December 2013 by McMahon Group

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • December 2013 • Vol. 8, No. 12

INSIDE HEMATOLOGIC DISEASE Bruce Cheson, MD: How I Manage Follicular Lymphoma— Part II ......................................... 20 SOLID TUMORS Tolerability better with weekly paclitaxel ................... 6 MRI use common, but not always evidencebased .......................................... 12 For BRCA mutation carriers, tamoxifen may reduce contralateral breast cancer risk ............................... 17 T-VEC shows efficacy in melanoma trial ...................... 19

IMAGES in ONCOLOGY

Clinical Pathways Reduce Costs Critics contend that pathways are a diversion from real cost issues Chicago—An oncology clinical pathways program led to a 15% reduction in cancer-related claims costs and a 7% reduction in the likelihood of a hospital admission, according to data presented on the program at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 6553). A reduction in the number of lines of therapy appeared to be one factor driving down costs. “These results show that payor–provider collaborations through pathways see PATHWAYS, S page 8

Microscopic image of kidney carcinoma. Image courtesy of Science Photo Library

Spotting Spin and Bias Reading clinical trial results critically

CURRENT PRACTICE Top cancer drugs new to market .................................... 4 Maurie Markman, MD: ‘Normal’ screening test results ................................. 5 Balancing ‘rational’ and ‘rationed’ care .............. 13 The Tumor Board: Breast lump following previous augmentation ......................... 14 Clinical Conundrums ........................... 22

Chicago—In recent years, oncologists have adopted standards of care based on clinical trial data that is not always scientifically solid. In some cases, new practice patterns may have caused more harm than good. At the recent annual meeting of the American Society of Clinical Oncology (ASCO), three clinicians discussed how doctors can approach reports of clinical trial data more critically and spot spin and bias. According to Mike Glantz, MD, a professor of neurosurgery and oncology at Penn State College of Medicine in Hershey, Pa., a recent trial that compared memantine with placebo in patients undergoing whole brain radiation therapy (2012 ASTRO annual meeting; abstract 2) is a good example of a lapse in critical appraisal. The study, designed with 80% power and a significance of P<0.025, had a primary end point of cognitive improvement at six months. see SPIN AND BIAS, S page 10

AT A GLANCE | Study Bias In three months of Phase III randomized trials comparing two treatments published in the Journal of Clinical Oncology: • 17 of 28 trials were not only statistically nonsignificant, but had confidence intervals that included the possibility of both clinically meaningful benefit and clinically meaningful harm. • Half of the remaining nine studies afforded a post-study conviction of, at most, 60%. “We are left with less than one in five studies that we have seen in the last three months in the JCO that we can really hang our hats on.” —Michael Glantz, MD Penn State College of Medicine

RE VIE WS & COMMENTAR IES

Expert Insights From Massachusetts General Hospital Cancer Center Dose-dense therapy improves ovarian cancer survival ....................... 16 Michael J. Birrer, MD, PhD

In advanced cancer, dexamethasone helps ease fatigue ...................... 18 Mihir M. Kamdar, MD

Harnessing the Immune System in NSCLC Implications of Emerging Data and Immunotherapeutic Strategies for Personalized Medicine To participate in this FREE CME activity, log on to

Release date: October 1, 2013

www.CMEZone.com

Expiration date: September 30, 2014

Editor

TARGET AUDIENCE

Suresh S. Ramalingam, MD

The target audience for this activity is medical oncologists, hematology/oncology fellows, oncology specialty pharmacists, and other health care professionals involved in the management of individuals with nonsmall cell lung cancer (NSCLC).

Professor of Hematology and Medical Oncology Director, Division of Medical Oncology Emory University School of Medicine Winship Cancer Institute Atlanta, Georgia

EDUCATIONAL OBJECTIVES At the conclusion of this activity, participants should be able to:

Faculty Julie R. Brahmer, MD

1 Review fundamental concepts of antitumor immune responses in NSCLC.

Associate Professor Johns Hopkins University School of Medicine Baltimore, Maryland

2 Evaluate key eﬃcacy and safety data from ongoing clinical trials evaluating immunotherapeutic strategies for NSCLC, including tecemotide (formerly known as L-BLP25), belagenpumatucel-L, melanoma-associated antigenA3 (MAGE-A3) vaccine, immune checkpoint inhibitors, toll-like receptor agonists, and mycobacterial adjuvant-based agents.

John Nemunaitis, MD Executive Medical Director Mary Crowley Cancer Research Centers Dallas, Texas

Roman Perez-Soler, MD Professor of Medicine Chair, Department of Oncology Monteﬁore Einstein Center for Cancer Care Chief, Division of Medical Oncology Department of Medicine Deputy Director Albert Einstein Cancer Center Bronx, New York

3 Identify eﬀective immunotherapeutic strategies for early- and advanced-stage NSCLC based on patient and disease characteristics. 4 Recall the ongoing clinical trials evaluating immunotherapeutic approaches for NSCLC to aid appropriate patients for study participation.

MEDIA Monograph

ESTIMATED TIME TO COMPLETE ACTIVITY 1.0 hour

Sponsored by

DESIGNATION OF CREDIT PHYSICIAN CONTINUING EDUCATION Accreditation Statement Educational Concepts Group, LLC is accredited by the Accreditation Council for Continuing Medical

Supported by an Educational Grant from

Education to provide continuing medical education for physicians.

Credit Designation Statement Educational Concepts Group, LLC designates this enduring material for a maximum of 1.0 AMA PRA Category 1 Credit™. ™ Physicians should claim only the credit commensurate with the extent of their participation in the activity.

PHARMACIST CONTINUING EDUCATION Educational Concepts Group, LLC is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Educational Concepts Group, LLC designates this continuing education activity for 1.0 contact hour (0.10 CEU) (UAN 0199-0000-13-034-H01-P).

TYPE OF ACTIVITY Knowledge-based

METHOD OF PARTICIPATION There are no fees for participating and receiving CME/CE credit for this activity. During the period October 1, 2013 through September 30, 2014, participants must 1) read the educational objectives and faculty disclosures; 2) study the educational activity; and 3) complete the post-activity assessment.

CME/CE CREDIT Physicians and pharmacists who complete the postactivity assessment with a score of 70% or better may view and print their credit letter or statement of credit via the website, www.educationalconcepts.net.

Distributed via

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

Solid Tumors Bone Metastases Allan Lipton, MD Milton S. Hershey Medical Center, Penn State University Hershey, PA

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD University of California, San Diego, CA

Michael A. Carducci, MD Johns Hopkins Kimmel Cancer Center Baltimore, MD

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Oncology Nursing

Hematologic Malignancies Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Edward Chu, MD University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Mayo Clinic Rochester, MN

Syed A. Abutalib, MD

Leonard Saltz, MD

Cancer Treatment Centers of America Zion, Illinois

Gynecologic y g Cancer Maurie Markman, MD Cancer Treatment Centers of America Philadelphia, PA

Susan K. Seo, MD Memorial Sloan-Kettering Cancer Center New York, NY

Mission Statement Michael J. Fisch, MD, MPH University of Texas, MD Anderson Cancer Center Houston, TX

Steven Vogl, MD

he mission of Clinical Oncology News is to be an independent source of unbiased, accurate and reliable news combined with in-depth expert analysis about the issues that oncologists and hematologists care about most. We strive to be a valuable source for oncologists and hematologists in providing the best possible care for their patients.

Medical Oncologist New York, NY

Editorial Philosophy Symptom Control and Palliative Care William S. Breitbart, MD Memorial Sloan-Kettering Cancer Center New York, NY

Steven D. Passik, PhD

Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Vanderbilt University Medical Center Nashville, TN

Albert Einstein College of Medicine, New York, NY

Infection Control

Mercy Medical Center St. Louis, MO

Edward S. Kim, MD

Richard J. Gralla, MD

VP, Public Policy & Reimbursement Strategy McKesson Specialty Health The US Oncology Network Washington, DC

John W. Finnie, MD

Lung g and Head and Neck Cancers

Lung g Cancer,, Emesis

Matt Brow

University of Colorado Cancer Center Denver, CO

Community Oncology

Genitourinary y Cancer Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

The Pritchard Group Rockville, MD

Cindy O’Bryant, PharmD

The Mount Sinai Medical Center New York, NY

Ephraim Casper, MD

Ronald M. Bukowski, MD

Mary Lou Bowers, MBA

Sara S. Kim, PharmD

Richard Stone, MD

University of Texas, MD Anderson Cancer Center Houston, TX

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Policy and Management

Pharmacy

Cathy Eng, MD

Gastrointestinal Cancer and Sarcoma

Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

University of Alabama Birmingham, AL

Dana-Farber Cancer Institute, Harvard Medical School Boston, MA

Memorial Sloan-Kettering Cancer Center, Weill Cornell Medical College New York, NY

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD

Gastrointestinal Cancer

Betty Ferrell, RN, PhD

Michele Neskey, MMSc, PA-C

Harry Erba, MD, PhD Maura N. Dickler, MD

Joseph P. DeMarco, PhD Cleveland State University Cleveland, OH

Jennifer R. Brown, MD, PhD Andrew Seidman, MD

Bioethics

Joseph V. Pergolizzi Jr., MD Johns Hopkins University School of Medicine Baltimore, MD

Russell K. Portenoy, MD Beth Israel Medical Center New York, NY

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print. Additionally, all news articles that appear in Clinical Oncology Newss are sent to the sources quoted in each article to review and verify the accuracy of the article’s content. Educational review articles, commentaries, and other clinician-authored pieces are written exclusively by the named authors.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

Top Cancer Drugs New to Market 2013 saw the introduction of several new blockbuster cancer drugs, including trastuzumab emtansine (Kadcyla, Roche/Genentech) for breast cancer and, just last month, ibrutinib (Imbruvica, Pharmacyclics/ Janssen) for mantle cell lymphoma. This year also saw an impossible-to-ignore increase in criticism targeting the costs of cancer drugs, and not only from outside the cancer community, but also

from within. Cancer specialists published editorials decrying the high costs of cancer care in journals such as Blood d and the Journal of Clinical Oncology, as well as in newspapers including The New York Times. As the year draws to a close, Clinical Oncology News takes a critical look at the most important cancer drugs recently to market. Sales figures and cost data come from a variety of pharmaceutical industry

and investment sources. Comments in italics were provided by Balazs Halmos, MD, the section chief of Thoracic Oncology at NewYork-Presbyterian Hospital/Columbia University Medical Center, in New York City.

Balazs Halmos, MD

Drug name: ado-trastuzumab emtansine injection (Kadcyla) Company: Roche/Genentech FDA approval: February 2013 Indication: Breast cancer Drug class: Antibody–drug conjugate Price: $9,800 per month; $94,000 for treatment course Sales: $91 million (first half 2013) Sales potential: $2.55 billion Pros: “Novel approach for targeting ErbB2-positive breast cancer: anti-tubulin cytotoxic attached to trastuzumab.” Cons: Severe side effects, including hepatotoxicity, cardiac and embryofetal toxicity.

Drug name: vandetanib (Caprelsa) Company: AstraZeneca FDA approval: April 2011 Indication: Thyroid cancer Price: $594 per day (300 mg); $17,820 for 30-day supply Sales: $19 million (nine months in 2012) Sales potential: $112 million to $130 million Pros: “This multitargeted kinase inhibitor (RET, EGFR, VEGFR) is the first approved therapy for advanced medullary thyroid cancer.” Cons: Shows improvements in PFS but so far no OS differences.

Drug name: ipilimumab (Yervoy) Company: Bristol-Myers Squibb FDA approval: March 2011 Indication: Metastatic melanoma Price: $30,000 per infusion; $120,000 for four-dose regimen Sales: $706 million (2012); $462 million (first half 2013) Sales potential: $1.54 billion Pros: “This anti-CTLA-4 antibody is the first of a series of breakthrough agents to prove that T-cell activation can have anti-cancer properties.” New data shows patients receiving ipilimumab can survive up to 10 years, with 22% of 1,861 alive after three years. Cons: Serious immune-related side effects in 10% to 26% of patients.

Drug name: brentuximab (Adcetris) Company: Takeda Pharmaceutical/Seattle Genetics FDA approval: August 2011 Indication: Hodgkin lymphoma, CD30-positive anaplastic large cell lymphoma Price: $4,500 per vial; $94,500-$121,500 per course Sales: $138.2 million (2012); $69.7 million (first half 2013) Sales potential: $423 million Pros: “Accelerated approval for this antibody–drug conjugate based on excellent efficacy in CD30-positive malignancies.” Cons: “Rare but serious side effect is progressive multifocal leukoencephalopathy.”

Drug name: vemurafenib (Zelboraf) Company: Hoffmann-La Roche FDA approval: August 2011 Indication: Metastatic melanoma with BRAF V600E mutation Price: $9,400 per month; $56,400 per course Sales: $245 million (2012) Sales potential: $574 million Pros: “Early responses can be dramatic.” ” First to show improvements in OS and PFS for indication. Cons: “Multiple resistance mechanisms limit durability of responses and can accelerate growth of K-ras-mutated cancers, such as skin cancers.”

Drug name: crizotinib (Xalkori) Company: Pfizer FDA approval: August 2011 Indication: Non-small cell lung cancer (NSCLC) Price: $7,079 per month; $100,000 per year Sales: $120 million (first half 2013) Sales potential: $1.3 billion Pros: First to target abnormal anaplastic lymphoma kinase (ALK) gene; one-year OS of 74%, two-year OS of 54% for indication Cons: Indicated for small percentage of NSCLC patients expressing abnormal ALK gene (1%-7%); hefty price tag.

Drug name: abiraterone acetate (Zytiga) Company: Johnson & Johnson FDA approval: April 2011 Indication: Prostate cancer Price: $5,000 per month; $40,000 for eight-month course Sales: $301 million (2011); $961 million (2012); $739 million (first half 2013) Sales potential: $2.3 billion Pros: “This CYP17A1 inhibitor is the first of a series of novel, highly effective hormonal agents for metastatic castration-resistant prostate cancer.” Cons: “Due to the mechanism of action, adrenal insufficiency and mineralocorticoid excess are potential complications, and the drug needs to be given along with prednisone.”

