before are living with and surviving cancer. However, even the most promising cancer treatments may cause unexpected side effects to the skin, hair, and nails. How can your patients navigate these changes while staying on treatment and maintaining some quality of life? Written for people living with cancer by Dr. Mario Lacouture, an expert in the dermatologic side effects of anticancer medications, this book offers your patients clear information and practical suggestions for preventing, treating, and living through these skin, hair, and nail changes.

Look inside for these important topics! • Preparation for the rash, itching, or dry skin that may come with cancer treatment • Care for the fingernails, and suggested products that will contribute to their health • Awareness of the risks for hair loss, and resources your patients may need • Suggested moisturizers and cosmetics that are appropriate for your patients’ use • Specific information for survivors

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About the Author Mario E. Lacouture, MD Associate Member Memorial Sloan-Kettering Cancer Center New York, NY Mario E. Lacouture, MD, is a board-certified dermatologist with a special interest in dermatologic conditions that result from cancer treatments. His clinical focus is the recognition and management of the side effects and conditions of the skin, hair, and nails that may arise in cancer patients and survivors as a consequence of surgery, chemotherapy, radiation, or transplantation. His research focuses on exploring new skin treatments that do not interfere with the effectiveness of anticancer medications.

The ASCO Post | MAY 1, 2013

PAGE 50

In the Literature

Emerging Clinical Data on Cancer Management BREAST CANCER Progression-free Survival in HER2-positive Metastatic Breast Cancer Improved with T-DM1 First-line treatment with ado-trastuzumab emtansine (T-DM1) “provided a significant improvement” in progressionfree survival when compared to trastuzumab (Herceptin) plus docetaxel in a randomized phase II study among patients with HER2-positive metastatic or recurrent locally advanced breast cancer. The median progression-free survival was 14.2 months with T-DM1 vs 9.2 months with the trastuzumab/docetaxel combination (hazard ratio = 0.59; 95% CI = 0.36–0.97), according to the study report published in the Journal of Clinical Oncology. T-DM1, an antibody-drug conjugate composed of the cytotoxic agent DM1 conjugated to trastuzumab, also had a favorable safety profile compared to the trastuzumab/docetaxel combination, with fewer grade ≥ 3 adverse events (46.4% vs 90.9%). “In this phase II, multicenter, openlabel study, patients were randomly assigned 1:1 to either T-DM1 3.6 mg/kg intravenously (IV) once every 3 weeks or trastuzumab 8 mg/kg IV loading dose followed by 6 mg/kg once every 3 weeks and docetaxel 75 or 100 mg/m2 (per investigator discretion) IV once every 3 weeks,” with treatment continuing until progressive disease or unacceptable toxicity, the investigators explained. “T-DM1 provided a clinically meaningful and statistically significant 41% reduction in the relative risk” of progressive disease compared with standard treatment, the researchers reported. The overall response rate was 58.0% (95% CI = 45.5%–69.2%) with three complete responses vs 64.2% (95% CI = 51.8%– 74.8%) with seven complete responses in the TDM1 arm (P = .458). The improvement in progression-free survival observed with T-DM1 “was associated with a more durable response, which could result from greater potency related to its unique mechanisms of action, longer treatment duration enabled by its favorable safety and tolerability, or both,” the authors wrote. Grade 4 adverse events were reported for 57.6% of patients receiving trastuzumab/docetaxel vs 5.8% of those receiving T-DM1. Adverse events leading to treatment discontinuation (of either drug) occurred in 40.9% of patients in the trastuzumab/ docetaxel group vs 7.2% in the T-DM1

group, the investigators noted. Due to study limitations, including the open-label design, immaturity of overall survival data, and large numbers of crossovers from the trastuzumab/ docetaxel arm to the T-DM1 arm after disease progression, “these data should be considered hypothesis-generating, and they need to be validated by the results of MARIANNE,” the researchers stated. MARIANNE is an ongoing phase III randomized study of T-DM1 with or without pertuzumab (Perjeta) vs trastuzumab plus a taxane for the first-line treatment of HER2-positive metastatic breast cancer. Hurvitz SA, et al: J Clin Oncol 31:11571163, 2013.

