The November 2012 Digital Edition of Clinical Oncology News

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Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • November 2012 • Vol. 7, No. 11

INSIDE SOLID TUMORS Gene mutation predicts aromatase inhibitor adherence ............. 5 Melanoma: Dabrafenib comparable to vemurafenib . . . . . . . . . . . . . ........... 9 Dose-dense paclitaxel in ovarian cancer . . . . ........... 19 FDG-PET fails in lung cancer diagnosis . . . . . ........... 21 Should thromboprophylaxis be used in solid tumor patients? . . . . . . . . . . . . . . . . . .......... 26

The first comparison of oral, multikinase angiogenesis inhibitors Vienna—Pazopanib is noninferior to sunitinib as first-line treatment for metastatic renal cell carcinoma (mRCC), based on progression-free survival (PFS), a Phase III trial has found.

Because quality of life (QOL) and adverse-event data gathered during the trial favored pazopanib, some clinicians say pazopanib should be the drug of choice in the first-line setting.

“The side effects that we see with higher incidence with sunitinib are more troublesome in day-to-day life for see mRCC, C page 8

HEMATOLOGIC DISEASE Assessing treatment response in blast phase myeloproliferative neoplasm . . . . . . . . . . . . . . . . . .......... 22 Expert Review: Clinical Developments from ASH and ASCO . . . . . . . . ......... 24

CURRENT PRACTICE Maurie Markman, MD: The value of ‘reassurance’ in oncology . . . . . . . . . . . . . . ........... 4 Clinical Oncology News essay contest winner announced . . . . . . . . . . . . . . . ........... 6 Clinical Conundrums: Focus on NEJM, M JCO and Blood . . . . . . . . . . . . . . . . .......... 29

Study Bolsters Use of Crizotinib in ALK+ K NSCLC

Pazopanib Versus Sunitinib For mRCC

By the NUMBERS Political Contributions by Health Care Organizations

Researchers say crizotinib is standard of care for this patient population Vienna—A Phase III trial hass demonstrated that crizotinib significaantly improves progression-free survvival (PFS) in patients with previouslyy treated, advanced ALK-positive non n-small cell lung cancer (NSCLC) comp pared with standard treatment.

Crizotinib (Xalkori, Pfizer) receeived accelerated approval from the FD DA in August 2011, based on encourraging response data from two sin nglearm trials. The drug was approveed simultaneously with a compan nion diagnostic test for anaplastic lymphoma kinase (ALK).

The new study, named PROFILE 1007, showed that crizotinib Crizotinib bound to improved PFS, the primary end p point, by 4.7 binding pockets in ALK protein.. months compared with chemotherapy h ((7.7 vs.

3.0; P<0.0001; Table 1). The results were presented at the recent annual meeting of the European Society of Medical Oncology (ESMO; abstract LBA1).

According to Ed Kim, MD, the chair of Solid Tumor Oncology and Investigational see CRIZOTINIB, B page 28

$166,669,314 Total amount the health care sector has spent in the 2012 election cycle

56 Percent given to Republicans

Vogl, NY...

POINTBREAK Results: Big Disappointment

FOR MORE, see

Pemetrexed fails to be superior in metastatic non-squamous lung cancer

Political Contributions

by Health Care Organizations ............................ 16

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Health Insurance PACs ............................................... 25

oyti Patel, MD, a lung cancer specialist at Northwestern University in Chicago, presented the results of the POINTBREAK study at the 2012 Chicago Multidisciplinary Symposium in Thoracic

Steven Vogl, MD

Oncology (sponsored by the IASLC and ASTRO) last month. My initial suspicion was that the reason for presenting the results at this relatively obscure meeting in front of a small audience was that see POINTBREAK, K page 10

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Doublet or Monotherapy for Metastatic Breast Cancer? ................... 22 Michael J. Naughton, MD

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer Michael A. Carducci, MD AEGON Professor in Prostate Cancer Research, Co-Director, Prostate/GU Cancer and Chemical Therapeutics Programs, Johns Hopkins Kimmel Cancer Center Baltimore, MD

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

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

Maura N. Dickler, MD

Harry Erba, MD, PhD

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

University of Alabama Birmingham, AL

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

Cathy Eng, MD University of Texas, MD Anderson Cancer Center Houston, TX

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

Gastrointestinal Cancer and Sarcoma

Sara S. Kim, PharmD

University of California, San Diego, CA

The Mount Sinai Medical Center New York, NY

Infection Control

Bioethics

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

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

Oncology Nursing Betty Ferrell, RN, PhD City of Hope National Medical Center Duarte, CA

Michele Neskey, MMSc, PA-C University of Texas, MD Anderson Cancer Center Houston, TX

Shaji Kumar, MD Mayo Clinic Rochester, MN

Paul J. Ford, PhD Cleveland Clinic Foundation Lerner College of Medicine of Case Western Reserve University Cleveland, OH

Policy and Management Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Pharmacy Cindy O’Bryant, PharmD Richard Stone, MD

University of Colorado Cancer Center Denver, CO

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

Rhonda M. Gold, RN, MSN The Pritchard Group Rockville, MD

Syed A. Abutalib, MD Cancer Treatment Centers of America Zion, Illinois

Community Oncology John W. Finnie, MD Mercy Medical Center St. Louis, MO

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

Charles F. von Gunten, MD

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

Mission Statement

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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.

Genitourinary y Cancer Ronald M. Bukowski, MD Taussig Cancer Center, Cleveland Clinic Foundation Cleveland, OH

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

Steven Vogl, MD Medical Oncologist New York, NY

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

Lung, g, and Head and Neck Cancers Edward S. Kim, MD University of Texas, MD Anderson Cancer Center Houston, TX

Lung g Cancer,, Emesis Richard J. Gralla, MD Hofstra North Shore-Long Island Jewish School of Medicine, Monter Cancer Center North Shore University Hospital and Long Island Jewish Medical Center Lake Success, NY

Steven D. Passik, PhD Vanderbilt University Medical Center Nashville, TN

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

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

Editorial Philosophy 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. They then review the articles before they are published.

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.

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

The Economic Value of ‘Reassurance’ in Oncology B

ecause of widely recognized unsustainable increases in health care costs—including in oncology—there has been an appropriate focus on defining the value of care that is being delivered. Medical organizations, such as the American Society of Clinical Oncology, have joined in the discussion and have attempted to identify specific strategies or procedures that they feel are either ineffective or fail the test of being backed by sufficient evidence-based data to justify their use in routine disease management (sidebar).1 Unfortunately, although cost and costeffectiveness are clearly critical considerations, it is important to acknowledge that sometimes the perspective of one highly relevant constituent in this debate has been lost: the patient.

Specifically, I’m speaking of the value of “reassurance” given to an individual patient following a “positive” or “negative” test result that suggests either the absence or lack of progression of a cancer, independent of any objective populationbased clinical trial evidence that such a test result favorably affects survival.2 Consider, for example, serum CA-125 monitoring of women with advancedstage ovarian cancer who have achieved a clinically defined complete response (no symptoms of disease; normal physical examination; unremarkable computed tomography [CT] scan of the abdomen/pelvis; CA-125 antigen level within “normal limits”) to primary platinum-based combination chemotherapy. The results of a landmark, randomized Phase III trial revealed that routine serum CA-125 monitoring in this patient population does not affect survival, compared with deferring evaluation (including CA-125 testing) until

Comments or feedback on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor Gabriel Miller at

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Although there is clearly a striking difference in the “economic cost” of these tests compared with intermittent serum CA-125 testing, from the perspective of an individual patient the purpose of doing the procedure is quite similar.

Again, there may be no evidence that these test results affect breast cancer survival; but knowing the scan is “negative” for metastatic disease may have an enormous effect on an individual patient’s overall quality of life.5 One rational approach would be to formally acknowledge the desire of many— perhaps even most—patients to be reassured in difficult clinical circumstances like these. At the same time it is critical to recognize that any reassurance, as profoundly relevant as it might be for an individual, may come at a monetary cost that simply cannot be borne by third-party payers (e.g., Medicare, basic employer-paid health insurance).

I’d further argue that this serious

There may be no evidence that a test result affects survival, but knowing a scan is ‘negative’ for metastatic disease may have an enormous effect on an individual patient’s overall quality of life.

EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

gap between population-based data and individual patient desires could be filled by a supplemental form of commercial medical insurance, likely purchased prior to the development of a serious cancer or other medical illness.

This insurance might focus on very specific circumstances (such as the cancer conditions above and other realistic scenarios) where additional diagnostic testing may reasonably be desired and can provide “reassurance” to the individual patient, despite the absence of any definitive population-based data documenting clinical utility for the approach.