Drug name: vismodegib (Erivedge) Company: Genentech FDA approval: January 2012 Indication: Skin cancer Price: $7,500 per month; $75,000 full course Sales: $30.9 million (2012); $13.8 million (first quarter 2013) Sales potential: Up to $4.65 billion Pros: “First approved therapy for metastatic or locally advanced basal cell cancer with promising activity in medulloblastoma as well.” Cons: “Responses can be transient due to resistance-emerging mechanisms.”

OS, overall survival; PFS, progression-free survival

—Table compiled by Victoria Stern

POSTMASTER: Please send address changes to Clinical Oncology News, 545 W. 45th St., 8th Floor, New York, NY 10036. www.mcmahonmed.com McMahon Publishing is a 41-year-old, family-owned medical publishing and medical education company. McMahon publishes seven clinical newspapers, seven special editions, and continuing medical education and custom publications. Clinical Oncology News (ISSN 1933-0677) is published monthly by McMahon Publishing, 545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896 Copyright© 2013 McMahon Publishing, New York, NY. All rights reserved.

EDITORIAL STAFF Kevin Horty, Group Publication Editor khorty@mcmahonmed.com Gabriel Miller, Managing Editor gmiller@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director David Bronstein, Editorial Director Robin B. Weisberg, Manager, Editorial Services

Elizabeth Zhong, Associate Copy Chief

Dan Radebaugh, Director of Production and Technical Operations

SALES STAFF

Brandy Wilson, Circulation Coordinator

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Mark Neufeld, Associate Director, Project Management

Lauren Smith, Classified Advertising Sales lauren@mcmahonmed.com

MCMAHON PUBLISHING

ART AND PRODUCTION STAFF Michele McMahon Velle, Creative Director, MAX Graphics Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics

Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner Matthew McMahon, General Manager, Partner Lauren Smith, Michael McMahon, Michele McMahon Velle, Rosanne C. McMahon, Partners

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

‘Normal’ Screening Test Results Unfortunately, not so simple EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

anxiety patients feel even when negative screening test results legitimately should be considered reassuring.

References

example, in the lung cancer study noted above, undergoing screening did not appear to affect a current smoker’s likelihood of quitting smoking. It is important to emphasize that a change in screening behavior is not necessarily a favorable outcome. For example, a woman with a strong family history of breast cancer should not discontinue regular mammograms simply because of

one negative exam. However, it is important to try to understand the implications of screening test results. Researchers need to investigate the inappropriate discontinuation of screening due to a “negative test result” and the failure to modify risky behaviors due to a “negative test result” (e.g., smoking cessation), as well as the continued, excessive

1. JAMA Intern Med. 2013;173:407-416, PMID: 23440131. 2. Cancer. 2013;119:1306-1313, PMID: 23280348. 3. Acad Radiol. 2010;17:1012-1025, PMID: 20599157. Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com

he value of certain cancer screening strategies (e.g., cervix, breast or colon) is undisputed. Approaches to other disease sites, such as prostate and lung cancer, remain less well defined or even completely unproven and potentially harmful, as with ovarian cancer. Understandably, most of the discussion about cancer screening has centered on the ability of a test to reduce cancer-related mortality or cancer treatment–related morbidity. One example: a case where a similar survival rate is observed but less aggressive surgery is required to achieve the same outcome. False-positive results are also a major part of the decision to consider screening as a public health strategy, as are the costs associated with any cancer screening strategy. The opposite situation, however, has received far less attention in the oncology literature: the effect on the patient provided with the result that “there is no cancer.” Specifically, I am addressing the actual degree of reassurance a negative result provides a patient that she or he does not have cancer. In fact, the limited data in the medical literature on the issue are not terribly optimistic. In a review of 14 Phase III randomized trials where the patients’ degree of concern, the presence of symptoms and the subsequent use of health care resources were evaluated after undergoing a test with a “low pretest probability of serious illness,” the investigators found very little evidence of any meaningful effect of testing on these outcomes.1 In a survey conducted among 430 individuals who participated in the National Lung Screening Trial, there were no significant differences in their own perceived risk for lung cancer among those surveyed one year after the screening, regardless of the actual study findings.2 This was the case for both current and former smokers. Similar outcomes were observed in previous studies examining the issue.3 These data highlight an important area for future cancer screening research: Patients’ perception of the meaning of study results and how participation in a screening strategy affects future behaviors to modify risk. For

in Your Inbox Clinical Oncology News is available as an E-newsletter.

Get the latest news delivered directly to your computer and PDA. The interactive format has embedded Web Site links that give you instant access to additional information, unique searching features and printing capabilities. Each installment contains brief summaries of the most important articles from the current month’s issue, as well as breaking news ahead of print.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

ASCO 2013

Tolerability Better With Weekly Paclitaxel Chicago—As adjuvant therapy for highrisk breast cancer, once-weekly paclitaxel without a growth factor is just as effective—but generally better tolerated—than every-two-week paclitaxel with a growth factor, according to new data presented at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO). The once-weekly regimen, which

may be less convenient, is not necessarily the best choice for every patient, but the greater tolerability of a weekly regimen without growth factors also has the potential advantage of lowering costs. “What this tells me is that in terms of efficacy, you have a choice,” said lead author G. Thomas Budd, MD, an oncologist at Cleveland Clinic in Ohio. Dr.

Budd reported that the main tolerability advantage with the weekly paclitaxel regimen was a significantly reduced risk for grade 3 or 4 neuropathy and musculoskeletal pain. The multicenter, intergroup study, called SO221, randomized patients with high-risk stage I to III invasive breast cancer to weekly paclitaxel at a dose of 80 mg/m2 or every-two-week

Paclitaxel molecule.

paclitaxel at a dose of 175 mg/m2 plus pegylated granulocyte colony-stimulating factor (G-CSF). High risk was defined as nodal involvement, a

... to receive the monthly e-newsletter from

at clinicaloncology.com

Get the latest news delivered directly to your computer and PDA. The new interactive format has embedded website links that give you instant access to additional information as well as unique search features and printing capabilities. Each installment contains brief summaries of the most important articles from the current issue and breaking news ahead of print.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

primary tumor of at least 2 cm, or a primary tumor of at least 1 cm if hormone receptor–negative or having recurrence scores of at least 26. The study, using a 2 × 2 factorial design, also tested a weekly versus an every-two-week regimen of doxorubicin plus cyclophosphamide. Results of that randomization, which showed no advantage for the weekly regimen, were reported earlier. There were no significant differences between weekly and every-two-week paclitaxel for major outcomes such as disease-free survival (DFS) or overall survival (OS) after a mean follow-up

of 4.2 years. DFS, for example, was 82% for weekly paclitaxel and 81% for the every-two-week regimen. When patients were stratified by tumor subtype, there was a slight OS advantage for the every-two-week regimen in those with HER2-positive breast cancer, but this exception was not representative of other subtypes. The major difference between the two dosing schedules was adverse events. Although grade 3 or 4 leukopenia (6% vs. 1%; P<0.001) and neutropenia (11% vs. 2%; P<0.001) were higher with onceweekly paclitaxel, this was attributed

to an “ascertainment bias” from weekly versus every-two-week monitoring. More critically, there was no greater rate of infectious complications with the weekly regimen despite the absence of G-CSF. Most other grade 3 or 4 events were significantly less common on weekly paclitaxel, particularly neuropathy (10% vs. 17%; P<0.001), musculoskeletal pain (3% vs. 11%; P<0.001) and allergic reactions (0.6% vs. 1.4%; P=0.0035). “I think we can individualize therapy based on other considerations [than efficacy], such as toxicity,” Dr. Budd said. Andrew D. Seidman, MD, an

oncologist in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City, offered a similar perspective. Although he plans to discuss the options with patients based on this data, he stated, “This is going to change my practice. It tells me that weekly paclitaxel delivers the same benefits with less toxicity.” —Ted Bosworth Dr. Budd reported serving in an advisory role for Amgen. Dr. Seidman has no relevant disclosures.

CURRENT PRACTICE

PATHWAYS continued from page 1

can support community oncology via higher reimbursement while lowering the overall cost of cancer care and reducing hospitalizations,” Jeffrey A. Scott, MD, an oncologist and principal at Cardinal Health Specialty Solutions in Dublin, Ohio, said. Cardinal Health Specialty Solutions developed the oncology clinical pathway program in partnership with CareFirst BlueCross BlueShield, which engaged

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

providers across its network to participate. The program was initially developed in 2008 and characterized as the first oncology clinical pathway program launched by a major regional insurer “across its entire network of disparate providers.” Cost-efficacy data has been presented previously, but this most recent study was the most ambitious. In the study, costs were compared between 2,424 oncology patients included in the pathways program and 1,490 oncology patients treated by physicians in a similar geographic area but not in the CareFirst network. The control

patients were retrospectively drawn from a database maintained by a third party (Truven Health Analytics MarketScan). The groups were balanced by propensity scores weighted for relevant variables, such as primary diagnosis and demographics. Additionally, boosted decision tree models were used to control for nonlinearities and interactions. The primary end point was the sum of cancer costs for 270 days after a patient’s first chemotherapy treatment, which was expressed as a treatment coefficient between the groups. The study showed that cost was reduced by

an estimated 15% for those in the pathways program. The secondary study end point—hospital admissions over the same period—demonstrated an estimated 7% reduction. Both advantages persisted across a broad range of sensitivity tests in which cost assumptions were altered, although the magnitude of the advantage was diluted in some boosted decision tree models. A reduction in the number of drug combinations used for patients in the clinical pathways program was one major difference between the two groups. Although reductions in these combinations were

Visit

ClinicalOncology.com Late-brea Late brea breakin ak kin k ng Newss Links to O Other ther Therapeutic Areas

Free CME Medical di l Educa Education d tion i Archives i Most M ost l Popular A Articles rticles & d Reade Reader C Co Comments omments e ts Tabbed Navigati Navigation ion ion

Educational ucational Reviews R i

Opti mize d for wide scr disp een lays

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

seen for both groups over the four-year period included in the study, the decline was steeper among patients in the clinical pathways program. Not surprisingly, there was also substantially less variability in the lines of treatment among patients treated in the pathways program relative to those who were not. In theory, clinical pathways in medicine have the potential to lower costs and improve quality of care by ensuring that patients receive evidence-based treatment that offers the most favorable risk–benefit balance. However, not everyone is convinced that these track

together. In a separate symposium at the 2013 ASCO meeting that dealt with physician payment reform, there seemed to be a greater willingness to accept that clinical pathways improve quality of care rather than that they reduce costs. “No one has really shown that clinical pathways save money,” said Steven Mamus, MD, the founder of Cancer Center of Sarasota in Sarasota, Fla. Although he said more evidence is needed to show that clinical pathways reduce costs even as they improve quality, Dr. Mamus also suggested that the whole issue diverts attention from the steady and persistent

rise in drug costs that underlies health care cost increases, thereby misdirecting attention toward physician reimbursement for cost savings. “In terms of our particular area in south Florida, we have done analyses in HMOs that include cost and quality and have seen absolutely no impact,” Dr. Mamus said. Although he did not oppose clinical pathways as a tool for improving either quality of care or lowering costs, he questioned whether this approach has been overemphasized. However, several experts believe that cost data will eventually show savings

Read Clinical Oncology News Anywhere, Anytime! Download the iPad App here.

from clinical pathways. Responding to Dr. Mamus, Jeffery Ward, MD, of the Swedish Cancer Center in Edmonds, Wash., suggested that “we really have not had good studies of value-based pathways” as opposed to pathways focused solely on quality. Noting that these types of studies are being initiated now, he believes that these show promise for lowering costs. —Ted Bosworth Dr. Scott reported that he owns stock in and is employed by Cardinal Health. Dr. Mamus had no relevant disclosures.

ASCO Releases Second “Choosing Wisely” List

he American Society of Clinical Oncology (ASCO) released its second “Choosing Wisely” list to improve the quality and value of oncologists’ care on October 25. The list—which targets cancer tests and treatments that are routinely performed despite a lack of evidence—was developed by ASCO’s Value of Cancer Care Task Force, which made the recommendations based on a review of current high-level clinical evidence. 1. Do not give anti-nausea drugs (anti-emetics) to patients starting on chemotherapy regimens that have low or moderate risk for causing nausea and vomiting. 2. Do not use combination chemotherapy (multiple drugs) instead of single-drug chemotherapy when treating an individual for metastatic breast cancer unless the patient needs urgent symptom relief. 3. Avoid using advanced imaging technologies—positron emission tomography, computed tomography and radionuclide bone scans— to monitor for a cancer recurrence in patients who have finished initial treatment and have no signs or symptoms of cancer. 4. Do not perform prostate-specific antigen testing for prostate cancer screening in men with no symptoms of the disease when they are expected to live less than 10 years. 5. Do not use a targeted therapy intended for use against a specific genetic abnormality unless a patient’s tumor cells have a specific biomarker that predicts a favorable response to the targeted therapy. For more information on ASCO’s Top Five list and the Choosing Wisely campaign, visit asco.org/topfive. —From an ASCO press release