ACUTE MYELOID LEUKEMIA Bortezomib Added to Standard Induction Therapy Produced Encouraging AML Remission Rate Adding bortezomib (Velcade) to standard daunorubicin and cytarabine induction chemotherapy for acute myeloid leukemia (AML) “resulted in an encouraging remission rate” in previously untreated older adults, according to results of Cancer and Leukemia Group B (CALGB/Alliance) study 10502. The frequency of complete remission was 65% (62 of 95 patients), and 4% of patients achieved complete remission with incomplete platelet recovery. The researchers had found a similar remission frequency—61% complete remission rate and 10% rate of complete remission with incomplete platelet recovery—in a previous study of bortezomib added to induction therapy with idarubicin and cytarabine in patients with relapsed AML and older patients with de novo disease. Patients in the current study were 60 to 75 years old and received bortezomib at 1.3 mg/m2 intravenously (IV) on days 1, 4, 8, and 11 with daunorubicin at 60 mg/m2 on days 1 through 3 and cytarabine at 100 mg/m2 by continuous IV infusion on days 1 through 7. Patients who achieved complete remission received up to two courses of consolidation chemotherapy with cytarabine at 2 g/m2 on days 1 through 5 with bortezomib, the researchers explained. Three dose levels of bortezomib (0.7, 1.0, and 1.3 mg/m2), were tested during consolidation therapy, with the highest dose proving tolerable. The researchers had previously dem-

onstrated that expression of CD74 “was associated with clinical outcome in patients with AML treated with bortezomib, idarubicin, and cytarabine,” and assessed the relationship in this study also. “Lower CD74 expression was associated with [complete remission/ complete remission with incomplete platelet recovery] (P = .04) but not with diseasefree or overall survival,” the investigators stated. Median disease-free survival was 8 months, and median overall survival was 12 months. Eleven patients developed grade 3 sensory neuropathy at some point during therapy. Neuropathy generally lessened or resolved with weeks of treatment, although several patients experienced persistent long-term grade 11 sensory neuropathy.” “A phase III study in which patients are randomly assigned to receive bortezomib or a double-blinded placebo would be required to define the specific clinical benefit of bortezomib with induction and consolidation chemotherapy,” the researchers concluded. Attar EC, et al: J Clin Oncol 31:923929, 2013.

Successful Salvage Treatment Possible in Some Patients Who Do Not Have a Transplant in First Remission Among 3,919 patients with acute myeloid leukemia (AML) who did not undergo transplantation in first complete remission, 1,271 relapsed and 19% were successfully treated with salvage therapy, according to an analysis of three AML trials in the United Kingdom. This percentage can be improved with a transplant, except in favorable disease, the investi-

gators concluded. “This result suggests that, for intermediate-risk patients in particular, equivalent overall survival can be achieved by delaying transplantation until after relapse, which would require many fewer transplants,” the authors of the analysis concluded in the Journal of Clinical Oncology. Second complete remission was achieved in 642 or 55% of patients who relapsed. “This percentage varied by risk group as follows: favorable (82%), intermediate (54%), adverse (27%), and unknown (53%), which resulted in 5-year survivals of 32%, 17%, 7%, and 23%, respectively,” the researchers reported. Among those who relapsed, 433 patients, or 67%, “received an allotransplant that delivered superior survival compared with patients who did not receive a stem-cell transplant (42% vs 16%). A more-stringent assessment of a transplant by using delayed-entry (Mantel-Byar) analysis confirmed the benefit of transplant overall and within intermediate and adverse risk groups but not the favorable subgroup,” the authors continued. “In this study of a large number of patients did not undergo transplantation in [first complete remission], 19% of patients were alive after only receiving chemotherapy in [first complete remission], whereas only 7% survived if they relapsed after transplant,” the investigators stated. They concluded: “The data suggest the possibility of producing the same number of survivors overall by reserving transplantation for relapse, which would require many fewer transplants and avoid the transplant-asso-

ASCOPost.com | MAY 1, 2013

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In the Literature

ciated morbidity and extra health-related interventions. This dilemma is particularly acute for patients with intermediate- risk disease. The decision requires the support of accurate information concerning the risk of relapse and, of relevance to this study, the possibility of successful salvage treatment of a patient when relapse happens.”