Of course, it is essential that all interested parties acknowledge that this patient-centered perspective is worthy of serious consideration.

References

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n April, the ASCO Cost of Cancer Care Task Force released a “Top 5” list of procedures “whose common use and clinical value are not supported by available evidence.”1 They are: 1. Don’t use cancer-directed therapy for solid tumor patients with the following characteristics: low performance status (3 or 4), no benefit from prior evidence-based interventions, patient not eligible for a clinical trial and no strong evidence supporting the clinical value of further anticancer treatment.

2. Don’t perform PET, CT or radionuclide bone scans in the staging of early prostate cancer at low risk for metastasis.

3. Don’t perform PET, CT or radionuclide bone scans in the staging of early breast cancer at low risk for metastasis.

4. Don’t perform surveillance testing (biomarkers) or imaging (PET, CT or radionuclide bone scans) for asymptomatic individuals who have been treated for breast cancer with curative intent.

5. Don’t use white cell stimulating factors for primary prevention of febrile neutropenia for patients with less than 20% risk for this complication.

1. Schnipper LE, Smith TJ, Raghavan D, et al. American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: The top five list for oncology. J Clin Oncol.

2012;30:1715-1724, PMID: 22493340.

gmiller@mcmahonmed.com

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© 2012 McMahon Publishing, New York, NY. All rights reserved.

there is symptomatic evidence of possible disease progression, such as abdominal pain, pressure, bloating and so on.3 Yet, in a separate study when patients were asked why they would want to know their CA-125 following primary therapy, the reassurance a “normal value” provided—that is, that the cancer had not returned—was an often-cited reason.4 There is evidence-based trial data demonstrating that this knowledge does not affect the ultimate outcome of a population of women in a similar setting, but this does not necessarily influence an individual patient’s personal desire to be provided with what she feels is a meaningful degree of reassurance in the face of uncertainty.

Similarly, a bone scan or perhaps even a positron emission tomography (PET) scan following adjuvant treatment of high-risk breast cancer (>10 “positive” local lymph nodes) may be justified from the perspective of an individual patient.

EDITORIAL STAFF

SALES STAFF

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

Marlena McMahon, Associate Publication Director marlena@mcmahonmed.com

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

ART AND PRODUCTION STAFF

James Prudden, Group Editorial Director

Michele McMahon Velle, Creative Director, MAX Graphics

1. Schnipper LE, Smith TJ, Raghavan D, et al.

American Society of Clinical Oncology identifies five key opportunities to improve care and reduce costs: the top five list for oncology. J Clin Oncol. 2012;30:1715-1724, PMID: 22493340.

2. Detsky AS. Underestimating the value of reassurance. JAMA. 2012;307:1035-1036, PMID: 22416098.

3. Rustin GJ, van der Burg ME, Griffin CL, et al.

Early versus delayed treatment of relapsed ovarian cancer (MRC OV05/EORTC 55955): a randomized trial. Lancet. 2010;376:11551163, PMID: 20888993.

4. Markman M, Petersen J, Belland A, et al.

CA-125 monitoring in ovarian cancer: patient survey responses to the results of the MRC/ EORTC CA-125 Surveillance Trial. Oncology.

2010;78:1-2, PMID: 20215782.

5. Margenthaler JA, Allam E, Chan L, et al.

Surveillance of patients with breast cancer after curative-intent primary treatment: Current practice patterns. J Oncol Pract.

2012;8:79-83.

Brandy Wilson, Circulation Coordinator Mark Neufeld, Associate Director, Project Management

MCMAHON PUBLISHING Raymond E. McMahon, Publisher & CEO, Managing Partner Van Velle, President, Partner

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Can a Gene Mutation Predict AI Discontinuation?

Chicago—Researchers have identified a single-nucleotide polymorphism (SNP) associated with the joint pains and musculoskeletal toxicity that often emerge from treatment with the aromatase inhibitor (AI) exemestane.

The genetic marker needs to be validated in other studies, investigators said, but has the potential to affect clinical care.

In the study, led by Lynn Henry, MD, PhD, an assistant professor at the University of Michigan Comprehensive Cancer Center in Ann Arbor, researchers set out to identify associations between SNPs in candidate genes and the discontinuation of therapy because of AIassociated musculoskeletal syndrome (AIMSS). The study population included 467 postmenopausal breast cancer patients receiving letrozole or exemestane, with researchers examining 176 SNPs in 24 candidate genes involved in estrogen metabolism and signaling.

Of patients, 33% discontinued medication because of toxicity and roughly 75% did so because of AIMSS. The researchers found that a variant in the gene encoding estrogen receptor (ER)-α, ESR1, predicted discontinuation due to AIMSS, but only in the exemestane arm. The results were reported at the annual meeting of the American Society of Clinical Oncology (abstract 525).

“An ER-α SNP might provide insight into which patients simply won’t continue therapy and further may differentially predict adherence between the aromatase inhibitors,” said Bryan Schneider, MD, an associate professor of medical and molecular genetics and an oncologist at Indiana University Simon Cancer Center in Indianapolis. He was not involved with the investigation and said “these findings require validation.”

But taking a broader view, Dr. Schneider said, the clinical implications of the study are unclear. “Will knowing earlier

AT A GLANCE ESR1 gene amplification is frequent in breast cancers Two inherited genetic variations in ESR1 were linked with discontinuing aromatase inhibitor (AI) therapy The association was much stronger with exemestane than with letrozole If validated, the genetic marker could be used to guide initial AI choice

allow for focused attention on a group that may quit therapy? The answer is yes. But will this improve adherence, I don’t know. In 2011, a randomized study of intervention versus standard of care to improve [AI] adherence was taken on and this was, unfortunately, a negative study,” said Dr. Schneider, referring to an abstract presented at the 2011 ASCO meeting (abstract 526). He said the optimal scenario would be to understand how to treat and prevent AIMSS. This side

effect is responsible for early discontinuation of AI therapy in 20% of patients.

Dr. Henry said that if the results are validated, it might be appropriate for clinicians to advise patients with the SNP to start on an AI other than exemestane initially, but that if the other AIs are not tolerated, it would also be appropriate to try exemestane because there is no evidence of a negative effect of the SNP other than possibly causing reversible toxicity.

“I think it is also important to perform

®

preclinical studies to try to understand why the SNP has this effect, in case it has an impact on breast cancer outcomes,” said Dr. Henry.

—Kate O’Rourke Dr. Schneider disclosed a consultant or advisory role with Bristol-Myers Squibb, Genentech and Genomic Health; honoraria from GlaxoSmithKline; and research funding from Genentech.

Dr. Henry received research funding from AstraZeneca, Eli Lilly and Sanofi.

Now Available... in Non-Hodgkin’s Lymphoma

Evolving Treatment Paradigms To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM111” Release Date: August 22, 2012

Expiration Date: August 22, 2013

Chair

Learning Objectives

Julie M. Vose, MD, MBA

Review optimal therapy for the management of newly diagnosed and relapsed/refractory follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL), taking into consideration the heterogeneity of patient and tumor characteristics.

Neumann M. and Mildred E. Harris Professor Chief, Division of Hematology/Oncology Professor of Medicine

1 Identify the most recent data pertaining to emerging single and combination therapies for the treatment of relapsed/refractory NHL.

Nebraska Medical Center Omaha, Nebraska

Faculty

John P. Leonard, MD

2 Explain the most significant new data on consolidation and maintenance strategies in NHL.

Myeloma

3 Describe current and emerging prognostic clinical and molecular markers to aid in treatment decision making for NHL.

Professor of Medicine

Intended Audiences

Weill Medical College of Cornell University

The intended audiences for this educational activity are hematologists, community oncologists, oncology nurses, pharmacists, and other hematology/oncology health care professionals. These professionals constitute the core audience for this initiative as they direct treatment for patients with NHL.

Clinical Director, Center for Lymphoma and

NewYork-Presbyterian Hospital New York, New York

Jonathan W. Friedberg, MD Professor of Medicine and Oncology Chief, Hematology/Oncology Division James P. Wilmot Cancer Center University of Rochester Medical Center Rochester, New York

challenges for clinicians, who must stay abreast of the new data and be prepared to incorporate emerging therapeutic strategies into their practice.

Course Format Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Statement of Need

Method of Preparation

The incidence of NHL is increasing steadily, and new therapeutic strategies are needed; FL remains incurable, and 30% to 40% of patients with DLBCL still die from their disease. The abundance of ongoing research into therapeutic strategies for these conditions presents opportunities for improved patient outcomes as well as

To receive CME credit, participants should read the preamble, complete the pre-test, read the monograph, and complete the post-test and evaluation. A score of at least 75% (in 3 attempts) is required to complete this activity successfully.