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

SPIN AND BIAS continued from page 1

The researchers accrued a large number of patients, but only one-third were evaluable at six months (primarily because of attrition from death), and the study failed to achieve its primary end point. In the study’s conclusion, the researchers focused instead on the secondary observation that a lower percentage of patients in the memantine group had cognitive decline at six months, and clinicians would only have to treat nine people with memantine, a relatively benign intervention, to prevent one case of cognitive decline. Reports of the study that followed, including one in the National Cancer Institute’s Cancer Bulletin, stated that memantine would likely become the standard of care. Clinicians also should have paid attention to the wide 95% confidence interval (relative risk, 0.651.07). “This study is equally consistent with a 35% benefit from memantine or a 7% harm,” Dr. Glantz said. Generally, studies can be misleading because of random error (caused by unrepresentative sampling) or because of bias and confounding (caused by study design flaws). Clinicians can spot statistical mistakes, spin and bias by examining a study’s methodology, scrutinizing sample sizes, P values, confidence intervals, randomization strategies, patient characteristics and loss to follow-up. In determining a study’s reliability, clinicians should reflect on how a study influences their post-study conviction compared with their pretest conviction, Dr. Glantz said. He estimated that because roughly 10% of oncology drugs entering Phase III trials are ultimately approved for the proposed indication, 10% is a reasonable pretest conviction that a therapy will work in a Phase III study. Dr. Glantz analyzed three months of Phase III randomized trials comparing two treatments published in the Journal of Clinical Oncology. Of the 28 trials identified, 17 were not only statistically nonsignificant, but had confidence intervals that included the possibility of both clinically meaningful benefit and clinically meaningful harm. Thus, the studies were completely uninformative. Half of the remaining nine studies afforded a post-study

conviction of, at most, 60%. “They were statistically significant, but poorly powered. We are left with less than one in five studies that we have seen in the last three months in the JCO that we can really hang our hats on,” Dr. Glantz said. According to Gary Gronseth, MD, a professor and vice chair of neurology at the University of Kansas Medical Center in Kansas City, and an evidencebased methodologist for the American Academy of Neurology, one mistake that clinicians sometimes make is believing that the probability of having a disease decreases if a patient has a negative result from a test that has a sensitivity of, for example, 90%. “You can’t look at specificity and sensitivity in isolation,” he said. For diagnostic tests, sensitivity is the proportion of patients with the disease that the test is positive for, and specificity is the proportion of patients without the condition who have a negative result. “The trick to correct the flawed heuristic in your head is to add up the specificity and sensitivity. If they add up to 100%, the test is useless,” Dr. Gronseth said. The test for prostate-specific antigen (PSA) has a sensitivity of 91% and a specificity of 20%. The test is only slightly better than useless, but its widespread application wasn’t disastrous because prostate cancer is very prevalent, and prevalence affects predictive value. “The positive predictive value of the PSA test isn’t horrible, mainly because prostate cancer is so common, but you don’t get a lot out of the test,” Dr. Gronseth said. “With a positive PSA, you go from a 16% probability of prostate cancer in a population with this kind of prevalence to a 22% [post-test] probability.” The damage from using such a test is the false-positive results and the consequences that come from them. In analyzing medical literature, Dr. Gronseth said, some clinicians fail to recognize the effect that false positives can have on patients. Other studies may be faulty in not recognizing overdiagnosed patients—those who would have the same outcome whether or not they receive treatment. Dr. Gronseth also pointed out that researchers need to be cautious about studies that focus on relative measures of benefit instead of absolute numbers. This can inflate benefit. According to Ian Tannock, MD, PhD,

Any number of factors can bias a study’s results: statistical mistakes, small sample sizes, wide confidence intervals, unbalanced patient characteristics or loss to follow-up, among many others.

a professor of medicine and medical biophysics at the University of Toronto Princess Margaret Cancer Centre, in Ontario, Canada, clinicians should expect that a clinical trial has a primary end point that reflects benefit to patients and is explicitly defined in a study abstract, that an abstract should include a statement of major toxicity, and that the abstract’s concluding sentence should relate to the primary end point. “Unfortunately, many reports, both in high-level journals and at the ASCO meetings, do not meet these simple requirements,” Dr. Tannock said. In a recent study, Dr. Tannock and his colleagues searched PubMed to identify randomized trials of breast cancer that involved more than 200 patients and were published between 1995 and 2011 (Ann ( Oncol 2013;24:1238-1244, PMID: 23303339). In 59% of the 92 trial

reports, the abstract’s concluding statement used secondary end points to suggest benefit. One-third of the studies reported the frequency of grade 3/4 toxicities in the abstract. Positive results for the primary end point were associated with underreported toxicity. Dr. Tannock pointed out that the only two ways that a new treatment benefits a patient are by helping patients live longer or live better. “End points such as tumor response show biological activity, but are poorly correlated with survival,” he said. A 2008 study that surveyed adjuvant breast cancer trials from 1996 to 2006 found that early differences in disease-free survival (DFS) predict for much smaller, if any, differences in overall survival (OS; Ann Oncol 2008;19:481486, PMID: 18029973). “We have a huge problem in the literature with surrogate end points,” Dr.

Clinical Oncology News TWEETS! Follow us @ClinOncNews And send your Twitter handle to managing editor Gabriel Miller at gmiller@mcmahonmed.com so we can follow you.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

Tannock said. “As long as the FDA and EMA [European Medicines Agency] allow registration of drugs on the basis of surrogate end points, we are going to have this continuous problem.” He said some clinicians may argue that BOLERO-2 proves that exemestane plus everolimus (Afinitor, Novartis) should be used for postmenopausal women with hormone receptor–positive breast cancer who have progressed on a nonsteroidal aromatase inhibitor, but the combination hasn’t been proven to improve OS, and it increases adverse events (AEs; N Engl J Med 2012;366:520-529, PMID: 22149876). Twenty-four percent of patients receiving the combination therapy discontinued the trial because of serious AEs or withdrawn consent. Clinical trials often don’t provide an accurate assessment of a drug’s toxicity. “To get into a clinical trial, you need to be an Olympic athlete with cancer,” he said. “We are highly selective, yet we apply those results to people who have all sorts of other comorbidities.” A recent study concluded that 58% of potentially fatal AEs are not in the initial FDA drug label and 39% are not reported in any published randomized trial (J ( Clin Oncoll 2009;29:174-185, PMID: 21135271). Many trials detect trivial differences that are statistically, but not clinically, significant. These small differences in treatment outcomes may disappear—and toxicities increase—when a treatment is used in the general population. When clinicians read a study, they should ask themselves how trial results fit with other study results and clinical experience, and whether the results are relevant to their patients. Doctors also need to be on guard to detect intentional spin. For example, Dr. Tannock said, the ATAC (Arimidex,

‘To get into a clinical trial, you need to be an Olympic athlete with cancer. We are highly selective, yet we apply those results in people who have all sorts of other comorbidities.’ —Ian Tannock, MD, PhD Tamoxifen Alone or in Combination) trial group has published roughly 30 papers concluding that aromatase inhibitors (AIs) are superior to tamoxifen for postmenopausal women with estrogen receptor–positive breast cancer, based on an

end point of recurrence-free survival. “I cannot find a single plot of overall survival in that data,” Dr. Tannock said. The cynic in him thinks that perhaps AstraZeneca, the maker of Arimidex, may have had some influence in the reporting of

studies, and perhaps the survival curves of the patient groups are superimposable. A meta-analysis, he said, shows the curves are identical (J ( Clin Oncol 2010;28:509-518, PMID: 19949017). In other words, “newly approved” does not always mean “new and improved.” —Kate O’Rourke Dr. Glantz disclosed receiving honoraria and research funding from Enzon, and relationships with the American Academy of Neurology and the American Association of Neurological Surgeons. Drs. Gronseth and Tannock had no relevant disclosures.

SEND US YOUR NEWS Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication. Write to managing editor Gabriel Miller at gmiller@ mcmahonmed.com

RESEARCH Advancing Genomic Medicine To Create Precision Therapies.

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

MRI Use Common, But Not Always Evidence-Based National Harbor, Md.—In recent years, clinicians have increasingly ordered magnetic resonance imaging (MRI) for breast cancer patients; however, evidence for the practice is not conclusive. At the Society of Surgical Oncology annual meeting, experts debated the ever-expanding use of MRI in breast cancer management. Sarah McLaughlin, MD, an assistant professor of surgery at Mayo Clinic in Jacksonville, Fla., said MRI use is increasing for many reasons. In addition to screening mammography, MRI is now recognized as an important screening tool in women at high risk for breast cancer, especially those with a genetic mutation predisposing them to breast cancer or an estimated lifetime risk for breast cancer greater than 20%. In these populations, mammography alone has a low sensitivity, particularly in women with dense breasts, young women and BRCA carriers, and it provides limited visualization of the far medial and posterior breast. Furthermore, only 25% to 40% of lesions detected on mammogram are positive at biopsy, Dr. McLaughlin said. In a meta-analysis of 11 prospective, nonrandomized studies involving 8,266 patients, MRI detected more breast cancers than mammography and had a sensitivity nearly 2.5 times greater than mammogram alone (75% vs. 32%; Ann Intern Med d 2008;148:671-679, PMID: 18458280). Combined mammogram/MRI had the highest sensitivity: 84%. All 11 studies, however, evaluated women deemed highrisk and therefore the data should not be generalized to women who have an average or low risk for breast cancer. Dr. McLaughlin said MRI has a broader specificity compared with mammography (75%-99% vs. 93%-99%) and a higher callback rate for further testing. Although many of the false-positives can be resolved without biopsies, approximately 3% to 15% of women having an MRI will require biopsy as a result of an MRI finding. MRIs also are more costly than mammography, ranging from $1,000 to $4,000. According to the American Cancer Society (ACS) guidelines, scientific evidence supports annual MRI as an adjunct to mammography in women who have BRCA1/2 mutations, first-degree relatives of a BRCA mutation carrier or a lifetime breast cancer risk greater than 20%. From a consensus-based standpoint, annual MRI screening is recommended for PTEN N and TP53 mutation carriers and their first-degree relatives, and patients who received chest radiation before age 30. National Comprehensive Cancer Network guidelines incorporate these ACS recommendations. Determining which patients are at high

risk can be difficult. The Tyrer-Cuzick, BRCAPPRO and Claus statistical models, for example, rarely agree on who is highrisk (Cancer Epidemiol Biomarkers Prev 2013;22:146-149, PMID: 23093547). Clinicians need to recognize the limitations of the different models, Dr. McLaughlin said. Finally, the timing of the MRI in relation to a woman’s menstrual cycle remains important, as significantly less background enhancement is present if clinicians perform MRIs between days 7 and 20 of the menstrual cycle. In BRCA mutation carriers, performing annual MRIs between the ages of 25 and 30, and then alternating MRI and mammography at six-month intervals after age 30 appears to be the most cost-effective screening approach, although this remains controversial (Cancer 2012;118:2021-2030, PMID: 21935911).

concluded that preoperative MRIs had no effect on positive margin rates (Ann ( Surgg 2013;257:249-255, PMID: 23187751). In a Surveillance, Epidemiology, and End Results/Medicare database study of 33,775 invasive nonmetastatic disease patients having initial breast conservation surgery, despite an increasing use of MRI and a massive increase in localization, the re-excision rate and conversion to mastectomy more than doubled from less than 9% to 18% (SSO 2013 meeting; poster 36). “MRI is more sensitive and more accurate than other modalities and nobody disputes that, but it appears that it is of little utility in selecting patients for breast conservation therapy versus mastectomy, at least in the routine preoperative setting,” Dr. Bleicher said. “MRI does not help surgeons achieve negative margins,

‘There is no evidence or suggestion that MRI can improve survival after breast cancer.’ —David McCready, MD Few clinicians question that MRI has superior sensitivity. An analysis of 12 studies demonstrated that 8.2% to 40% of cancers detected on MRI are not detected with other modalities (CA Cancer J Clin 2009;59:290-302, PMID: 19679690). But does increased sensitivity enhance patient selection for breast conservation surgery? Richard Bleicher, MD, a co-leader of the breast service line and an associate professor of surgical oncology at Fox Chase Cancer Center in Philadelphia, said it does not. As evidence, he pointed to two randomized controlled trials, COMICE (Comparative Effectiveness of MR Imaging in Breast Cancer) and MONET (MR mammography of Nonpalpable Breast Tumors), that prospectively randomized breast cancer patients to MRI or no MRI. COMICE involved 1,623 patients and examined the cost-effectiveness of contrast-enhanced high-field MRI in women with primary breast cancer scheduled for wide local excision (Health ( Technol Assess 2010;14:1-182, PMID: 20025837). It showed that MRI did not reduce reoperation rates or reduce local recurrence-free interval rates, but did improve tumor localization. MONET, a 418-patient trial examining preoperative MRI and surgical management in patients with nonpalpable breast cancer, found that patients receiving an MRI had a higher re-excision rate (34% vs. 12%; P<0.008; Eur J Cancer 2011;47:879-886, PMID: 21195605). A recent meta-analysis that included two randomized trials and seven comparative cohorts also

and it increases the mastectomy rate.” MRI is also no help to clinicians who use neoadjuvant chemotherapy. “There are no prospective data available regarding the use of MRI to select your patients receiving neoadjuvant chemotherapy for breast conservation therapy,” said Elizabeth Mittendorf, MD, an assistant professor of surgical oncology at the University of Texas MD Anderson Cancer Center in Houston. The only study to attempt to evaluate this was a 34-patient, nonrandomized study ((Eur J Surg Oncol 2005;31:1129-1134, PMID: 15905068). Dr. Mittendorf said MRI was clearly good at assessing response to chemotherapy, but its effect on long-term survival is unclear. The ACRIN 6657/I-SPY trial demonstrated that MRI imaging findings are stronger predictors of pathologic response to neoadjuvant chemotherapy than clinical assessments, with the greatest advantage observed with the use of volumetric measurement of tumor response from the first MRI obtained after the initial cycle of anthracycline ( (Radiology 2012;263:663-672, PMID: 22623692). Lack of an early response may prompt clinicians to consider changing a regimen or proceeding right to surgery, but more data is needed to determine how some of the trial end points affect survival, Dr. Mittendorf said. Another study in 746 patients, conducted by the Translational Breast Cancer Research Consortium, concluded that the relatively low negative predictive value of MRI following neoadjuvant systemic therapy does not support using

AT A GLANCE Breast Imaging Sensitivity, %

MRI

Mammography

Specificity, % 75-99

93-99

Cost

$250-$350

$1,000$4,000

MRI radiographic complete response alone to accurately identify patients who can safely avoid surgery (Cancer 2013;119:1776-1783, PMID: 23436342). It also found that performance of MRI varied by breast cancer subtype, with the most benefit seen in triple-negative and HER2-positive phenotypes. According to David McCready, MD, a professor of surgery and the chair in breast surgical oncology at the University of Toronto in Canada, a literature review shows that MRI provides a 3% to 4% increased incremental detection rate of contralateral breast cancers. “Sixty-five percent of the tumors found were invasive,” he said. “Roughly a quarter of the cancers were more than 1 cm.” However, he pointed out, in recent years, clinicians have realized that not all contralateral breast cancers detected by MRI become clinically relevant. Dr. McCready agreed that the evidence supporting the use of MRI in breast cancer was weak. Of five published cohort studies evaluating the effect of MRI on local recurrence, four demonstrated that it had no effect. A fifth study concluded that MRI decreased local recurrence and metachronous cancer but, according to Dr. McCready, clinicians should take this study “with a grain of salt” because it had short follow-up and did not adjust for tumor size or other prognostic variables (Eur ( Radiol 2004;14:1725-1731, PMID: 15248080). “Preoperative breast MRI is not associated with any consistent improvement in three- to eight-year local recurrence rates after breast-conserving surgery and radiation,” Dr. McCready said. “There is no evidence or suggestion that MRI can improve survival after breast cancer.” So why, with evidence lacking, did a study in press find that 60% of surgeons currently use MRI? Surgeons, said Dr. McCready, are used to optimal pre-op imaging, don’t want second-guessing if margins are positive, and don’t want someone else to order it postoperatively and find something. —Kate O’Rourke Drs. McLaughlin, Bleicher, Mittendorf and McCready have no relevant disclosures.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

In Community Practice...