Burnett AK, et al: J Clin Oncol 31:12931301, 2013.

1.15–3.35) and the relative risk of experiencing a 50% pain reduction was 2.43 (95% CI = = 1.11–5.30). Pain-related quality of life improved more for those initially receiving duloxetine than for those initially receiving placebo. The investigators commented: “To our knowledge, the current study is the first large phase 3 trial to elucidate an ef-

patients receiving duloxetine for US Food and Drug Administration–approved indications for painful diabetic neuropathy, fibromyalgia, and osteoarthritis.” n

Smith EM, et al: JAMA 309:13591367, 2013. In the Literature is compiled and written for The ASCO Post by Charlotte Bath.

InsIght

PERIPHERAL NEUROPATHY

New iN every issue Of

Duloxetine Reduced Painful Chemotherapy-induced Peripheral Neuropathy

JnCCn

NEW

Read the May Issue of JNCCN: • NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®): Thymomas & Thymic Carcinomas and Penile Cancer NEW

The use of duloxetine (Cymbalta) for 5 weeks “was associated with a statistically and clinically significant improvement” in painful chemotherapy-induced peripheral neuropathy when compared with placebo in a phase III randomized, double-blind crossover trial reported in the Journal of the American Medical Association. The 231 patients were 25 years and older and were recruited by the Cancer and Leukemia Group B (CALGB/ Alliance) from eight multisite cooperative research networks funded by the National Cancer Institute (NCI). Patients with any cancer or stage were potentially eligible, although most had breast or gastrointestinal tumors. “Eligibility required that patients have grade 1 or higher sensory neuropathy according to the NCI Common Terminology Criteria for Adverse Events and at least 4 on a scale of 0 to 10, representing average chemotherapy-induced pain, after paclitaxel, other taxane, or oxaliplatin treatment,” the researchers explained. The patients took one capsule daily of either 30 mg duloxetine or placebo for the first week, and then two capsules of either 30 mg duloxetine or placebo daily for 4 weeks. “Patient-reported pain severity and functional interference was assessed weekly using the well-validated Brief Pain Inventory Short Form (BPI-SF),” the authors explained. “At the end of the initial treatment period, patients in the duloxetine-first group reported a larger decrease in average pain [mean change score = 1.06; 95% CI = 0.72– 1.40] than those in the placebo-first group [mean change score = 0.34; 95% CI = 0.01–0.66; P = .003]. The effect size attributed to duloxetine was moderately large at 0.513.” Compared with placebo, the relative risk of experiencing a 30% pain reduction with duloxetine was 1.96 (95% CI =

fective intervention for painful chemotherapy-induced peripheral neuropathy caused by platinum and taxane agents (mainly paclitaxel or oxaliplatin). During initial treatment, the mean difference between the 2 groups of the change in average pain score was 0.73 (P = .003), which compares favorably to mean differences in average pain scores (range, 0.60-0.98) observed in

NCCN Guidelines® insights: Colon Cancer and Gastric Cancer In this new section, Panel members shed light on the process behind the creation of the NCCN Guidelines, clarifying why and how these important decisions are made.

• Current Concepts in Penile Cancer • A young woman with Bilateral Breast Cancer: identifying a Genetic Cause and implications for Management • The international Thymic Malignancy interest Group • Thymoma versus Thymic Carcinoma: Differences in Biology impacting Treatment

DowNloaD The JNCCN aPP Visit the iTunes store or use your QR code reader to download the JNCCN mobile application.

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