CME certificates will be issued immediately upon successful completion.

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

This activity is supported by educational grants from Genentec

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM111”

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Clinical Oncology News Writing Contest Winners Editor’s Note:

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his summer, Clinical Oncology News launched the magazine’s inaugural writer’s contest, asking readers to submit essays on the theme of change in oncology/hematology. We are proud to announce two winners in this year’s contest.

First place winner Paulette Mehta, MD, MPH, is a professor of internal medicine and pediatrics and was the associate director of the hematology and oncology fellowship program at the University of Arkansas for Medical Sciences, in Little Rock, Ark. Dr. Mehta’s essay poignantly details her own early experience with medicine set against the broad changes that oncology and hematology have undergone in the past 50 years. Ultimately, Dr. Mehta’s essay serves as a powerful reminder of how far the field has come in the last half-century.

Second place winner Atis Barzdins, MD, is a hematologist-

oncologist at the Seattle Cancer Treatment and Wellness Center in Renton, Wash. Dr. Barzdins’ essay, to be published in the December issue of Clinical Oncology News, thoughtfully outlines many of the fundamental problems in contemporary cancer care, from both physicians’ and patients’ points of view, and looking toward the future, asks how we can best use the ever-growing body of personalized information that modern diagnostic testing offers.

Clinical Oncology News thanks all of the readers who submitted essays as part of the inaugural writer’s contest; the second annual contest will open in summer 2013.

Changing Times in Hematology/Oncology Practice

By Paulette Mehta, MD, MPH

Prelude to Medical Practice

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have been seeing patients since I was 5 years old. That’s when I started making house calls with my father in New York City. He was an internist who worked in a clinic during the day, made hospital calls in the afternoon and ventured out on house calls at night. He would come home for dinner and then would call out to us, his four children: “Who wants to do house calls with me?”

Invariably, I was the one who raised my hand the fastest.

As we traveled the dark lonely roads in New York City neighborhoods in the early 1950s, my father would relay patients’ problems, speak about their troubles and lead me into their homes.

There, people would be waiting desperately for us, as though we alone could save them, even though there was usually not much to offer in those days. In fact, all that was available fit comfortably in my father’s small black bag: a stethoscope for hearing seemingly mysteri-

tools and examine the patient’s chest, abdomen, extremities, reflexes and nervous system.

Then when he finished his exam, he would move forward almost as though he was confiding a great secret. “Do this, this or that,” he would say. And often it was as simple as “take more rest, drink more fluids.” Sometimes he would administer a medication, like sulfa or penicillin, and sometimes he would offer a prescription. The prescription sometimes held the name of a medication he wasn’t carrying with him, but other

medical school, after which I returned to New York for my internship and residency. Shortly after I returned, my father died suddenly while on the way out to make a house call. I was devastated but determined to follow in his path, inspired every moment by the words of wisdom he had shared with me during our earlier house calls. Subspecialty practice was just developing, with subspecialty training, board exams and certification, and with the possibility of interesting work at high pay with only slightly more training than that required for general medicine.

My father died suddenly while on the way out to make a house call.

I was devastated but determined to follow in his path, inspired every moment by the words of wisdom he had shared with me during our earlier house calls. ... Hematology/oncology was beckoning and I heard its clarion call loud and clear. ous sounds, a hammer for eliciting reflexes, a tuning fork for evaluating sensations, some medications, syringes and a prescription pad.

We would be escorted through living rooms and halls into the private interior spaces of patients. He would sit down eye-to-eye at his patient’s level, or lower, and would listen carefully to every word, spoken and unspoken. Then he would take out his

times it simply read: “rest,” “relax.”

Then we would leave and he would whisper to me, in those glorious preHIPAA days, about the patients, the possible pathophysiology of the disease, the treatments and the lack thereof. “One day,” he mused, “we’ll figure out the science behind these problems and one day we’ll be able to find specific ways to target the disease pathophysiology. That’s for your generation to do; that’s your challenge, if you take it up.”

Entering the Field of Medicine I made up my mind “to take it up.” With my father’s mentorship and guidance I followed in his footsteps, studying biology in college and then leaving home for

Hematology/oncology was beckoning and I heard its clarion call loud and clear.

In those days of the 1970s, there was talk of amazing advances in childhood cancer. There were reports of children with acute lymphoblastic leukemia who were responding to medicines and some, even, who were achieving remission. Others were maintaining remission for weeks and even months.

There were then reports of children with Hodgkin’s disease and non-Hodgkin’s lymphoma responding to treatment. These were followed by successes in children with Wilms’ tumor and others. The field was abuzz. I was excited—here was a place where I could do something incredible, and where I

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

could perhaps even add to the field and help other children. Maybe I could realize my father’s dreams.

I did my fellowship at Bellevue Hospital at New York University and rotated through Memorial Sloan-Kettering Cancer Center. New treatments for osteogenic sarcoma had become available, and people were coming from all over the world to be treated. Patients were living, surviving!

Establishing my Career in Hematology/Oncology After training, I began a long 24-year practice at the University of Florida as a clinician and a research scientist in platelet physiology. In 2000, I moved into the field of adult and geriatric hematology/ oncology at the University of Arkansas for Medical Sciences and at the Central Arkansas Veterans Healthcare System, where I continue to practice medicine.

The field was abuzz. I was excited—here was a place where I could do something incredible, and where I could perhaps even add to the field and help other children. Maybe I could realize my father’s dreams. protocols. There were fewer spectacular cures as in pediatrics, and patients didn’t bounce back nearly as well, but cancer patients were improving over time, with most patients achieving a durable remission of at least five years.

Changes in Supportive Care Advances in supportive care in the 1980s and 1990s revolutionized cancer care. No longer did patients retch through days of treatment, or need to be put to sleep to alleviate vomiting. Now patients could be awake during treatment, and could even play, enjoy, eat and drink through treatment. Few of my young colleagues can imagine an oncology ward prior to effective antiemetic

Information not previously imaginable is now instantly available at anyone’s fingertips. Not long ago we treated disease based on simple morphology using a few stains of cells indicating the type of malignancy. Now there is a wide array of detailed molecular information from immunophenotyping, karyotyping, gene array, genomics and proteomics.

In my clinical rounding in pediatrics, I used protocols from the Pediatric Oncology Group (POG) to which my medical school belonged, and later I became principal investigator of the Phase I, II, and III clinical trials from POG at the University of Florida. Clinical trials used dozens of combinations and permutations of the few available drugs that were being tested, often with only incremental or very minor benefits. In some settings like Burkitt’s lymphoma, results were so good that we were shortening treatments to see if less treatment could yield better results.

At the VA hospital in Little Rock, I witnessed new types of cancer I hadn’t seen before—smoking- and war-related cancers. The ward was filled with patients who had cancers that might have been preventable, including smoking-related lung cancers, alcohol- (and smoking-) related head and neck cancer and others. Here too, I saw veterans of the Vietnam War with Agent Orange–related cancers of all types, including multiple myeloma, chronic lymphocytic leukemia and non-Hodgkin’s lymphomas, as well as obesity-related tumors of the esophagus and others. Unlike my days in pediatric hematology/oncology, few patients were placed on protocol and few protocols were available. Many protocols were based on the successes of the pediatric

treatment. Few can remember treating without growth factor availability. Few can remember the days before effective antiviral and antifungal drugs were introduced.

Advent of Stem Cell Transplantation Stem cell transplantation became a part of our repertoire and allowed for longer and better remissions in many patients with leukemia and lymphoma.

But allogeneic and especially unrelated transplants led to awful graft-versushost disease (GVHD) and fulminating fungal infections in some patients, leading some of my colleagues to leave the field completely. Later, better treatments for GVHD and more effective antifungal medications made treatment more tolerable. Also, the fascinating discovery that hematopoietic stem cells could be harvested not only from bone marrow, but also from peripheral blood and umbilical cord blood led to new methods in transplantation. Newly recognized stem cell sources, such as adipose tissue, may lead to even newer approaches in the future.

The Information Technology Boom Information technology further revolutionized cancer care. In my early faculty days, I spent hours and days sitting

at the many volumes of Index Medicus searching for an article or two that related to patient care or to my research.

After finding a few relevant articles, I would write out the entire reference and work with the medical librarian to locate the source document and have it sent to us. It would take days for each piece of information to arrive. Compare that to the present day when voluminous information is available with a click on a handheld, laptop or desktop computer. In a series of clicks, it is now possible to download tons of information on any topic in seconds. The problem has shifted from findingg information, so difficult in those early days, to filteringg information, so voluminous these days. Few of my colleagues can imagine those days before computers, faxes, the Internet, tablets, iPods, iPads and iPhones.