Balancing Between ‘Rational’ and ‘Rationed’ Care Washington—Balancing personalized cancerr care with the need to lower health care costs reliess on a number of factors, including thinking rationally about cancer treatments, better educating patients abou ut their options, and educating payers, said a panel of onccology experts at the Association of Community Cancer CenC ters’ (ACCC) national meeting. In a discussion of “rational versus rationeed care,” Jennie Crews, MD, the medical director off PeaceHealth St. Joseph Cancer Center in Bell-ingham, Wash., said the words “rationing” and d “rational” both come from the same Latin root:: reason, yet have very different connotations: “I think the two can really be married together. If you look at the history of oncology, I think we haave done that. We’ve limited the care based on very rrational and evidence-based choices.” There are a few theories about how to reeduce spending on oncology, said Peter Bach, MD D, the director of the Center for Health Policy and d Outcomes at Memorial Sloan-Kettering Cancer Center in New York City. One is to shift the risk for discretionary spending to oncologists. A payer would provide an oncologist with a lump-sum payment to cover all costs for a typical patient with breast cancer, for example, and the oncologist would then be responsible for achieving high-quality care without overspending. Another theory calls for removing physicians’ financial incentive to spend health care dollars. A third idea, being employed at his hospital, is to make treatment decisions piece by piece while considering cost, Dr. Bach said. For example, Memorial SloanKettering decided not to stock the drug ziv-aflibercept (Zaltrap, Sanofi/Regeneron) in its formulary for patients with advanced colorectal cancer because it was more than twice the price of a similar medicine, bevacizumab (Avastin, Genentech/Roche). “We don’t know how to deal with the big problem, and we don’t want to shift risk maybe, but we are going to more diligently go through and say ‘we’re not going to do this thing,’ like ordering a PET [positron emission tomography] scan for someone with a low risk for metastatic prostate cancer,” Dr. Bach said. Rational care must include both technical advances like genomics and information technology, and adaptive changes like redesigning clinical trials and limiting endof-life care, Dr. Crews said: “It costs a fortune to conduct large, Phase III studies, and we end up with information that applies to a broad spectrum of people but only benefits perhaps a small group of those people.” Rational care also means that payers should fund genetic tests and broader use of cancer drugs for common cellular pathways, she said.

The words ‘rationing’ and ‘rational’ both come from the same Latin root: reason, yet have very different connotations.

There also is confusion about what spending needs to happen, said ACCC immediate past president George Kovach, MD, the medical director of the Genesis Cancer Center in Davenport, Iowa. He estimated that there is up to 60% waste in health care spending because of duplicate services and defensive medicine. “We waste money on diagnostic and follow-up services that may not improve outcomes,” Dr. Kovach said. Evidence-based guidelines provided by organizations like the National Comprehensive Cancer Network are “perfect for controlling overutilization,” he said. He called for an expansion of guidelines, including those for essential treatment drugs, patient evaluation and follow-up, and issues related to end-of-life care. Dr. Kovach also expressed concern that responsibility for health care decisions stay with health care professionals, not insurance company representatives: “The key is that we make the treatment decisions; that’s the rational care. Rational care will ration costs.” To reduce health care costs, providers also must do a better job educating patients about their treatment options, said Eric Cohen, RN, BSN, a program manager of patient and family education for Inova Health Systems’ Life with Cancer Program, in Fairfax, Va. From his experience, “people choose their treatments not so much on the risks versus benefits, but from a lack of understanding of how that treatment is going to affect them and their lives, and we don’t consider the context of their whole life enough.” Patients tend to get “emotionally stuck in a place where they cannot make a rational decision,”

M Cohen said, and tend to choose the Mr. most expensive treatment, the one that will extend their lives for a short time or have the fewest side effects, without perspective. p Patient stress and distress also contributte to inflating health care costs, he said. Cou unseling patients and lowering their stress can lead to fewer triage calls, less stress on the health h care team and less usage of pain and nausea medications. “Part of ou ur responsibility as providers is really managing pattient expectations,” Dr. Crews said. “We hand them tons to of data [about treatments and side effects] and we have limited time to discuss them. Decision-making tools will be key. A lot of patients do things because of our urging when perhaps it is not what they really want to do.” Doing distress screening and survivorship care planning at the time of diagnosis is a better way of partnering with the patient and family, Mr. Cohen added. At his hospital, a nurse and a social worker meet with patients, answering questions about potential treatments and what it means if patients opt out of those treatments. “That, in the long run, will lower costs,” he said. Dr. Kovach suggested fully explaining the risks and benefits of treatments to help manage patient expectations: “The more you educate patients on the absolute outcome, not relative outcome, the better you can provide care.” Clinical pathways to help physicians choose appropriate cancer treatments offer some help but need to be able to be tailored to individuals, he said. Dr. Crews added that getting multiple providers in agreement on treatment options can be tricky because physicians like to make their own decisions. Most health care settings that have employed them successfully have used some “brute force,” incentives or peer pressure, she said. The bottom line, Dr. Kovach said, is “we have to pay for the treatment that’s needed; get rid of waste; try to come to a consensus on the first-, second- and third-line treatment; and have an educated patient population.” —Karen Blum

TOP STORIES at ClinicalOncology.com Most-Read Stories

Most-Emailed Stories

340B: Helping Patients or Enriching Hospitals? Juggernaut CLL/MCL Drug, Ibrutinib, En Route to FDA Approval Enrollment in Ponatinib Clinical Trials Halted Bruce D. Cheson, MD: How I Manage Follicular Lymphoma

340B: Helping Patients or Enriching Hospitals? Chemo for Smoldering Multiple Myeloma? Not Yet! Juggernaut CLL/MCL Drug, Ibrutinib, En Route to FDA Approval No Advantage With Asymptomatic Screening for Ovarian Cancer

CURRENT PRACTICE

The

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

Tumor Board

Breast Lump Following Previous Augmentation Welcome to the December issue of The Tumor Board

his column focuses on the case of a patient with a malignant left breast mass, presented by Shali Gal, MD, a surgical oncologist at Mount Sinai Medical Center Comprehensive Cancer Center in Miami. I am very honored to have Juan C. Paramo, MD, an attending surgeon at Mount Sinai Medical Center Comprehensive Cancer Center, as our guest expert, providing his opinion for this patient’s treatment. Also, check out the discussion of the challenge from the July issue and take the new challenge posed in this issue! I hope our readers will enjoy this case. I welcome all opinions and further comments on this topic, as well as greatly encourage suggestions or submission of cases for future issues.

Conrad Simpfendorfer, MD Editor, The Tumor Board Hepato-pancreato-biliary and Transplant Surgeon Cleveland Clinic Weston, Florida

Case

40-year-old woman who had never undergone a mammogram presents with a fourmonth history of a lump that she felt on the outer aspect of her left breast. She was otherwise asymptomatic. Ten years prior, she had breast augmentations with subpectoral saline implants. Two years ago, she underwent Benelli lift mas- Shali Gal, MD topexies and exchange of the saline for silicone implants. She had no personal or family history of cancer. Workup with mammogram revealed a 2.9-cm mass with irregular margins in the posterior left upper outer quadrant at 2 o’clock. Breast ultrasound showed a 1.7 × 1.6-cm ill-defined solid mass with abnormal color flow, which corresponded to the mammographic finding. The final interpretation was suspicious (Breast ImagingReporting and Data System category 4). She therefore underwent ultrasound-guided core biopsy revealing a grade 3, triple-negative (estrogen receptor–, progesterone receptor– and HER2-negative) infiltrating ductal cell carcinoma. Magnetic resonance imaging (MRI) results of the breast were obtained revealing the known 2.9-cm biopsy-proven malignancy in the posterior left breast, with no other suspicious findings bilaterally and with intact subpectoral silicone implants (Figure 1). Her BRCA testing was negative for any mutations (Figure 2).

How would you treat this patient?

reast conservation using oncoplastic techniques followed by radiation therapy is an option for this patient. This is based on the size of the lesion in relation to the size of her breast, the lack of multifocal/multicentric disease, the distance from the tumor to the implant, and the fact that she does not have a BRCA mutation. Although it is a topic of debate, we Juan C. used breast MRI in this case to exclude Paramo, MD multicentric as well as contralateral disease. Also, if a neoadjuvant approach were considered, the MRI would allow adequate evaluation of the size and location of the tumor. Finally, breast MRI is considered the standard for evaluation of implant integrity. Because this patient’s cancer is triple-negative, she will require chemotherapy as part of her treatment. A neoadjuvant approach could be considered, as this may

Figure 1. MRI of the breast revealed the known 2.9-cm biopsy-proven malignancy in the posterior left breast, with no other suspicious findings bilaterally and with intact subpectoral silicone implants.

facilitate the surgery by decreasing the size of the tumor and will provide information about the in vivo response to chemotherapy. However, if there is progression during therapy, breast conservation may no longer be a feasible option. In patients with prior breast augmentation, other issues need to be considered to provide the best aesthetic outcome without sacrificing oncologic principles.1,2 Some reports have suggested that because of the smaller breast volume of women who have undergone prior breast augmentation, it may be more difficult to obtain tumorfree margins and acceptable cosmesis with a partial mastectomy. Additionally, because breast-conserving therapy requires postoperative radiation, there is concern for possible unfavorable cosmetic results, capsular contracture and possible reoperation for revision or even implant removal. In recent years, especially in younger women, there has been a trend toward choosing mastectomy rather than

Figure 2. BRCA testing was negative for any mutations.

breast conservation regardless of BRCA status. This may be due to the increased use of breast MRIs; social media, blogging and the Internet; the peace of mind that a woman feels with a perceived decreased fear of recurrence; improvements in reconstructive techniques; and an increased acceptance of mastectomy by the general public. As breast surgery continues to evolve, initially skin-sparing and now nipple-sparing mastectomy (NSM) have gained popularity in the surgical oncology community.3-5 Numerous articles have discussed the safety and efficacy of NSM in carefully selected women with breast cancer. These patients should have well-circumscribed tumors, a nipple-to-tumor distance greater than 2 cm and no evidence of axillary node metastasis. The carcinoma should have no lymphovascular invasion, and the retroareolar sampling during surgery should show no evidence of malignancy.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

gastric perforation. The gastrostomy was repaired. The surgeon also described a large vascular mass in the lesser sac, which displaced all the surrounding organs.

Case Challenge From the July Issue

36-year-old man presented to an outside hospital with abdominal distension, nausea and vomiting. A noncontrast computed tomography scan showed a 16-cm pancreatic cyst (Figure 1). The patient had an endoscopic ultrasound that reported a complex cyst with thick fluid and solid components. Fine-needle aspiration reported blood and no malignancy. The patient had an endoscopic cystogastrostomy stent placement.

A follow-up magnetic resonance imaging (MRI) of the abdomen reported a 16.0 × 19.8 × 18.1-cm thick-walled, complex mass-versus-collection (Figures 2 and 3). The mass abutted and partially compressed the inferior margin of the left lobe of the liver. This mass/collection demonstrated mass effect on the stomach and pancreas. Figure 1. A noncontrast CT scan showed a 16-cm pancreatic cyst.

The patient complained of abdominal discomfort, nausea and early satiety. The patient reports no history of pancreatitis or acute abdominal pain.

What is your differential diagnosis?

The following day the patient developed peritonitis and pneumoperitoneum and was taken to surgery for emergency laparotomy. During surgery, Figures 2 and 3. A follow-up MRI of the abdomen the previously placed reported a 16.0 x 19.8 x 18.1-cm thick-walled, complex mass-versus-collection. cystogastrostomy stent was found dislodged and there was contamination of the peritoneal cavity secondary to

How would you further evaluate and treat this patient?

Reply to Case Challenge

he patient underwent laparotomy with excision of a 16-cm lowgrade gastrointestinal stromal tumor (GIST). The tumor was easily dissected from the surrounding tissues and did not invade any of the surrounding organs. It originated from the posterior greater curvature of the stomach, and required only a partial gastrectomy. The patient’s postoperative course was uneventful.

Case Challenge for the Next Tumor Board

44-year-old woman from the Bahamas presented two years ago with right-sided abdominal pain. A computed tomography (CT) scan confirmed a large 10.5 × 10 × 8-cm infrapancreatic retroperitoneal mass with multiple hypodense masses in the liver suggesting metastatic lesions (Figure 1). A biopsy of the lesion confirmed the mass as GIST. The patient was started on imatinib (Gleevec, Novartis) two years ago. However, imatinib was discontinued two months ago by her oncologist to review the response. Her current CT scan shows that the mass has decreased in size to 6 cm (Figure 2). The patient remains asymptomatic with a good appetite. An endoscopy has been scheduled.

Should imatinib be stopped? How long does the patient need to take imatinib? Should the primary tumor—an infrapancreatic retroperitoneal mass—be resected?

Figure 1. CT scan confirming a large 10.5 × 10 × 8-cm infrapancreatic retroperitoneal mass with multiple hypodense masses in the liver.

Figure 2. CT scan shows that the mass has decreased in size to 6 cm.

Answers to this Case Challenge will be featured in the next Tumor Board column.

One of the main concerns with NSM is the known complication of partial- to full-thickness nipple necrosis, which can occur in about 2% to 9% of patients, and can lead to nippleareolar complex loss. This can be even higher in a previously augmented breast, where the blood supply already may have been compromised, and more so in cases of additional previous mastopexies. The dissection needs to be done with meticulous attention to consistent flap thickness. As far as a contralateral prophylactic NSM, management needs to be individualized

Figure 3. Patient two months after surgery with no evidence of skin flap or nipple necrosis. Photo courtesy of Gary Rosenbaum, MD.

and should consider the risk for carcinoma in the contralateral breast as well as the patient’s preference, including the desire for breast symmetry and the fear or potential anxiety that may be provoked by close follow-up if contralateral mastectomy is decided against. Based on all of the above, and after a thorough discussion with the patient, she was treated with bilateral NSMs, left sentinel node biopsies, reconstruction with bilateral silicone implant exchange and placement of a port. The final pathology revealed a 2.8-cm infiltrating ductal cell carcinoma and three negative sentinel nodes. She is currently two months postoperative, doing well

with no evidence of skin flap or nipple necrosis, and has started adjuvant chemotherapy (Figure 3).

References 1.

Tang SS, Gui GP. A review of the oncologic and surgical management of breast cancer in the augmented breast: diagnostic, surgical and surveillance challenges. Ann Surg Oncol. 2011;18:21732181, PMID: 21311984.

2. McCarthy CM, Pusic AL, Disa JJ, et al. Breast cancer in the previously augmented breast. Plast Reconstr Surg. 2007;119:49-58, PMID: 17255656. 3.

Alperovich M, Tanna N, Samra F, et al. Nipple-sparing mastectomy in patients with a history of reduction mammaplasty or mastopexy: how safe is it? Plast Reconstr Surg. g 2013;131:962-967, PMID: 23629078.

4. Mallon P, Feron JG, Couturaud B, et al. The role of nipple-sparing mastectomy in breast cancer: a comprehensive review of the literature. Plast Reconstr Surg. 2013;131:969-984, PMID: 23629079. 5. Piper M, Peled AW, Foster RD, et al. Total skin-sparing mastectomy: a systematic review of oncologic outcomes and postoperative complications. Ann Plast Surg. 2013 Mar 11. [Epub ahead of print], PMID: 23486127.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

Expert Insights From Massachusetts General Hospital Cancer Center Each month, Clinical Oncology News summarizes findings from several recently published, important studies and then asks clinicians from a top cancer center to offer their perspectives. The cancer center providing the expert commentaries changes every three months. Cancer centers are chosen based on reputation, availability and regional diversity, and we seek to have a mix of academic institutions together with regionally important hospitals with expertise in cancer care. We hope you find this Reviews & Commentaries section to be a valuable tool.

Dose-Dense Regimen Improves Ovarian Cancer Survival From Lancet Oncology

ong-term follow-up results of dosedense paclitaxel and carboplatin treatment for advanced epithelial ovarian cancer continue to show favorable progression-free survival (PFS) and overall survival (OS), besting the traditional chemotherapy regimen. The authors of this study, all based in Japan, suggested that the dose-dense approach might represent a new standard of care for first-line therapy for these patients. The JGOG (Japanese Gynecologic Oncology Group) 3016 study is a Phase

III, randomized controlled clinical trial that enrolled women from 85 study centers in Japan. Women diagnosed with stage II-IV epithelial ovarian cancer, primary peritoneal cancer or fallopian tube cancer were eligible. Patients (N=631) were treated over six 21-day cycles with either conventional therapy (n=319), which included carboplatin area under the curve (AUC) 6 mg/ mL per minute and 180 mg/m2 paclitaxel administered in a three-hour IV infusion on day 1 of each cycle, or the dosedense treatment (n=312), consisting of the same dosage of carboplatin plus 80

EXPERT INSIGHT Michael J. Birrer, MD, PhD Director of Medical Gynecologic Oncology Director, Gynecologic Oncology Research Program Massachusetts General Hospital Cancer Center Boston, Massachusetts

he JGOG 3016 study comparing standard carboplatin plus paclitaxel every three weeks with carboplatin plus weekly paclitaxel (dose-dense) for the treatment of newly diagnosed, advanced-stage ovarian cancer was first reported in 2009, and demonstrated a striking prolongation of PFS along with a dramatic improvement in three-year survival for the dose-dense regimen. This recent paper is the long-term follow-up of this study and again demonstrates significant improvement in OS in the dose-dense cohort. Although the initial results did not establish the dose-dense regimen as the standard of care, it did present an additional therapeutic option for these patients. The long-term follow-up strengthens that recommendation. Of interest, the mechanism for this advantage remains unclear. The total dose of chemotherapy was in fact lower

in the dose-dense arm compared with that of the standard regimen. Significant numbers of patients in the dosedense arm required dose delays and reductions with a higher number discontinuing treatment altogether. This strongly suggests the weekly delivery with its metronomic approach is important for effectiveness, perhaps by targeting the blood vessels. This may not extend to dose-dense therapy for platinum because the Italian MITO-7 (Multicenter Italian Trials in Ovarian Cancer) study, which compared thrice-weekly carboplatin (AUC 6) and paclitaxel 175 mg/m2 with weekly carboplatin (AUC 2) plus weekly paclitaxel 80 mg/m2, did not show a PFS advantage.1 General acceptance of this regimen has been somewhat cautious; there have been multiple concerns about the trial, which has tempered its interpretation and implementation. The trial

mg/m2 of paclitaxel in a one-hour IV infusion on days 1, 8 and 15. In 2009, Noriyuki Katsumata, MD, and colleagues published a three-year summary of findings that showed the dose-dense weekly paclitaxel therapy improved PFS. The concluding five-year follow-up for this study was recently published by the same authors in Lancet Oncology (2013;14:10201026, PMID: 23948349). For the current review, median follow-up was 76.8 months. Of the 631 original enrolled patients, 426 experienced disease progression or died; 307 deaths had been

reported. Outcomes were significantly better in the dose-dense group. Median PFS for the dose-dense group was 28.2 months (95% confidence interval [CI], 22.3-33.8) and was 17.5 months (95% CI, 15.7-21.7) for the conventional treatment group. Median OS was 100.5 months (95% CI, 65.2-∞) in the dose-dense treatment group and 62.2 months (95% CI, 52.1-82.6) in the conventional treatment group (hazard ratio, 0.79; 95% CI, 0.63-0.99; P=0.039). Patients with residual disease of at least 1 cm showed the greatest benefit from the dose-dense treatment.

General acceptance of this regimen has been somewhat cautious; there have been multiple concerns about the trial, which has tempered its interpretation and implementation. itself was rather small (N=631) compared with most randomized Phase III trials. Furthermore, there has been a concern about toxicity. The dosedense arm was considerably more toxic, especially related to myelosuppression and anemia (neuropathy was similar across both arms). In that context, there has been concern about ethnic differences between Asian and white populations, which could mask even worse toxicities. Finally, the additional clinic visits raised both convenience and cost issues, particularly in areas where patients have to travel long distances for treatment. Based on these concerns, confirmatory trials will be important. GOG262 is a randomized Phase III trial comparing paclitaxel every three weeks with dose-dense paclitaxel in advancedstage ovarian cancer. This trial also allows the use of bevacizumab as an option.2 This trial closed and its results should be available shortly. The ICON8 study is a three-arm trial comparing

carboplatin given every three weeks and dose-dense paclitaxel or dosedense carboplatin and paclitaxel with standard every-three-week therapy.3 The results of these studies will be critical to determining if dose-dense therapy will become the standard of care for up-front therapy for newly diagnosed, advanced-stage ovarian cancer.

References 1. Pignata S, Scambia G, Lauria R, et al. A randomized multicenter phase III study comparing weekly versus every 3 weeks carboplatin (C) plus paclitaxel (P) in patients with advanced ovarian cancer (AOC): Multicenter Italian Trials in Ovarian Cancer (MITO-7)—European Network of Gynaecological Oncological Trial Groups (ENGOTov-10) and Gynecologic Cancer Intergroup (GCIG) trial. J Clin Oncol. 2013;31(suppl): abstr LBA5501. 2. ClinicalTrials.gov Identifier: NCT01167712. 3. ClinicalTrials.gov Identifier: NCT01654146. Dr. Birrer disclosed a financial relationship with Roche.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

In BRCA, Tamoxifen May Reduce Contralateral Breast Cancer Risk From Journal of Clinical Oncology

recent review suggests that for patients who carry a BRCA1 or BRCA2 mutation with a first breast cancer, tamoxifen therapy may reduce the risk for a contralateral breast cancer (CBC). An international group of researchers, led by Kelly-Anne Phillips, MD, reviewed observational data from three international cohorts of women carrying BRCA1 and BRCA2 gene mutations. The study was designed to determine if the standard postsurgical treatment of tamoxifen for breast cancer in the

EXPERT INSIGHT Aditya Bardia, MBBS, MPH Hematology/Oncology Massachusetts General Hospital Cancer Center Boston, Massachusetts

he authors (Phillips, et al) report results from an observational cohort study looking at the association between tamoxifen use and risk for CBC among BRCA1 and BRCA2 mutation carriers. The analytical cohort for this study (N=3,627) comprised women with unilateral cancer who were BRCA1 or BRCA2 carriers and were enrolled in one of three cohort studies worldwide: the IBCCS (International BRCA1 and BRCA2 Carrier Cohort Study), the kConFab (Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer), and the BCFR (Breast Cancer Family Registry). The authors collected self-reported information on demographics, family history, tamoxifen use and breast cancer risk factors. Breast cancer incidence was ascertained by linkage to cancer registry. Those who had prior use of tamoxifen before their first breast cancer or those who had bilateral breast cancer at initial diagnosis (or within six months) were excluded from the analytical cohort. The authors analyzed the association between tamoxifen use and CBC incidence by Cox regression analyses, adjusting for various breast cancer risk factors and potential confounding factors. The authors observed that women taking tamoxifen (24% of BRCA1 carriers and 52% of BRCA2 carriers) had approximately one-third risk for breast cancer compared with those not taking tamoxifen (HR, 0.38 for BRCA1

general population would also benefit women who are BRCA mutation carriers. Personal and medical histories were reviewed for 1,583 women with the BRCA1 mutation and 881 with the BRCA2 mutation; all had at least one breast cancer diagnosis. Findings were published in the Journal of Clinical Oncology (2013;31:30913099, PMID: 23918944). CBCs occurred in 520 women (24% with BRCA1 and 17% with BRCA2). For BRCA1 mutation carriers treated with tamoxifen, the estimated hazard ratio [HR] was 0.38 (95% confidence interval [CI], 0.27-0.55; P<0.001); for

BRCA2 mutation carriers, the HR was 0.33 (95% CI, 0.22-0.50; P<0.001). In 44% of the patients studied, estrogen receptor (ER) status was recorded. The first breast cancer was ER-negative for 76% of BRCA1 mutation carriers and ER-positive for 77% of BRCA2 mutation carriers. Overall, 67% of ERpositive patients with breast cancer were administered tamoxifen (60% BRCA1 and 71% BRCA2) as were 17% of ER-negative patients with breast cancer (15% BRCA1 and 25% BRCA2). Study limitations included the fact that older, postmenopausal patients were more often given tamoxifen, whereas in

the study population 51% of the BRCA1 patients and 35% of the BRCA2 patients were younger than age 40 at the time of their first breast cancer. In addition, women treated with tamoxifen were also more likely to have received chemotherapy and undergone oophorectomy. The authors noted that many patients elect bilateral mastectomy at the time of the first breast cancer. Previous studies have suggested that tamoxifen reduces the risk for additional breast cancer in those who are ERpositive; this review showed a benefit in patients with either ER-positive or ERnegative status.

carriers and 0.33 for BRCA2 carriers). The observed risk reduction with tamoxifen was stronger for women who did not have oophorectomy compared with those who underwent oophorectomy for either BRCA1 or BRCA2 tumors. Interestingly, the results did not vary by hormone receptor (HR) status and the benefit was seen both for HR-positive and HR-negative tumors. This is an important study for several reasons. First, it illustrates the effectiveness of breast cancer prevention with tamoxifen, and highlights the importance of having a good chemoprevention discussion with patients. Despite data from multiple chemoprevention trials demonstrating that tamoxifen can reduce risk for breast cancer, less than 20% of women who are candidates for chemoprevention actually take tamoxifen.1 Second, as risk for CBC is higher among BRCA1 and BRCA2 carriers, this study suggests that tamoxifen potentially could be used to reduce the breast cancer risk in this population. So, are the study findings practicechanging? In other words, should we be routinely recommending tamoxifen for BRCA1 and BRCA2 carriers? Before we jump to conclusions, let us consider four issues. First, the study findings are based on a cohort study rather than a randomized trial and are thus subject to bias. For example, it is possible that women who took tamoxifen were more health-conscious in general (i.e., they had a healthy diet, participated more in exercise, etc.), all of which could reduce risk for breast cancer.2 Similarly, patients taking tamoxifen might have been more regular with follow-ups and mammograms and thus had disease detected earlier as ductal carcinoma in situ (DCIS). Because the authors only looked at incidence of breast cancer (not DCIS), they could have artificially seen a lower risk for breast cancer. There could be multiple other factors that were imbalanced

between tamoxifen users and nonusers that could skew the results. To the authors’ credit, they did adjust for a number of breast cancer risk factors in the multivariate analyses, but it is just not possible to adjust for all possible factors, and that is why randomized trials remain the gold standard for demonstrating efficacy of a therapy, including preventive therapy. Unfortunately, doing a well-designed randomized, placebo-controlled chemoprevention trial of tamoxifen among BRCA carriers is not practically feasible, as it would be difficult to accrue, would be very expensive, would require a large sample size with a long duration of follow-up and would be ethically challenging. In such a scenario, it is helpful to have at least one additional study with a separate cohort that confirms (or refutes) the observed study findings before they can be considered practice-changing. Second, a number of women with BRCA mutations opt for bilateral mastectomy up-front, and many undergo oophorectomy as well. The authors noted weaker benefit with tamoxifen for women who had oophorectomy, and thus possibly the risk–benefit ratio might not be favorable for this group. Third, the lack of differential benefit by the HR status is surprising, as tamoxifen has consistently been shown to reduce risk for HR cancers.3,4 The authors suggest a few potential biological hypotheses but this also could be due to the bias associated with observational study design or to lack of adequate power. Moreover, when the authors only looked at the prospective cohort (as opposed to the combined retrospective and prospective cohorts), the beneficial association of tamoxifen with reducing the risk for breast cancer was weaker and statistically not significant. Finally, the study does not shed light on the potential utility of the aromatase inhibitor exemestane, which is

an FDA-approved medication for chemoprevention among postmenopausal women and in general is safer and better tolerated than tamoxifen.4 So, while we wait for additional data and consensus opinions, how should we counsel our patients? I would recommend we be up-front with our patients about the data and the potential caveats. If a patient is interested in taking tamoxifen, by all means we should support the decision and monitor closely. On one hand, these discussions are lengthy, complex and should not be attempted in a rush. On the other hand, when done properly, these conversations are very meaningful and go a long way in fostering a strong doctor–patient relationship.