Information not previously imaginable is now instantly available at anyone’s fingertips. Not long ago, we treated disease based on simple morphology using a few stains of cells indicating the type of malignancy. Now there is a wide array of detailed molecular information from immunophenotyping, karyotyping, gene array, genomics and proteomics. Classification of disease is changing from anatomic location to biological pathways.

Already, there are striking examples of individualized therapies for molecular defects detected through gene sequencing of tumor cells. I can imagine a day when all patients will have their tumors genotypically typed and specific treatments will be tailored to molecular abnormalities.

Integrating Molecular Biology Into Clinical Care Better understanding of cancer cells has led to a wide array of unimaginable smart drugs designed to attack specific proteins and receptors. Smart drugs like imatinib [Gleevec, Novartis] now take the place of chemotherapy and even stem cell transplantation for patients with chronic myelogenous leukemia.

Smart antibodies like rituximab [Rituxan, Biogen Idec/Genentech] have vastly improved treatment of many forms of leukemia and lymphoma, while simple retinoid molecules can stop proliferation of promyelocytic leukemia.

Cancer Survivorship Comes of Age as New Subspecialty These remarkable developments have led to long-term survivorship in many cancer patients, which in turn has given rise to a new sub-subspecialty—hematology/oncology survivorship. The area

of survivorship, happy though it is, is replete with new medical, financial, social and psychological issues creating a new chronic disorder of its own. Cancer survivorship has now become a major focus of the Centers for Disease Control and Prevention (CDC), the Lance Armstrong Foundation and all of the national cancer societies.

The Role of the Physician Changes From Solo Doc to Team Leader My father practiced solo as a general practitioner, probably sometimes seeing patients with hematologic or oncologic diseases for which no treatments would have been available. When I started my career, I practiced alone but side by side with subspecialists in other fields. Now I practice in a team, meeting daily with nurses, nurse practitioners, data managers, social workers, psychologists and others. I meet regularly with scientists, information technologists, data managers and others. At every session, whether it be clinical or research, the patient is now center stage surrounded by experts devoted to helping him or her and all others afflicted with cancer. Nowadays, it takes a village to treat a patient!

A Sea Change I’ve witnessed a sea change in the practice of medicine and of hematology/ oncology. Changes have been awesome in unraveling the mysteries of cancer cell biology and in bridging scientific discoveries with clinical treatment. Changes in supportive care have allowed for much kinder, gentler and yet more effective treatment than previously imaginable.

Associated medical services including radiation oncology, physical therapy, pain management and others have made treatment more effective and tolerable.

The burgeoning field of information sciences has radically improved our ability to interpret massive amounts of data and to share this information with investigators, institutions and nations, allowing for massive new collaboration. The Genome Project deciphered the human genome and thereby created the technology to study and understand the molecular defects of virtually every single tumor cell. This allows for much better classification of disease, has identified new targets for new drugs, and holds promise for individualizing treatments according to each patient’s specific oncogenes.

These and other changes have put us on the cusp of understanding, managing and even curing cancer in our lifetimes.

My father would be amazed!

The second place–winning essay in Clinical Oncology News writer’s contest, by Atis Barzdins, MD, will be published in the next issue of Clinical Oncology News.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

mRCC

Table 1. Progression-Free Survival in COMPARZ continued from page 1

patients. Pazopanib would be the treatment of choice, in my opinion,” said Robert Motzer, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center in New York City. He presented the study at the European Society for Medical Oncology annual meeting (LBA8).

In first-line treatment of good- and intermediate-risk patients with mRCC, clinicians usually prescribe sunitinib (Sutent, Pfizer), pazopanib (Votrient, GlaxoSmithKline) or interferon plus bevacizumab (Avastin, Genentech).

The Phase III COMPARZ trial offered the first head-to-head comparison of the two oral, multikinase angiogenesis inhibitors. Patients with advanced RCC or mRCC with clear-cell histology and no prior systemic therapy were randomized to pazopanib (800 mg every day continuous dosing; n=557) or sunitinib (50 mg every day, four weeks on and two weeks off; n=553).

An independent review showed patients receiving pazopanib had a similar PFS as those receiving sunitinib (8.4 vs. 9.5 months; hazard ratio [HR], 1.047; Table 1) and a significantly higher objective response rate (31% vs.

25%; P=0.032). Interim analysis of overall survival was similar in both groups (HR, 0.908; P=0.275).

Patients receiving pazopanib had a lower incidence of hand–foot syndrome and fatigue, but a higher incidence of liver function test abnormalities (Table 2).

All statistically significant differences in QOL surveys favored pazopanib over sunitinib, including the Functional Kidney Symptom Index-19, Cancer Therapy Satisfaction Questionnaire, Supplemental Quality of Life Questionnaire, and Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) Scale.

For example, the researchers identified a 2.32-point average difference favoring pazopanib on the FACIT-F score, which ranges from 0 to 52.

Tim Eisen, PhD, of the NIHR Cambridge Biomedical Research Centre and the University of Cambridge, United Kingdom, said the efficacy and adverseevent data were convincing. “To me, dose reductions and discontinuations are a

Patients, n

Median PFS, mo (95% CI)

Pazopanib

557

8.4 (8.3-10.9)

Sunitinib

553

9.5 (8.3-11.1)

Hazard ratio = 1.047 (95% CI, 0.898-1.220) CI, confidence interval; PFS, progression-free survival

‘The quality-of-life data in this study are not as convincing as the efficacy data, which in my mind are highly convincing.’

—Tim Eisen, PhD Renal cell carcinoma.

real acid test, and they are very similar in these two groups of patients. Pazopanib seems to have fewer dose reductions but more dose discontinuations,” said Dr. Eisen. “Pazopanib does score in terms of having fewer side effects that matter to patients. Fatigue, stomatitis and hand– foot reactions all trouble patients badly.”

Dr. Eisen was not convinced by the

QOL data, which were gathered on day 28 every cycle through cycle 9 and then on day 42 of each subsequent cycle.

“Patients, after four weeks of sunitinib, do not feel too chipper,” said Dr. Eisen, pointing to the way sunitinib is dosed.

“If you are looking at day 28, you are timing the quality-of-life assessments to favor pazopanib. The quality-of-life

Pazopanib, %

Sunitinib, %

Dose reductions

44

50

Discontinuations due to AEs

24

19

data in this study are not as convincing as the efficacy data, which in my mind are highly convincing.”

He pointed out, however, that data from the PISCES study support the choice of pazopanib over sunitinib ((J Clin Oncol 2012;suppl:abstr CRA4502).

This trial used a crossover design, so patients were exposed to both agents.

It found that 70% of patients preferred being on pazopanib; 22% preferred sunitinib; and 8% had no preference.

According to Ronald Bukowski, MD, a kidney cancer expert and professor emeritus at Cleveland Clinic Foundation in Ohio, pazopanib use is likely to rise. “Most physicians still choose sunitinib, but the recent studies with pazopanib from ASCO [American Society of Clinical Oncology] and ESMO [European Society for Medical Oncology] will probably result in an increase for this agent, with a decrease in sunitinib,” he said.

Diarrhea

63

57

—Kate O’Rourke

Fatigue

55

63

Hypertension

46

41

Nausea

45

46

ALT increase

31

18

Hair color changes

30

10

Hand–foot syndrome

29

50

Taste alteration

26

36

Thrombocytopenia

10

34

Because quality-of-life and adverse-event data gathered during the trial favored pazopanib, some clinicians say pazopanib should be the drug of choice in the first-line setting.

Table 2. Comparison of Selected Adverse Events In COMPARZ

AEs, adverse events; ALT, alanine aminotransferase

Dr. Motzer disclosed a consultancy with Pfizer and corporate-sponsored research for GlaxoSmithKline, Pfizer, Novartis, Aveo and BMS. Dr. Eisen disclosed research funding from Pfizer, GlaxoSmithKline, AstraZeneca and Bayer, and advisory board involvement with and honoraria from Pfizer, GlaxoSmithKline, AstraZeneca, Astellas, Aveo, Bayer and Roche. Dr. Bukowski disclosed being a speaker/consultant for Pfizer, GlaxoSmithKline and Novartis, and a consultant for Bristol-Myers Squibb.

Non-CML Myeloproliferative Diseases, An Issue of Hematology/Oncology Clinics of North America Ross Levine See page 27

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Dabrafenib Comparable to Vemurafenib in Melanoma Reinforces BRAF kinase as important therapeutic target Chicago—Another BRAF kinase inhibitor has been found to be highly active for the treatment of advanced melanoma in a Phase III trial.

Dabrafenib produced an improvement in progression-free survival (PFS) that was similar to vemurafenib when both were compared with dacarbazine (DTIC), according to the BREAK-3 trial presented at the 2012 annual meeting of the American Society of Clinical Oncology (ASCO; abstract LBA8500).

The data for overall survival (OS), which also was significantly improved with vemurafenib, are not yet mature for dabrafenib, but the data reinforce the BRAF kinase as an important target for halting melanoma growth.

Compared with DTIC, “a significant benefit for PFS and objective response rate was observed in all subgroups examined,” said Axel Hauschild, MD, a professor of dermatology at the University of Kiel in Germany. Dr. Hauschild, the principal investigator of the BREAK-3 study, reported that the safety profile of dabrafenib, although different from that of vemurafenib, was acceptable.

In the study, 250 patients were randomized in a 3:1 ratio to 150 mg of oral dabrafenib twice daily or 1,000 mg/m2 of DTIC administered every three weeks intravenously. The primary end point was PFS. The average age of the study patients was 52 years.

The median PFS rate was 5.1 months for dabrafenib compared with 2.7 months for DTIC, producing a 70% reduction in the hazard ratio (HR) for PFS (HR, 0.3; 95% confidence interval, 0.18-0.53; P<0.0001).

The objective response rate was 53% for dabrafenib versus 19% for DTIC. The most common adverse events (AEs) on dabrafenib were hyperkeratosis (37%), headache (32%), pyrexia (28%), arthralgia (27%) and skin papillomas. Although pyrexia was considered serious in 4% of patients, the other serious adverse events (AEs) were limited to skin malignancies, which included squamous cell carcinomas in 6% and new primary melanomas in 2%.

Michael B. Atkins, MD, the deputy director of the Georgetown-Lombardi Comprehensive Cancer Center in Washington, D.C., noted that pyrexia was not a common AE on vemurafenib, whereas phototoxicity, a common AE on vemurafenib, was not as frequent on dabrafenib.

Other studies presented at ASCO suggest that dabrafenib retains strong activity in melanoma with either the BRAF V600E or K mutations and appears to have the same effect of brain metastases as metastases elsewhere, Dr. Atkins said. Ipilimumab and the BRAF kinase

AT A GLANCE inhibitors appear to be pushing median survival past 10 months in advanced melanoma, he added.

“In my opinion, FDA approval should happen and this means that there will be competition among BRAF inhibitors, which is a good thing for patients and for investigators,” said Dr. Atkins, indicating that this will expand options for therapies while providing new regimens on which

to build the next set of advances.

—Ted Bosworth Dr. Hauschild reports serving as an advisor and receiving honoraria and research funding from GlaxoSmithKline; Dr. Atkins has served as a consultant for Bristol-Myers Squibb, Celgene, Curetech, Genentech, Merck, Novartis and Prometheus.

Dabrafenib improved PFS by 2.4 months for patients with stage III or IV melanoma compared with dacarbazine Response rate was 50% for dabrafenib versus 6% for dacarbazine

ONCOLOGYFellow S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com

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ONCOLOGYFellow

Vol. 3, Issue 3

S UPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com

Career Paths

Fellowship Training

A DAY IN THE LIFE

We highlight the work of fellowship director Timothy Gilligan, MD. 4 FELLOWSHIP TRAINING

Experts discuss what to expect in 6 the first year of fellowship.

FELLOWSHIP TRAINING

Communication skills are crucial for oncology fellows.

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is brought to you as a professional courtesy. This content is selected and controlled by McMahon Publishing and is funded by Lilly USA.

For the latest oncology fellow–related information, please visit www.oncologyfellowadvisor.com

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Mentor Memos

Survey Says

Physician Finance

Top-Tier Centerss Share Tips

H

ospitals in the United States are anx xious to be included in the annual US News and World Rep port’s list of top hospitals. To make the 2011 to 2012 cut, cancer centers had to treat at least 254 inpatients with h highlevel expertise in 2007, 2008, and 2009 9.1 The following are the top 10 cancer centerss in US News and World Report, in ascending orrder of quality: University of Texas MD Anderson n Cancer Center, Memorial Sloan-Kettering Cancer Center (MSKCC), Johns Hopkins (JH), Mayo Clinic, Dana Farber Cancer Institute/Brig gham & Women’s Cancer Center, University of Washington Cancer Center in Seattle e, Massachusetts General Hospital, UCSF F Medical Center, Cleveland Clinic, and d Ronald Reagan UCLA Medical Center.1 Oncology Fellow Advisor spoke witth Daniel Spratt, radiation oncology trainee at Memorial Sloan-Kettering (No. 2 on the

Top-Tier page 5

Master Work–Life Balance

T

raining to be an oncologist can be rough. In the face of long hours, sleep deprivation, and patient suffering, young oncologists may sacrifice hobbies, interests, and even relationships. Many fellows find comfort in reminding themselves that better days are ahead but experts say that they may be setting themselves up for disappointment.

Oncologists who cope by looking to the future may miss opportunities in the present to shape their career to meet their needs.1 “Putting aside one’s personal needs or personal wellness can eventually come back in a negative

or unhealthy way that can lead to burnout,” said Charles M. Balch, MD, FACS, professor of surgery in the Division of Surgical Oncology at University of Texas Southwestern Medical School in Dallas, Texas. “A successful medical career at the expense of personal wellbeing is not at all successful.”

One in 3 oncologists will experience significant career burnout— described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leads to decreased effectiveness at work.2 Some of its more tragic consequences see, Work–Life page 2

To obtain educational information for oncology fellows, please visit us online: www.oncologyfellowadvisor.com

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

POINTBREAK continued from page 1

the sponsor, Eli Lilly and Company, did not want to call attention to this clearly negative study, and that the dissemination of the results might hinder growing sales of its drug for non-small cell lung cancer (NSCLC), pemetrexed (Alimta).

Dr. Patel assures me that she had hoped to present it at ASCO or ESMO, but for reasons beyond her control or that of Eli Lilly, could not do so.

POINTBREAK Trial Summary This was a prospective, randomized, open-label trial in metastatic, nonsquamous, NSCLC with four cycles of carboplatin plus bevacizumab (Avastin, Genentech) during induction and then maintenance bevacizumab until disease progression with either four cycles of paclitaxel during the induction phase (the standard arm based on the Eastern Cooperative Oncology Group’s [ECOG] 4599 trial) or four cycles of pemetrexed given during induction plus continued pemetrexed during maintenance until disease progression.1

columns of Table 1, with results of two other relevant studies included for later comparison. Substituting pemetrexed for paclitaxel during induction and adding pemetrexed to bevacizumab during maintenance had essentially no detectable beneficial effect in this study! The study was designed to show superiority of prolonged pemetrexed over shortcourse paclitaxel, and there is no evidence that this is the case. The study was not designed to demonstrate noninferiority of the pemetrexed-containing regimen over the paclitaxel-containing regimen, but most reasonable people looking at the data would conclude that the results are about the same.

Dr. Patel did present a subgroup analysis showing a small benefit in median progression-free survival (PFS) of 1.7 months and in median overall survival (OS) of two months for patients who went on to maintenance in the pemetrexed-containing arm, but this analysis was neither impressive nor convincing, since it excluded 349 patients who did not go on to maintenance. The use of pemetrexed in maintenance was not the major question being asked in this trial.

Table 2 summarizes the toxicity seen

at Indiana University, in Indianapolis, that established pemetrexed as a second-line therapy for NSCLC.2 Similarly, the pemetrexed-containing arm was less myelosuppressive in a comparative study of cisplatin with either gemcitabine or pemetrexed by Giorgio Scagliotti, MD, PhD, at the University of Turin, in Italy.3 (See Table 4 for the efficacy results of this study.)

While the pemetrexed-containing arm had somewhat more hematologic toxicity in POINTBREAK, it had much less alopecia and neuropathy (Table 2). It had more fatigue, and significantly more grade 3-4 fatigue, than the paclitaxel arm. The extent of the fatigue surprised and impressed Dr. Patel.

Table 3 shows that equal numbers of patients with progressive tumor growth had second-line chemotherapy (about 60%), with some variation in the choice of treatment based on the failed initial treatment. I was surprised to note that 14% of patients whose tumors worsened on pemetrexed plus bevacizumab were re-treated with these agents.

Dr. Patel wonders if these were patients who were taken “off study” for toxicity—mainly fatigue—while their tumors

‘Our lung cancer patients are suffering and dying, and we are morally obligated to relieve their suffering and delay their dying. It seems that pemetrexed in induction and maintenance together with bevacizumab and carboplatin does not do either.’