References 1. Ravdin P. The lack, need, and opportunities for decision-making and informational tools to educate primary-care physicians and women about breast cancer chemoprevention. Cancer Prev Res. 2010;3:686688, PMID: 20522798. 2. Li CL, Daling JR, Porter PL, et al. Relationship between potentially modifiable lifestyle factors and risk of second primary contralateral breast cancer among women diagnosed with estrogen receptor-positive invasive breast cancer. J Clin Oncol. 2009;27:5312-5318, PMID: 19738113. 3. Visvanathan K, Hurley P, Bantug E, et al. Use of pharmacologic interventions for breast cancer risk reduction: American Society of Clinical Oncology clinical practice guideline. J Clin Oncol. 2013;31:29422962, PMID: 23835710. 4. Goss PE, Ingle JN, Alés-Martínez JE, et al; NCIC CTG MAP.3 Study Investigators. Exemestane for breast-cancer prevention in postmenopausal women. N Engl J Med. 2011;364:2381-2391, PMID: 21639806. 5. Vogel VG, Costantino JP, Wickerham DL, et al; National Surgical Adjuvant Breast and Bowel Project. Update of the National Surgical Adjuvant Breast and Bowel Project Study of Tamoxifen and Raloxifene (STAR) P-2 Trial: Preventing breast cancer. Cancer Prev Res (Phila). 2010;3:696706, PMID: 20404000. Dr. Bardia reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

In Advanced Cancer, Dexamethasone Helps Ease Fatigue From Journal of Clinical Oncology

examethasone was shown to be more effective than placebo for the treatment of cancer-related fatigue (CRF) in patients with advanced disease, according to a new study. Although as many as one-third of oncologists report the use of steroid therapy for management of CRF at the end of life, there have been no previously published reports of results from a double-blind, randomized, placebo-controlled trial of dexamethasone for symptom control in these patients. Researchers based at the University of Texas MD Anderson Cancer Center in

Houston, and the Four Seasons Hospice in Flat Rock, N.C., tested steroid therapy in patients who had a life expectancy of at least four weeks and reported three or more treatment-related symptoms: fatigue, pain, nausea, loss of appetite, depression, anxiety or sleep disturbance. Based on the Edmonton Symptom Assessment Scale (scale of 1-10), enrolled patients reported an average intensity score of 4 or more in the past 24 hours, ensuring that study participants experienced moderate to severe symptoms. The study evaluated changes in the Functional Assessment of Chronic Illness-Fatigue (FACIT-F), a validated quality-of-life assessment tool.

EXPERT INSIGHT Mihir M. Kamdar, MD Director, Cancer Pain Clinic Massachusetts General Hospital Cancer Center Boston, Massachusetts

RF is a significant clinical problem that affects 70% to 100% of patients undergoing active treatment, more than 75% of those with metastatic disease, and can even persist into survivorship.1,2 Often underrecognized and undertreated, the effects of CRF on patient quality of life can be marked. In fact, many patients report that CRF causes distress levels greater than cancer-related pain and nausea.1

l-carnitine and erythropoietin have not shown benefit, and although some positive data has been seen for psychostimulants such as methylphenidate, many question the volume of benefit.1,5-7 In this multicenter, double-blind, placebo-controlled trial, Sriram Yennurajalingam, MD, and colleagues explored the potential benefit of corticosteroids on CRF in patients with advanced malignancy. Targeting the theory that

The results of this trial are encouraging given the scope and effects of cancer-related fatigue, and the lack of marked efficacy with any other pharmacologic agents. Despite the widespread effects that CRF has on the quality of life of individuals with cancer, there has been a paucity of effective treatments. Nonpharmacologic therapies such as exercise and cognitive-behavioral therapies (CBTs) have shown benefit in CRF, but robust data for pharmacologic interventions has been lacking.3,4 Agents such as selective serotonin reuptake inhibitors,

CRF is in part mediated by inflammatory cytokines, corticosteroids have been used anecdotally for CRF for quite some time, but until now large, highquality studies have been absent. Over the course of this 15-day trial, patients randomized to 4 mg of oral dexamethasone twice daily for two weeks showed significantly improved outcomes in fatigue based on the

Patients completed a baseline survey, and then did so again on days 8 and 15. Patients completed additional pain and psychological assessment surveys to further validate study findings. Results were published in the Journal of Clinical Oncology (2013;31:30763082, PMID: 23897970). Patients were randomly assigned to receive dexamethasone or placebo, 4 mg twice a day for 14 days. Eighty-four patients (41 in the placebo group and 43 in the dexamethasone group) completed the treatment and surveys. The authors found that the dexamethasone group reported a greater change in symptom scores measured by the FACIT-F after

both one and two weeks of treatment. Mean improvement of scores in the dexamethasone group over the placebo group were P=0.005 at day 8 and P=0.008 at day 15. Standardized mean difference of improvement in the FACIT-F subscale at day 15 between the groups was 5.9 (9 ±10.3 in the dexamethasone group versus 3.1 ±9.59 in the placebo group). Psychological scores did not vary between the groups, and there was no difference in the frequency of adverse events. Prompt control of CRF is an important goal in the treatment of patients with advanced cancer; dexamethasone was shown to result in a rapid and effective response.

FACIT-F measure. Interestingly, the improvement in fatigue was relatively rapid in nature and independent of improvements in pain, depression or nausea that often are associated with corticosteroid therapy. Although side effects of corticosteroids are always a concern of clinicians, there were no significant differences in adverse events noted between the two study groups. Limitations of the trial include failure to reach adequate statistical power due to patient dropout. This was attributed to the symptomatic nature of patients with advanced malignancy, although a crossover design may have overcome this issue. Furthermore, patients were given fixed dosing of dexamethasone without the ability to titrate based on individual patient response. The limited 15-day length of the study also excluded the ability to fully evaluate adverse effects that can arise with chronic corticosteroid use, such as adrenal insufficiency, infection, glucose intolerance, and myopathy, and raises safety concerns about whether this study is applicable to patients with longer prognoses. Nonetheless, the results of this trial are encouraging given the scope and effect of CRF, and the lack of marked efficacy with any other pharmacologic agents. Future studies examining the effect of corticosteroids on CRF should involve a longer study length to more fully evaluate the safety concerns of chronic corticosteroid use; however, in those patients with a very

limited prognosis, whose quality of life is markedly affected by CRF and whose risk–benefit ratio is accepting of the potential adverse effects of corticosteroids, a trial of dexamethasone may be an entirely reasonable clinical consideration.

References 1. Berger AM, Abernethy AP, Atkinson A, et al. Cancer-related fatigue. J Natl Compr Canc Netw. 2010;8:904-931, PMID: 20870636. 2. Hofman M, Ryan JL, Figueroa-Moseley CD, et al. Cancer-related fatigue: the scale of the problem. Oncologist. 2007;12 (suppl 1):4-10, PMID: 17573451. 3. McNeely ML, Courneya KS. Exercise programs for cancer-related fatigue: evidence and clinical guidelines. J Natl Compr Canc Netw. 2010;8:945-953, PMID: 20870638. 4. Cramp F, Byron-Daniel J. Exercise for the management of cancer-related fatigue in adults. Cochrane Database Syst Rev. 2012;11:CD006145, PMID: 23152233. 5. Breitbart W, Alici Y. Psychostimulants for cancer-related fatigue. J Natl Compr Canc Netw. 2010;8:933-942, PMID: 20870637. 6. Minton O, Richardson A, Sharpe M, et al. Psychostimulants for the management of cancer-related fatigue: a systematic review and meta-analysis. J Pain Symptom Manage. 2011;41:761-767, PMID: 21251796. 7.

Cruciani RA, Zhang JJ, Manola J, et al. L-carnitine supplementation for the management of fatigue in patients with cancer: an Eastern Cooperative Oncology Group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol. 2012;30:3864-3869, PMID: 22987089.

Dr. Kamdar reported no relevant financial disclosures.

More REVIEWS and COMMENTARIES from Mass General Online Find additional, Web-exclusive expert commentaries on important published studies at

ClinicalOncology.com

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

ASCO 2013

T-VEC Shows Efficacy in Melanoma Trial Chicago—In a Phase III trial of stage IIIB-IV melanoma patients, a vaccine engineered from herpes simplex virus improved durable response rate compared with granulocyte macrophage colony-stimulating growth factor (GM-CSF). The trial of talimogene laherparepvec (T-VEC, Amgen), a virus engineered to carry two human GM-CSF genes, also showed hints of improving survival. T-VEC causes direct tumor lysis and induces a local and systemic immune response, said Robert Andtbacka, MD, an assistant professor of surgical oncology at the Huntsman Cancer Institute, Utah School of Medicine in Salt Lake City. He presented the study at the annual meeting of the American Society of Clinical Oncology (abstract 9008). To be eligible for the trial, patients were required to have non–surgically resectable melanoma, with limited visceral burden (three or fewer visceral metastases excluding lung lesions). Other criteria included Eastern Cooperative Oncology Group status of 0 or 1; at least one cutaneous, subcutaneous or nodal lesion; and no open herpetic skin lesions or chronic anti-herpetic agents. Any liver lesions had to be stable for at least one month and any brain lesions had to be stable for at least three months. Patients were randomized to receive intralesional T-VEC every two weeks for up to two years or until disease toxicity, or subcutaneous GM-CSF until disease toxicity or progression. Patients were stratified by disease substage, prior systemic treatment, site of disease at first recurrence and presence of liver metastases. The primary end point was durable response that began at any point within 12 months of therapy initiation and lasted continuously for six months or longer. Durable response rate was 16.3% in patients who received the vaccine (n=295) and 2.1% in the control arm (n=141; P<0.0001). T-VEC improved median time to treatment failure (8.2 vs. 2.9 months; P<0.0001) and rates of overall response (26.4% vs. 5.7%), complete response (10.8% vs. 0.7%) and partial response (15.6% vs. 5.0%). Overall survival data is not mature, but a planned interim analysis showed a trend toward improved survival (median survival, 23.3 vs. 19 months; P=0.07). Grade 3/4 toxicities in the T-VEC arm were rare (2.1% for cellulitis, and 1.7% each for vomiting, dehydration, deep vein thrombosis and tumor pain). According to Kim Margolin, MD, a melanoma expert at the Fred Hutchinson Cancer Research Center, University of Washington in Seattle, T-VEC “isn’t really practical” and survival benefits

remain to be proven. “Patients have to have accessible lesions only,” she said. She also pointed out that there are no biomarkers to select patients for therapy, and visceral disease control is unknown. Vernon Sondak, MD, a melanoma expert at Moffitt Cancer Center in Tampa, Fla., said researchers suspected that therapy with T-VEC would be better than systemic GM-CSF at inducing durable

responses, but the survival trend is unexpected. “Although results are still maturing, the strong statistical trend in favor of improved survival on the T-VEC arm, if confirmed by further follow-up, is a very impressive and important achievement,” he said. According to Dr. Sondak, T-VEC could have a role in selected patients with advanced melanoma, as a single agent or with other drugs. “Clearly, T-VEC is not

a drug that is for everybody with melanoma,” he said. “We will have to learn to select the best patients for this approach.” A trial of ipilimumab (Yervoy, BristolMyers Squibb) with or without T-VEC is ongoing. —Kate O’Rourke Dr. Andtbacka disclosed a consultancy/ advisory role with Amgen, as well as research funding from the company. Dr. Margolin disclosed research funding from Altor BioScience, Bristol-Myers Squibb, GlaxoSmithKline, Merck, Prometheus and Roche/Genentech. Dr. Sondak had no relevant disclosures.

Read Clinical Oncology News Anywhere, Anytime! Download the iPad App here.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

How I Manage ...

Follicular Lymphoma—Part II F

ollicular lymphoma (FL) is the most common of the indolent non-Hodgkin lymphomas (NHLs). Although it may exhibit a highly variable clinical course, FL is generally considered incurable, especially in its advanced stages. Watchful waiting remains a viable option for asymptomatic patients with low tumor burden. Carefully selected patients with early-stage asymptomatic disease may be considered for “curative” radiation or chemoimmunotherapy. Once treatment is indicated, management options usually include one of a number of chemoimmunotherapy regimens; the most commonly used are R-CHOP (rituximab [Rituxan, Genentech], cyclophosphamide, vincristine and prednisone) and BR (bendamustine and rituximab). The role for maintenance rituximab or consolidation radioimmunotherapy remains controversial, as neither prolongs overall survival (OS). New therapies that target the cell surface, pathways downstream from the B-cell receptor, apoptotic pathways and the tumor microenvironment have shown promising activity in FL and have the potential to change the current treatment paradigm. In keeping with this background, I continue with Part II, which discusses important and controversial issues related to the management of FL. Part I of this series was published last month and is available for readers at www.clinicaloncology.com.