The study accrued patients between 2008 and 2011, largely in the United States, in whom bevacizumab was felt to be safe. Median age was 64.7 years (range, 29.5 to 86 years); 53% were male; 44% had a performance status of 0; 90% had stage IV disease; 79% had adenocarcinoma; 11% had brain metastases that had been treated and controlled; and 88% had smoked at some point.

The key results in terms of outcome are given in the third and fourth

in the two arms. Surprisingly, there was more thrombocytopenia, febrile neutropenia, and use of red cell and platelet transfusions in the pemetrexed-containing arm, perhaps because only this arm included myelotoxic chemotherapy in maintenance. The finding that the pemetrexed arm is more toxic is somewhat surprising because pemetrexed as second-line chemotherapy was much less myelotoxic than docetaxel in the original study by Nasser Hanna, MD,

were still responding, and then resumed pemetrexed and bevacizumab after their strength recovered.

Why the Disappointment?

Several lines of evidence had suggested that pemetrexed was a superior drug for non-squamous cell lung cancer. This began with an Eli Lilly-sponsored noninferiority trial of cisplatin with either pemetrexed or gemcitabine, conducted in Europe and Asia. The

Table 1. Comparison of First- and Second-Line Therapies In Non-Small Cell Lung Cancer ECOG E4599

POINTBREAK Trial

AVAil Trial

850

939

1,043

Total Patients

Median PFS, mo

PacCb

PacCbBEV

PacCbBEV

PemCbBEV

GemCis

GemCis + BEV 7.5 mg/kg q21 days

4.5

6.2

5.6

6

6.1

6.5

6.7

6

7

Median TTDP, mo

GemCis + BEV 15 mg/kg q21 days

ORR, %

15

35

33

34

22

35

38

Median OS, mo

10.3

12.3

13.4

12.6

13

13.4

13.6

2-y Survival, %

16

24

21

24

23

24

22

BEV, bevacizumab; Cb, carboplatin; Cis, cisplatin; Gem, gemcitabine; ORR, objective response rate; OS, overall survival; Pac, paclitaxel; PFS, progression progression-free free surviv survival; val; TTDP, time to disease progression progressio on

EDITORIAL BOARD COMMENTARY Steven Vogl, MD Medical Oncologist, New York City

trial demonstrated noninferiority for the pemetrexed-containing arm, but a subgroup analysis showed this arm to be inferior for squamous cancer and superior for the rest (mostly adenocarcinoma).

The advantage of the pemetrexed-containing arm for adenocarcinoma turns out not to be very impressive, although statistically significant (Table 4).3 With this result, Eli Lilly and Company reanalyzed Dr. Hanna’s earlier trial of second-line chemotherapy comparing pemetrexed to docetaxel and also found pemetrexed superior in nonsquamous histologies.4 The differences for adenocarcinoma patients were, again, not very impressive, although statistically significant.

These two results led to a change in the FDA-approved label for pemetrexed and a general change in practice.

Further, maintenance pemetrexed was shown to improve PFS and OS both after induction chemotherapy with other drugs—2.8-month median OS benefit, and after induction therapy containing pemetrexed—2.9-month median OS benefit.5,6 Many of us hoped that pemetrexed, which seemed to be a better drug for adenocarcinoma when given in induction and also when given in maintenance, would be even better when given in both phases, with a major survival advantage in adenocarcinoma, which is becoming the predominant form of lung cancer.

Possible Explanations for the Negative POINTBREAK Result It seems very unlikely that chance led to a false-negative result in this study.

Given the large number of patients and the care with which the trial was conducted, it is exceedingly unlikely that a clinically significant benefit was missed.

It is also unlikely that the study was negative because the control group (paclitaxel, carboplatin and bevacizumab) did unusually well by chance. As shown in the second and third columns of Table 1, the control group results in POINTBREAK were almost identical to the results in the ECOG 4599 trial of the same regimen conducted by Alan Sandler, MD, at Oregon Health & Science University, in Portland.1 We should note that the magnitude of a “clinically significant benefit” in the treatment of metastatic NSCLC is really pretty small on an absolute scale from the patient’s point of view, where prolongation of remission and life by years

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Table 2. POINTBREAK Trial: Toxicity PacCbBEV

PemCbBEV

Grade 3-4 thrombocytopenia, %

6

23

Grade 3-4 neutropenia, %

41

26

Febrile neutropenia, %

5

11

Sensory neuropathy (any), %

40

12

Red cell transfusion, %

9

24

Platelet transfusion, %

2

7

Treatment-related hospitalization, %

19

20

Alopecia (any), %

38

7

Fatigue (any), %

53

45

Grade 3-4 fatigue, %

11

5

BEV, V, bevacizumab; bevac u ab; Cb, carboplatin; ca bop at ; Pac, ac, paclitaxel; pac ta e ; Pem, e , pemetrexed pe et e ed

‘Substituting pemetrexed for paclitaxel during induction and adding pemetrexed to bevacizumab during maintenance had essentially no detectable beneficial effect in this study.’ rather than months would be a much more desirable result, as would cure.

Compare the analysis of metastatic lung cancer trials to the issues being evaluated in trials testing treatments of testis cancer, Hodgkin and diffuse large B-cell lymphomas, and chronic myelogenous leukemia. Nonetheless, our lung cancer patients are suffering and dying, and we are morally obligated to relieve their suffering and delay their dying. It seems that pemetrexed in induction and maintenance together with bevacizumab and carboplatin does not do either compared to just 4 doses of generic paclitaxel.

Table 5 is a list of possible explanations for the negative result. I think the first four are credible hypotheses, and will discuss each in detail.

Perhaps Pemetrexed Is Not a Better Drug for Lung Adenocarcinoma The suggestion that pemetrexed was superior for lung adenocarcinoma came out of an Eli Lilly-sponsored trial designed to establish the equivalence of pemetrexed-cisplatin to the European standard of gemcitabine-cisplatin for metastatic NSCLC of all histologies.3 The trial was not stratified by histology, but when the preplanned analysis by histology was done, it seemed that gemcitabinecisplatin had a modest survival advantage for squamous cancer of the lung, and pemetrexed-cisplatin for non-squamous histologies (Table 4). The paper properly describes the result as hypothesis-generating. The paper does not break down PFS, objective response rate (ORR) and duration of objective response by histology. The survival differences are modest.

Eli Lilly then went back to another equivalence trial, this time of pemetrexed

compared with docetaxel as a single agent for second-line therapy of NSCLC, and found a similar difference with docetaxel favored for squamous cancer and pemetrexed for the rest. Although the difference in OS was statistically significant, the differences are not impressive for adenocarcinoma: For adenocarcinoma patients, pemetrexed produced a median OS of 9 months compared with 9.2 months for docetaxel, with a median PFS of 3.5 months for each, and an ORR of 13% for pemetrexed versus 10%, for docetaxel.

Neither of these noninferiority trials was designed to demonstrate pemetrexed superiority in adenocarcinoma or all non-squamous cancers. Such analyses are properly considered hypothesisgenerating only.

The lack of cumulative toxicity of pemetrexed (especially neurotoxicity and cytopenias) and the apparent advantage of pemetrexed in adenocarcinoma and large cell carcinoma, led to its use in two maintenance studies, where relatively large benefits were observed.

These may have resulted not from a particular sensitivity of adenocarcinoma to pemetrexed, but because pemetrexed was better than no maintenance chemotherapy in these studies.3,6 Indeed, a recently published French trial in which more than two-thirds of patients had adenocarcinoma showed that maintenance gemcitabine—another “nice drug” that lacks neurologic and other cumulative toxicities—prolongs median PFS to 3.8 months from 1.9 months with observation.7 Unlike pemetrexed in two trials, though, gemcitabine given before progression of disease did not prolong OS. Thus, gemcitabine is probably not as good a maintenance drug as pemetrexed.

In a large drug company-sponsored trial

whose subjects were of uncertain histologic subtype and had relatively poor performance status, maintenance gemcitabine had no detectable effect on PFS or OS.8 A Central European Oncology Group trial randomized 206 patients (45% adenocarcinoma) in 2:1 ratio to gemcitabine maintenance over observation. It found a 6-week statistically significant prolongation of median time to progression and an 8-week non-significant prolongation of median OS.9

New Trial Needed A conservative interpretation of the POINTBREAK results is that the trial should lead first to a prospective trial by histology of a pemetrexed doublet versus a taxane, vinorelbine or gemcitabine doublet for non-squamous histologies, and that this trial should include careful histologic review and definition of histologic types. Gene expression, methylation and mutation studies of the tumors from the patients entered

(Navelbine, Abbott Healthcare).

A simple explanation of the negative POINTBREAK result would be that bevacizumab improves the activity of paclitaxel-carboplatin but not pemetrexed-carboplatin, and that whatever benefit was gained by giving pemetrexed over paclitaxel was lost because bevacizumab did not make pemetrexed work better. It is also possible that pemetrexed and bevacizumab are antagonistic in some patients, and that this antagonism wipes out the benefit seen in others. How to define such subpopulations is still speculative in 2012.

The results of the AVAil Trial in comparison with Dr. Sandler’s ECOG trial suggest that bevacizumab benefit in lung cancer is also dependent on the partner drugs (compare the lateral portions of Table 1).10 This study, reported by Martin Reck, MD, from Germany, of gemcitabine-cisplatin with no bevacizumab, low-dose bevacizumab, or high-dose bevacizumab suggests that bevacizumab has a modest effect of raising objective

Table 3. POINTBREAK Trial: Therapy After Progression PacCbBEV

PemCbBEV

Any therapy, %

59

60

Pem, %

36

14

BEV, %

12

14

Erlotinib, %

15

15

Docetaxel, %

8

21

BEV, bevacizumab; Cb, carboplatin; Pac, paclitaxel; pac clitaxel; Pem, pemetrexed

would be of great interest, since histologic type seems a crude technique for determining drug sensitivity.

Because POINTBREAK is negative, bevacizumab should not be given in either arm of this hypothetical study.

Because of POINTBREAK, we already know that adenocarcinoma patients do not do better when pemetrexed is substituted for paclitaxel in combination with carboplatin and bevacizumab. Deleting bevacizumab remains ethical, I believe, especially for those subgroups that got little benefit from bevacizumab in ECOG 4599—those over age 65 and women—as well as for patients with contraindications to bevacizumab.

Perhaps Pemetrexed Is Not A Good Drug To Give With Bevacizumab Data from breast cancer studies (see “Weekly Pac-Bev Should Not Be Abandoned,” Clinical Oncology News, October 2012) suggest that bevacizumab is much more beneficial when given with weekly paclitaxel than with everythree-week docetaxel, capecitabine, ixabepilone (Ixempra, Bristol-Myers Squibb), gemcitabine or vinorelbine

response in non-squamous lung cancer, a trivial though statistically significant effect on PFS, and no effect on median or two-year survival. The benefits are much more impressive in the ECOG 4599 study when the partner drugs are paclitaxel and carboplatin.

Perhaps the POINTBREAK Patient Population Is Depleted of PemetrexedSensitive Patients Since POINTBREAK began accrual in December 2008 in the United States, it is likely that most patients considered for see POINTBREAK, K page 12

What are your thoughts?

Clinical Oncology News welcomes letters to the editor.

Do you have thoughts on Dr. Vogl’s commentary?

Please send comments to gmiller@mcmahonmed.com

11

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CURRENT PRACTICE

POINTBREAK continued from page 11

entry would have had testing for epidermal growth factor receptor (EGFR ( ) exon 19 and 21 mutations. If the tumors tested positive, patients were likely offered initial erlotinib rather than entering the trial. Dr. Scagliotti recruited patients about five years earlier. Most of his study candidates probably were not screened for EGFR mutations. Mutation carriers in the I-PASS trial responded better to chemotherapy than noncarriers.11 Perhaps it is the mutation carriers who derive benefit from pemetrexed over taxane, and their depletion from the POINTBREAK trial resulted in the negative result.

In contrast to the four fairly plausible explanations for this negative result, it seems unlikely that the other clinical characteristics of the POINTBREAK population explain the negative result, nor does it seem likely that excluding patients at higher risk for bevacizumab toxicity—for example, central-lung primary tumor, bleeding, advanced age, heart disease, gastrointestinal lesions, severe hypertension, likely to need imminent surgery or the presence of open or nonhealed wounds—would substantially affect the outcome of the trial.

Perhaps Pemetrexed Looked More Active in Maintenance Studies Because Entry to These Depended on Having Had Some Prior Benefit From Chemotherapy Results of first-line chemotherapy studies are very dependent on recruiting more patients to achieve a benefit, be this response, symptom relief or slowing of tumor growth. Mechanisms of multidrug resistance via drug efflux pumps are well known in oncology. If primary resistance to paclitaxel is associated with primary resistance to pemetrexed in most of the nonresponders to paclitaxel, then even if pemetrexed were superior in the minority of tumors sensitive to paclitaxel, this would be hard to demonstrate in the overall analysis unless the study population was very large. Even then, the effect

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

‘Even though the POINTBREAK trial was designed to show that pemetrexedcarboplatin-bevacizumab is superior to paclitaxel-carboplatin-bevacizumab in the treatment of metastatic non-squamous, non-small cell lung cancer, and failed to do so, it demonstrates to my satisfaction that pemetrexed is an acceptable alternative to paclitaxel in this setting.’ might seem small because the minority of patients gaining substantial benefit could not be identified.

Less Likely Explanations Perhaps new reagents for immunohistochemistry have changed the definitions for adenocarcinoma and squamous cancer over the years in the first decade of the 21st century. Unfortunately, histologic review and uniform definitions of cell type were not part of any of the studies cited here, even though a great deal has been made about pemetrexed’s relative superiority in the treatment of nonsquamous histologies.

Finally, in POINTBREAK, pemetrexed was paired with carboplatin rather than cisplatin, as it was in Dr. Scagliotti’s trial that first suggested the special sensitivity of adenocarcinoma and large cell carcinomas.3 Cisplatin has been associated repeatedly with a modest improvement in outcome over carboplatin at the cost of more toxicity and much more demanding care during administration. Perhaps cisplatin is also necessary for optimal activity of pemetrexed, although I know of no evidence for this hypothesis.

What About Maintenance Pemetrexed Plus Bevacizumab?

In his invited discussion of POINTBREAK in Chicago, Corey Langer, MD, the chief of thoracic oncology at the University of Pennsylvania in Philadelphia, spent a lot of time wondering if this regimen should be considered established.

POINTBREAK does demonstrate this, since comparing maintenance regimens with this trial makes the unwarranted assumption that different benefits and toxicities during the 12 weeks of induction therapy are precisely balanced between the arms, so that we can ignore

anything that happened in those 12 weeks and proceed as if the initial stratification assured comparable groups 12 weeks later. It did not!

Dr. Langer cites another study called AVAPERL that gave all 376 entered patients induction with pemetrexed, cisplatin and bevacizumab, and randomized 253 still “on study” after 12 weeks to

induction chemotherapy with cisplatin and pemetrexed based on the Paz-Ares data. Happily, maintenance single-agent pemetrexed is one arm of the ongoing ECOG 5508 trial. This study hopes to randomize 864 patients still fit and not worsening after paclitaxel, carboplatin and bevacizumab induction for 12 weeks to pemetrexed alone, bevacizumab alone

Table 4. Randomized, Controlled, Noninferiority Phase III Trial Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed GemCis

PemCis

10.3

10.3

Adenocarcinoma (847 patients)

10.9

12.6

Large cell histology (143 patients)

6.7

10.4

Squamous cell histology (473 patients)

10.8

9.4

Median PFS, mo

5.1

4.8

Median duration of response, mo

5.1

4.5

ORR, %

28

31

Median OS, mo (1,725 patients)

Results for all histologies combined

Cis, cisplatin; Gem, gemcitabine; ORR, overall response rate; OS, overall survival; Pem, pemetrexed; PFS, progression-free progression free survival

either bevacizumab alone or with pemetrexed.12 The doublet maintenance prolonged median PFS from start of maintenance to 7.4 months from 3.7 months with bevacizumab alone; survival data are still immature.

Unfortunately, AVAPERL has no real control arm that is “standard therapy” for metastatic NSCLC. Maintenance bevacizumab has not, to my knowledge, ever been shown to be better than observation. On the other hand, on Oct. 17, 2012, the FDA recognized maintenance pemetrexed as safe and effective after

or the combination. I believe that pemetrexed maintenance is the “standard arm” of this study.

Conclusion Even though the POINTBREAK trial was designed to show that pemetrexedcarboplatin-bevacizumab is superior to paclitaxel-carboplatin-bevacizumab in the treatment of metastatic nonsquamous, NSCLC, and failed to do so, it demonstrates that pemetrexed is an acceptable alternative to paclitaxel in see POINTBREAK, K page 15

Article and Review Reprints Reprints of Clinical Oncology News articles and reviews are available.

Call Julianna Dawson at (212) 957-5300 x271.

Reprints can be ordered in black & white or 4-color.

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POINTBREAK continued from page 12

this setting. Since long-term survival or cure is not at issue, for practical (but not statistical) purposes, I believe that we can proceed from the conclusion that the regimens are equivalent!