What is the role of rituximab monotherapy in follicular lymphoma? Despite decades of study, no uniformly accepted standard initial treatment has emerged for patients with FL. Early Phase II studies with rituximab monotherapy in relapsed indolent B-cell lymphomas have demonstrated overall response rates (ORRs) of 43% to 47% and median time to progression of six to eight months.1 Published studies using single-agent rituximab at a dose of 375 mg/m2 weekly for four weeks in patients with low tumor burden demonstrated an ORR of 80% with a complete response/ unconfirmed complete response (CR/ CRu) of 52%.2 The median progressionfree survival (PFS) was 24 months and 51 months for those who achieved a CR/ CRu. Durable responses of more than five years were seen in 25% of patients. However, there remains no evidence to suggest an OS benefit with rituximab monotherapy compared with observation in patients with low tumor burden. The NLCS (National LymphoCare Study), which reflected routine oncology

practices, reported that less than 15% of previously untreated patients were offered rituximab monotherapy.3

What are the data for combination chemoimmunotherapy in follicular lymphoma? The majority of patients are now treated with chemoimmunotherapy, based on several trials demonstrating a survival benefit when rituximab is added to various chemotherapy regimens.4-6 However, the optimal chemotherapy combination remains elusive. R-CHOP has been widely considered standard of care and was used in 55% of patients in the NLCS as of its 2009 publication.3 Alternative chemoimmunotherapy regimens included R-CVP (cyclophosphamide, vincristine and prednisone) in 23% of patients, R-fludarabine (F) in 15.5%, and other combinations with rituximab, including mitoxantrone-based (M) regimens, in 6.4%. This data suggested that the three regimens were similar in terms of ORR (88%-95%), PFS (72%-76% at two years) and OS. Notably, a higher OS was noted with R-CHOP than with R-CVP in

AT A GLANCE • Despite decades of study, no uniformly accepted standard initial treatment has emerged for patients with FL. • Both BR and R-CHOP regimens are reasonable options as initial therapy. • The role of maintenance therapy following induction remains controversial. • As better treatments become available, older prognostic models will become less relevant. • A new generation of non-cytotoxic agents in development will likely change the therapeutic landscape of FL.

patients with a poor-risk FL international prognostic index (FLIPI) score, with greater toxicity from the FR regimen. The prospective, multicenter FOLL05 study, in which 534 patients with stage II-IV FL were randomized to R-CVP, R-CHOP or R-FM, was an attempt to resolve this issue.7 The three-year timeto-treatment failures were 47%, 57% and 60%, respectively, favoring R-CHOP and R-FM over R-CVP (R-CHOP vs. R-CVP, P=0.003; R-FM vs. R-CVP, P=0.006; R-FM vs. R-CHOP, P=0.763). The threeyear OS, however, was similar among the treatment arms (92%-97%). The R-FM regimen was associated with greater neutropenia than the other arms. Their conclusion, therefore, was that R-CHOP was the standard.

How active is the BR regimen compared with other regimens in follicular lymphoma? Bendamustine (B) is a bifunctional alkylating agent developed more than 50 years ago in Jena, in the German Democratic Republic. Early studies from Germany suggested important single-agent activity in a variety of B-cell malignancies, including FL.8,9 In Phase II studies conducted in the United States, bendamustine produced ORRs greater than 70%, including in patients refractory to alkylating agents and purine analogues with rituximab-refractory indolent NHL.10-12 The group, led by Mathias Rummel, MD, was the first to evaluate a BR regimen in recurrent, primary FL.13 In this Phase II study, 63 patients received bendamustine at a dose of 90 mg/m2 on days 1 and 2 and rituximab at a dose of 375 mg/m2 on day 1 of a 28-day cycle for four cycles. Most patients had received a prior alkylating agent. The ORR was 90% (CR, 60%) among all patients, but was 96% (CR, 71%) in FL.

Bruce D. Cheson, MD Professor of Medicine Head of Hematology Deputy Chief, Division of Hematology/Oncology Georgetown University Hospital Lombardi Comprehensive Cancer Center Washington, DC

The median PFS was 24 months for all patients, but the median PFS for those with FL had not yet been reached at the time of analysis. In a separate study by K. Sue Robinson, MD, 66 patients with relapsed indolent and mantle cell NHL were studied.14 Forty of these patients had follicular histology, 97% had prior chemotherapy and 56% had prior rituximab exposure. Comparable with Dr. Rummel’s data, the ORR in indolent NHL was 93% (CR/CRu, 55%) and median PFS was 23 months.13 There was little difference in patients who were refractory to prior alkylating agents. Common grade 3/4 adverse events (AEs) included neutropenia (36%), infection (10%) and thrombocytopenia (9%).

Should the BR regimen be the standard front-line therapy in follicular lymphoma? The German Study Group Indolent Lymphomas (StiL) conducted the first randomized study comparing R-CHOP with BR in previously untreated, advanced stage FL and other low-grade and mantle cell lymphomas, in which 548 patients received rituximab at a dose of 375 mg/m2 on day 1 with either standard CHOP every 21 days or bendamustine at a dose of 90 mg/m2 on days 1 and 2, every 28 days for up to six cycles.15 Although the ORRs were similar in both arms, 93% for BR and 91% for R-CHOP, CR rates were 40% with BR and 31% with R-CHOP (P ( =0.03), and the median PFS was 70 and 31 months, respectively ((P<0.0001), with no difference in OS. In general, R-CHOP was associated with more AEs, notably grade 3/4 neutropenia (47% vs. 11%; P<0.0001) and infection (121 vs. 95; P=0.04). The incidence of secondary malignancies was similar: 20 cases with BR and 23 cases with R-CHOP. In the subsequent BRIGHT

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

(Bendamustine Rituximab InvestiGational non-Hodgkin’s Trial) study, which compared BR with R-CHOP or R-CVP in previously untreated, advanced-stage, indolent NHL and mantle cell lymphomas, CR rates were similar between arms in the patients with indolent NHL: 27% with BR versus 23% with R-CHOP or R-CVP regimens.16 Additionally, the ORR was slightly higher with BR at 94% compared with 84% with R-CHOP and R-CVP regimens. The BR regimen was associated with a greater risk for rash, nausea, hypersensitivity reactions and opportunistic infections, specifically varicella zoster. Although there were similar numbers of deaths in both arms, six fatal AEs occurred in the BR arm, whereas only one fatal AE, septic shock, occurred in the cyclophosphamide-based arm. The R-CHOP and R-CVP regimens were associated with more neuropathy and grade 3/4 neutropenia, despite an increased use of granulocyte colony-stimulating factors. Grade 3/4 anemia and thrombocytopenia were similar in both arms, as was fatigue. Thus, in the BRIGHT study, BR was noninferior to the other regimens in indolent NHL, but not superior. There were a greater number of opportunistic infections with BR than previously reported. Both BR and R-CHOP regimens are reasonable options as initial therapy. I personally favor the BR regimen in FL.

What is the role of maintenance therapy in follicular lymphoma? The role of maintenance therapy following induction remains controversial. In the SAKK (Swiss Group for Clinical Cancer Research) study, two rituximab schedules were tested in primarily advanced-stage FL.17 Half the patients had bulky disease and most had received prior chemotherapy. Patients received rituximab at a dose of 375 mg/m2 weekly for four weeks followed by randomization to either observation or four additional doses every two months, if they achieved at least a partial response (PR). The ORR among all patients was 52%. Responses were similar in the two arms (ORR, 75%-77%; CR, 31%-38%), but the median event-free survival was longer with prolonged exposure at 24 months than at 13 months (P ( <0.001). Although the OS curves trended in favor of prolonged exposure, the difference was not significant ((P=0.08). In the BNLI (British National Lymphoma Investigation) study, 462 patients with non-bulky stage II-IV FL who did not require therapy were randomized to observation, weekly rituximab for four weeks, or weekly rituximab for four weeks, followed by rituximab maintenance every two months for two years.18 Of note, only 5% of patients enrolled met Groupe d’Étude des Lymphomes Folliculaires (GELF) criteria for initiation of therapy, solely by elevated lactate

dehydrogenase (LDH) levels. The second arm was closed early due to promising results in the maintenance arm of the PRIMA (Primary Rituximab and Maintenance) study of high-tumor-burden patients. Although median time to next therapy and PFS were superior in the rituximab arms, the initiation of rituximab had no effect on OS. In the RESORT (Rituximab Extended Schedule or Retreatment Trial) study, patients with low tumor burden were randomized to four weekly doses of rituximab followed by either indefinite maintenance on an every-two-month schedule, or observation and retreatment at recurrence.19 Time to event was comparable, despite considerably more rituximab in the maintenance arm. The PRIMA study was the first to test maintenance in the context of currently used treatment strategies.20 In this study, 1,217 patients with high-tumor-burden FL were treated with eight cycles of R-CVP, six cycles of R-CHOP or six cycles of R-FCM (fludarabine, cyclophosphamide and mitoxantrone) at the treating physician’s discretion. Those who achieved CR or PR were randomized to observation or maintenance rituximab every eight weeks for two years. Maintenance was associated with an improvement in three-year PFS to 75% from 58% ((P<0.0001) with no maintenance; however, there was no survival advantage. There was a higher incidence of infections with maintenance: 37% versus 22%. Conversion from PR to CR/CRu was experienced by a greater number of patients in the maintenance arm (52% vs. 30%; P=0.0001). In a subsequent analysis, patients whose positron emission tomography scan was negative following therapy had a significantly longer PFS than those with positive scans, with little evidence of benefit with maintenance in the former group.21 My general practice is not to use maintenance therapy with rituximab.

Why I do not favor maintenance therapy in follicular lymphoma Rituximab maintenance is expensive, time-consuming and inconvenient. In each randomized study, maintenance was associated with increased infections in the rituximab groups compared with observation groups. Importantly, none of the front-line studies demonstrated maintenance associated with a prolongation of survival. Retreatment is as effective as continued therapy without the risk for developing rituximab resistance.

Why does FLIPI score not influence my treatment decisions in follicular lymphoma? The International Prognostic Index was developed to distinguish prognostic subgroups in diffuse large B-cell lymphoma, but was found to be less useful when

applied to patients with FL.22 The FLIPI score was constructed by Philippe SolalCéligny, MD, and co-workers from a retrospective analysis of patients with FL treated with a variety of induction regimens in the pre-rituximab era.23 The index was developed in 1,795 patients and tested on 919 patients. Using number of nodal areas, LDH, age, stage and hemoglobin levels, patients were segregated into three groups: no or one factor; two factors; and three or more factors, associated with five-year survival rates of 90.6%, 77.6% and 52.5%, respectively. In a subsequent analysis using prospectively collected data in the rituximab era, the FLIPI-2 identified the importance of tumor bulk, bone marrow involvement, hemoglobin and β2-microglobulin to define groups with three-year PFS of 91%, 69% and 51%, and OS of 99%, 96% and 84% for low-, intermediate-, and high-risk, respectively.24 Because patients can be divided into prognostic groups, the resulting tendency is to treat them differently, with less intensive treatment used for low- and intermediate-risk groups, and more aggressive measures in higher-risk patients. However, there are limited data to support this concept. Indeed, in the StiL study, there was no difference in outcome in patients treated with BR by FLIPI group.15 Neither was FLIPI a predictor of outcome in a Phase II study of rituximab and lenalidomide (Revlimid, Celgene) as initial treatment for FL.25 Thus, as better treatments become available, older prognostic models will become less relevant. As I tend to use the BR regimen in most patients for whom a clinical trial is not available, I do not use the FLIPI to guide my treatment approach.

Future Prospects The approach to patients with FL is evolving rapidly. Regimens such as R-CVP, R-FM and even R-CHOP are being supplanted by BR more frequently. However, a new generation of noncytotoxic agents in development will likely change the therapeutic landscape. In previously untreated advancedstage follicular NHL, R2 (rituximab plus lenalidomide) achieved an ORR of 98% with CR rates of 87% in patients with FL, with an estimated two-year PFS of 89%.25 The majority of patients were considered high risk by FLIPI score, but only 50% met GELF criteria (refer to Part I of this article at ClinicalOncology.com for the GELF criteria) for high tumor burden. Similar results were generated in a trial conducted by Cancer and Leukemia Group B (CALGB; now the Alliance for Clinical Trials in Oncology). Given the remarkable results of these two studies, the R2 combination is now being compared with R-chemotherapy (CVP, CHOP or B) in the Phase III RELEVANCE (Rituximab Lenalidomide Versus Any Chemother-

apy) study for stage II-IV FL (ClinicalTrials.gov: NCT01650701), the results of which may alter our approach to these patients. Perhaps the most exciting developments in lymphoma therapies reflect a growing number of small molecules, specifically oral kinase inhibitors. These agents target specific altered cell pathways and regulating proteins critical to the pathogenesis of B-cell malignancies. Ibrutinib (Imbruvica, Pharmacyclics) is a specific inhibitor of Bruton’s tyrosine kinase, a mediator of B-cell receptor signaling that is critical to B-cell maturation. In a Phase I study of relapsed and refractory FL, ibrutinib produced an ORR of 55% with a median PFS of 13.4 months.26 Idelalisib (Gilead) is an inhibitor of the δ isoform of the phosphatidylinositol 3-kinase (PI3K), a subtype of the enzyme critical for hematopoietic cell proliferation, migration and survival. A study of 125 patients with relapsed or refractory indolent NHL, including 72 with FL, treated with idelalisib achieved an ORR of 50.4% with a median PFS of 11.4 months. When combined with rituximab and/or bendamustine in previously treated indolent B-cell malignancies, the ORR among all regimens was about 80%, with no difference in PFS, thus questioning the need for chemotherapy in this setting. ABT-199 (Roche), a second-generation, selective BCL-2 inhibitor, demonstrated an ORR of 43% with nodal disease reductions of 18% to 40% in four of five patients with FL in a Phase I trial.27 The most common toxicities were gastrointestinal, and only 10% of patients experienced grade 3/4 neutropenia in this highly pretreated cohort. Other agents are in development, such as the PI3K δ,γ inhibitor, IPI-145 (Infinity).28-30 References for this article can be found online at http://goo.gl/InfuFX or by searching ClinicalOncology.com

Series Editor Syed Abutalib, MD Assistant Director, Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America, Zion, Illinois

Coming Soon How I Manage: Newly Diagnosed Acute Promyelocytic Leukemia Farhad Ravandi, MD University of Texas MD Anderson Cancer Center

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

Prepared by

Syed A. Abutalib, MD

Clinical Conundrums Clinical Hematology Review: Highlights From NEJM, Blood and d JCO QUESTIONS

1. True or False. On Nov. 1, 2013, the

FDA approved obinutuzumab (Gazyva, Genentech) for use in combination with chlorambucil to treat patients with previously untreated chronic lymphocytic leukemia (CLL).

chronic graft-versus-host disease (GVHD), a higher two-year relapse incidence and a trend toward lower non-relapse mortality (NRM) with an IV busulfan and cyclophosphamide (Bu/Cy) myeloablative conditioning regimen compared with total-body irradiation and Cy (TBI/Cy) in patients with acute myeloid leukemia (AML) who underwent allogeneic hematopoietic cell transplantation (allo-HCT) with sib-

blast-phase CML or Phpositive ALL with resistance to or unacceptable side effects from dasatinib or nilotinib or with the T315I mutation.

5. True or False. In

study published in NEJM, M the cumulative incidence of serious arterial thrombotic events with ponatinib was reportedly 7.6% in patients with chronicphase CML, accelerated-phase CML,

NEJM, M the results of the SWOG-9704 study were published, confirming the overall survival (OS) benefit with front-line autologous hematopoietic cell transplantation (auto- Primum non nocere. HCT) in patients with (First, do no harm.) high-risk (as defined by International Prognostic Index [IPI]) dif- ling donors. fuse large B-cell lymphoma. True or False. A German study pubTrue or False. The MCL-001 lished in Blood confirms the association of (EMERGE) study demonstrated durable HLA-A, -B, -C, and -DRB1 incompatibilefficacy of lenalidomide (Revlimid, Cel- ities with adverse outcome in recipients gene) with a predictable safety profile in of allo-HCT. heavily pretreated patients with mantle cell lymphoma (MCL) who had relapsed True or False. Investigators from or progressed after or were refractory to City of Hope Cancer Center showed in bortezomib (Velcade, Millennium). a study published in Blood d that T cells obtained from patients with active AML True or False. In the Journal of can be modified to express CD123 (interClinical Oncology, the European Group leukin-3 receptor α chain) chimeric antifor Blood and Marrow Transplantation gen receptors (CARs) and are able to lyse (EBMT) reported lower rates of acute and autologous AML blasts in vitro.

ANSWERS

3. True. Response rates tended to

2. True or False. Unlike rituximab

(Rituxan, Biogen Idec/Genentech), obinutuzumab has no black box warnings.

3. True or False. In a Phase II study

published in The New England Journal of Medicine (NEJM ( M), ponatinib (Iclusig, Ariad) showed clinically significant activity in patients who had chronic-phase chronic myeloid leukemia (CML), acceleratedphase CML, blast-phase CML or Philadelphia (Ph)-positive acute lymphoblastic leukemia (ALL) with resistance to or unacceptable side effects from dasatinib (Sprycel, Bristol-Myers Squibb) or nilotinib (Tasigna, Novartis) or CML patients with T315I mutation.

4. True or False. In the Phase II

1. True. Obinutuzumab’s approv-

al for CLL is based on a study of 356 patients in a randomized, open-label multicenter trial comparing obinutuzumab in combination with chlorambucil with chlorambucil alone in patients with previously untreated CLL. Participants receiving obinutuzumab plus chlorambucil demonstrated a significant improvement in progression-free survival (PFS)—an average of 23 months compared with 11.1 months with chlorambucil alone. The most common side effects observed in participants receiving obinutuzumab plus chlorambucil were infusion-related reactions, neutropenia, thrombocytopenia, anemia, musculoskeletal pain and fever. http://www.fda.gov/NewsEvents/Newsroom/ PressAnnouncements/ucm373209.htm

2. False. Obinutuzumab is approved

with a boxed warning regarding hepatitis B virus reactivation and progressive multifocal leukoencephalopathy (PML).

8. 9.

be higher among patients treated with fewer previous tyrosine kinase inhibitors and at an earlier phase of CML. Among 83 patients with acceleratedphase CML, 55% had a major hematologic response (MaHR) and 39% had a major cytogenetic response (MCyR). Among 62 patients with blast-phase CML, 31% had an MaHR and 23% had an MCyR. Data from this study, together with the Phase I data did not show a single mutation conferring resistance to ponatinib. Among 32 patients with Phpositive ALL, 41% had an MaHR and 47% had an MCyR. N Engl J Med. 2013;369:1783-1796, PMID: 24180494. N Engl J Med. 2012;367:2075-2088, PMID: 23190221.

4. False. Over a follow-up period

of 24 months, 11.8% (compared with 7.6% as initially reported in December 2012) of the patients had serious arterial thrombotic events in the Phase II PACE (Ponatinib Ph-positive acute lymphoblastic leukemia [ALL] and CML Evaluation) trial. The incidence of all

arterial thrombotic events, serious or not, was 17.1%. When longer patient exposure is taken into account, the rates of these events per unit of time have not changed. However, the accumulation of adverse events has prompted a partial clinical hold on ongoing trials of ponatinib and the termination by the sponsor of the front-line randomized trial of ponatinib versus imatinib (Gleevec, Novartis). N Engl J Med. 2013;369:1783-1796, PMID: 24180494. ARIAD Pharmaceuticals. ARIAD announces changes in the clinical development program of Iclusig. October 9, 2013. http://investor.ariad.com. Accessed November 11, 2013. Food and Drug Administration. FDA drug safety communication: FDA investigating leukemia drug Iclusig (ponatinib) after increased reports of serious blood clots in arteries and veins. October 11, 2013. www.fda.gov. Accessed November 11, 2013.

5. False.

Front-line auto-HCT improved PFS among patients with high intermediate-risk or high-risk disease who had a response to induction therapy. However, the OS after auto-HCT was not improved probably because of the effectiveness of salvage transplantation.

Assistant Director Hematology & Stem Cell Transplantation Program Cancer Treatment Centers of America Zion, Illinois

10. True or False. In a Phase II dose-

expansion study (PX-171-006), carfilzomib (C; Kyprolis, Onyx), lenalidomide (R), and low-dose dexamethasone (d) was not active in patients with relapsed or progressive multiple myeloma (MM) who had received three prior therapies.

11. True or False. According to the

World Health Organization’s classification of tumors of hematopoietic and lymphoid tissues, the enumeration of blast count in myelodysplastic syndromes (MDS) should be derived from bone marrow aspirates and cannot be extrapolated precisely from the CD34+ percentage in trephine biopsies.

12. True

or False. Fluorescence in situ hybridization (FISH) would be abnormal in up to 30% of karyotypically normal patients with MDS and normal cytogenetics.

13. True or False. Mutant isocitrate

dehydrogenase 1 (IDH1) promotes leukemogenesis in vivo and can be specifically targeted in human AML.

N Engl J Med. 2013;369:1681-1690, PMID: 24171516.

6. True. In this trial, patients received

oral lenalidomide 25 mg on days 1 through 21 every 28 days until disease progression or intolerance. An overall response rate of 28% with median time to response of 2.2 months was observed. Median PFS was four months (95% confidence interval [CI], 3.6-5.6 months) and median OS was 19 months (95% CI, 12.523.9 months). J Clin Oncol. 2013;31:3688-3695, PMID: 24002500.

7. True.

This retrospective study shows that myeloablative conditioning in patients with AML in first or second remission using IV Bu/Cy (n=795) was not statistically different from those after TBI/Cy (n=864) in recipients of allo-HCT from sibling donors. J Clin Oncol. 2013;31:3549-3556, PMID: 23980086.

8. True. In this retrospective German study, the highest mortality in an OS analysis of 2,646 patients with a

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • DECEMBER 2013 • CLINICALONCOLOGY.COM

variety of malignant hematologic diseases was seen for HLA-A, -B and DRB1 mismatches. HLA-C antigen mismatches were strongly predictive for adverse outcome, whereas the effect of HLAC allele mismatch remained uncertain. Older patient age, more advanced disease, transplantations before 2004, patient C2C2 killer cell immunoglobulin-like receptor (KIR)-ligand phenotype, and unavailability of a national donor (in the German population) adversely influenced outcomes in a multivariate analysis. Blood. 2013;122:3220-3229, PMID: 24046013.

with anti-CD34 allows the identification and enumeration of CD34+ blast cells. This method may be used in the cases of suboptimal aspirate due to bone marrow fibrosis or hypocellularity. Blood. 2013;122:2943-2964, PMID: 23980065.

12. False. A FISH study can detect

abnormalities in up to 15% (not 30%) of karyotypically normal patients with MDS. According to the available evidence, the use of FISH to detect targeted chromosomal abnormalities in interphase nuclei is recommended in

the case of repeated failure of standard G-banding. Blood. 2013;122:2943-2964, PMID:23980065.

13.

True. Mutations in the metabolic enzymes IDH1 and IDH2 are frequently found in patients with glioma, AML, melanoma, thyroid cancer and chondrosarcoma. Mutant IDH produces 2-hydroxyglutarate (2HG) instead of α-ketoglutarate (intermediate in the Krebs cycle), which induces histone and DNA hypermethylation through inhibition of epigenetic regulators. By computational screening, the

investigators of this study identified an inhibitor of mutant IDH1, which inhibited mutant IDH1 cells and lowered 2HG levels in vitro, and efficiently blocked colony formation of AML cells from IDH1-mutated patients but not normal CD34(+) bone marrow cells. These data demonstrate that mutant IDH1 has oncogenic activity in vivo and suggest that it is a promising therapeutic target in human AML cells. Blood. 2013;122:2877-2887, PMID: 23954893.

9. True. In addition, CD123 CAR T

cells exhibited anti-leukemic activity in vivo against a xenogeneic model of disseminated AML. These results suggest that CD123 CAR T cells may be a promising immunotherapy approach for patients with high-risk AML. Of interest, these CD123 CAR T cells did not eliminate normal progenitor colony formation in vitro. Blood. 2013;122:3138-3148, PMID: 24030378.

10. False. Results from this study

demonstrated that the CRd combination was highly active in patients with relapsed or progressive MM who had received one to three prior therapies. At the maximum planned dose (MPD) of carfilzomib 20 mg/m2 on days 1 and 2 of cycle 1 and 27 mg/m2 on days 8, 9, 15, 16 and thereafter, more than threefourths of patients (76.9%) achieved at least a partial response, despite 25% and 44.2% being refractory to bortezomib and lenalidomide, respectively. Among patients previously treated with bortezomib or lenalidomide, disease progression must have occurred within three months of treatment initiation and patients must not have discontinued lenalidomide due to toxicity. CRd is currently being investigated in the Phase III ASPIRE trial (ClinicalTrials.gov: NCT01080391), a randomized controlled trial that will formally compare CRd with RD in patients with relapsed MM and one to three prior therapies (estimated sample size of 780 patients). Additionally, two Phase II studies evaluating CRd in patients with newly diagnosed MM are ongoing and have reported promising early findings, and encouraging results have recently been reported on the combination of pomalidomide, carfilzomib and lowdose dexamethasone in the relapsed and refractory settings. Blood. 2013;122:3122-3128, PMID: 24014245.

RESEARCH Advancing Genomic Medicine To Create Precision Therapies.

Blood. 2012;120:1801-1809, PMID: 22665938. Haematologica. 2013;98(suppl 1):Abstract P228. Clin Lymphoma Myeloma Leuk. 2013; 13(suppl 1):Abstract P-250.

11. True. In the absence of bone mar-

row aspirate, immunohistochemistry

Targeted for Personalized Medicine nyp.org 877 NYP-WELL (877-697-9355)

In the research of advanced cancers

What if the PD-1 checkpoint pathway played an important role in tumor growth? The programmed death 1 (PD-1) checkpoint pathway plays a key role in modulating the immune system. However, some tumors exploit this pathway to evade the bodyâ&#x20AC;&#x2122;s protective immune response to cancer1-5 In a normal state, the immune system recognizes tumors and can mount an active antitumor response6,7 Antigen-presenting cell

Step 1:

Tumor releases antigen8 T cells

Through tumor-immune surveillance, activated T cells can eradicate tumor cells from the body 6,7

Step 2:

Antigen-presenting cells activate T cells that proliferate, migrate to, and attack the tumor8

Tumor

One way that tumors can evade normal immune attack is by exploiting the PD-1 immune checkpoint pathway via the PD-1 receptor1,2,5

PD-L1 ligand

Tumor cell

PD-L2 ligand

PD-1 receptor

Inhibited T cell

Both PD-L1 and PD-L2 on the tumor cells bind to the PD-1 receptor on T cells to exploit the immune checkpoint pathway. This inhibits activated T cells and suppresses T-cell attack1,2,4,5

PD-1 receptor

By exploiting the PD-1 checkpoint pathway, cancer cells evade the immune response and continue to proliferate1,2,6,8 PD-L1=programmed death 1 ligand 1; PD-L2=programmed death 1 ligand 2. References: 1. Azuma T, Yao S, Zhu G, Flies AS, Flies SJ, Chen L. B7-H1 is a ubiquitous antiapoptopic receptor on cancer cells. Blood. 2008;111(7):3635-3643. 2. Pardoll D, Drake C. Immunotherapy earns its spot in the ranks of cancer therapy. J Exp Med. 2012;209(2):201-209. 3. Freeman GJ, Long AJ, Iwai Y, et al. Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med. 2000;192(7):1027-1034. 4. Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268. 5. Dong H, Strome SE, Salomao DR, et al.Tumor-associated B7-H1 promotes T-cell apoptosis: a potential mechanism of immune evasion. Nat Med. 2002;8(8):793-800. 6. Hanahan D,Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(3):646-674. 7. Finn OJ. Cancer immunology. N Engl J Med. 2008;358(25):2704-2715. 8. Mellman I, Coukos G, Dranoff G. Cancer immunotherapy comes of age. Nature. 2011;480(7378):480-489.

Bristol-Myers Squibb Company is committed to furthering the understanding of immuno-oncology. Learn more at www.bmsimmunooncology.com. ÂŠ2013 Bristol-Myers Squibb Company. All rights reserved. ONCUS13UB01112-02-01 06/13 Printed in USA.