Pemetrexed has the advantage of causing less neurotoxicity and alopecia, although I doubt the accuracy of alopecia reporting in this trial—it seems much too low as reported in the paclitaxel arm. In contrast, pemetrexed causes more thrombocytopenia and leads to more transfusions of red cells and platelets, as well as more severe fatigue. These disadvantages would seem easy to mitigate by modest dose reductions and delays, especially in maintenance.

If you are a poor country (and is there a rich one, except those with small populations and awash in oil?) or selfinsured and pressured to contain costs, you may substitute generic paclitaxel for brand-name and outrageously expensive Alimta (pemetrexed) in the setting of first-line chemotherapy of non-squamous

‘Note, however, that this hypothetical poor country or strapped insurer, having decided to substitute paclitaxel for pemetrexed to save money at the price of causing hair loss and numb hands and feet, may already be on the way to the International Monetary Fund for a loan or facing fiscal crisis to pay for the prolonged and similarly outrageously expensive bevacizumab.’ metastatic lung cancer with carboplatin and bevacizumab. As a solo practitioner, I pay about $7,200 monthly to provide pemetrexed to a male patient whose body surface area calculates to 2.0 square meters. Larger purchasers probably can negotiate a lower price, but Medicare part D prescription plans (which are forbidden by law to negotiate on price), probably pay even more despite being very large purchasers.

Note, however, that this hypothetical poor country or strapped insurer, having decided to substitute paclitaxel for pemetrexed to save money at the price of causing hair loss and numb hands and feet, may already be on the way to the International Monetary Fund for a loan or facing fiscal crisis to pay for the prolonged and similarly outrageously

Table 5. Possible Explanations for the Negative POINTBREAK Trial Result 1. Pemetrexed was never a better drug for adenocarcinoma; we just thought so because of two unplanned drug company–sponsored subgroup analyses of noninferiority trials.

2. Pemetrexed is actually a better drug for adenocarcinoma, but something about the POINTBREAK trial obscures the benefit. a. Pemetrexed is a poor partner for bevacizumab. b. The patient population does not favor pemetrexed—depleted of tumors with EGFR mutations, relatively old, 10% black, selected to avoid bevacizumab toxicity. c. Induction patients are different from maintenance patients. Those resistant to paclitaxel induction are just as resistant to pemetrexed induction. d. Pathology techniques and histologic grouping have changed the “patient characteristics” of studies between 2004 and 2008. e. Carboplatin is an inferior partner for pemetrexed (compared with cisplatin).

expensive bevacizumab ($8,318 per month in my office for the same 91-kg male patient). Since bevacizumab was given in ECOG 4599 and POINTBREAK until disease progression, death or intolerable toxicity, this monthly cost starts on day 1 of induction and continues all through maintenance. To riff on Dr. Corey Langer’s pun in his discussion in Chicago, I wonder if the POINT is that these very expensive treatments given for prolonged periods will BREAK the bank!

References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550, PMID: 17167137.

2. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol.

2004;22:1589-1597, PMID: 15117980.

3. Scagliotti GV, Parikh P, von Pawel J, et al.

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008;26:3543-3551, PMID: 18506025.

4. Scagliotti G, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two Phase III studies. Oncologist. 2009;14:253263, PMID: 19221167.

5. Ciuleanu T, Brodowicz T, Zielinski C, et al.

Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: a randomised, double-blind, phase 3 study. Lancet.

2009;374:1432-1440, PMID: 19767093.

6. Paz-Ares L, De Marinis F, Dediu M, et al.

PARAMOUNT: Final overall survival (OS) results of the phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo (plb) plus BSC immediately following induction treatment with pem plus cisplatin (cis) for

advanced nonsquamous (NS) non-small cell lung cancer (NSCLC). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract LBA7507.

7. Pérol M, Chouaid C, Pérol D, et al. Randomized, Phase III study of gemcitabine or erlotinib maintenance therapy versus observation, with predefined secondline treatment, after cisplatin-gemcitabine induction chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol.

2012;30:3516-3524, PMID: 22949150.

8. Belani C, Waterhouse DM, Ghazal H, et al. Phase III study of maintenance gemcitabine (G) and best supportive care (BSC) versus BSC, following standard combination therapy with gemcitabine-carboplatin (G-Cb) for patients with advanced non-small cell lung cancer (NSCLC). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 4-8, 2010; Chicago, IL. Abstract 7506.

9. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabine firstline chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer. 2006;52:155163, PMID: 16569462.

10. Reck M, von Pawel J, Zatloukal P, et al. Overall survival with cisplatin-gemcitabine and bevacizumab or placebo as first-line therapy for nonsquamous nonsmall-cell lung cancer: results from a randomised phase III trial (AVAiL). Ann Oncol.

2010;21:1804-1809, PMID: 20150572.

11. Mok TS, Wu YL, Thongprasert S, Yang CH, et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med. 2009;361:947-957, PMID: 19692680.

12. Barlesi F, de Castro J, Dvornichenko V, et al. AVAPERL (MO22089): Final efficacy outcomes for patients (pts) with advanced non-squamous non-small cell lung cancer (nsNSCLC) randomised to continuation maintenance (mtc) with bevacizumab (bev) or bev+pemetrexed (pem) after firstline (1L) bevcisplatin (cis)-pem treatment (tx). Presented at the Annual Meeting of the European Society of Medical Oncology, September 23-27, 2011; Stockholm, Sweden.

Abstract 34LBA.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Nix Lymphadenectomy in Low-Risk Endometrial Ca From Gynecologic Oncology

T

he role of lymphadenectomy in endometrial cancer remains controversial.

However, a new study published by a team of researchers from Mayo Clinic, an institution where the procedure is not part of the preferred management approach, has found that it can actually increase morbidity and cost of care in patients with so-called lowrisk forms (stages Ia and Ib or grades 1 and 2) of the uterine cancer. Patients with low-risk forms of endometrial cancer encompass more than 25% of those with the disease.

The study, published in the October issue of Gynecologic Oncology (2012;127:5-10, PMID: 22771890), reviewed 1,393 consecutive surgically managed cases from Mayo Clinic during the period from January 1999 to December 2008. Of these, 385 met the inclusion criteria for the study, meaning that they had been diagnosed with a low-risk form of endometrial

cancer and did not have synchronous or grossly apparent metastases.

Among these cases, 80 of the patients had undergone lymphadenectomy and 305 had not.

The researchers found that complications within the first 30 days of treatment were more common in the lymphadenectomy group (37.5% vs.

19.3%; P<0.001). The five-year causespecific survival rate was slightly lower in the lymphadenectomy group (97.3%) than in the non-lymphadenectomy group (99.0%; P=0.32) and recurrence-free survival rates followed a similar pattern (96.0% and 97.6%, respectively; P=0.64).

A cost-of-care analysis revealed that the median 30-day cost of care was $15,678 for lymphadenectomy cases compared with $11,028 for nonlymphadenectomy cases (P ( <0.001).

The researchers found that the addition of lymphadenectomy significantly increased costs for both open ($4,098) and closed ($5,500) approaches and that the cost to identify a single node-positive

EXPERT INSIGHT David G. Mutch, MD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Ira C. and Judith Gall Professor of Obstetrics and Gynecology and Chief, Division of Gynecologic Oncology, Washington University School of Medicine in St. Louis

T

he management of endometrial cancer is evolving. Of all the cancers that a gynecologic oncologist treats, this is the most difficult. In 1987, a prospective staging study was published by the Gynecologic Oncology Group (GOG-33).1 This large study showed that a significant number of patients had lymph node metastases.

We also learned from this study that there were significant prognostic features that included age (>70 years), deep invasion, lymphovascular space involvement and grade that were associated with lymph node involvement and survival. At that point in time, the standard of care became total abdominal hysterectomy, bilateral salpingo-oophorectomy with pelvic and para-aortic lymph node dissection for all patients.

Since the publication of GOG 33, newer data has suggested that there may not be a survival advantage associated with the actual lymph node dissection. The knowledge of this information does allow us to avoid adjuvant therapy and, we believe, decrease the morbidity of management by minimizing adjuvant therapy. Data from many studies suggest that if a patient has no poor prognostic features, the risk for nodal metastasis and recurrence is low. The problem is that this data cannot be known until the final pathology is returned. The recent index paper published in Gynecologic Oncology by Mayo Clinic suggests the same as these other studies.

Pathology is processed at Mayo Clinic as a frozen section, so all pathology is essentially completed at the end of the operation. Hence, in this very

patient among the 80 patients having lymphadenectomy ranged from $327,866 (if managed via laparotomy) to $439,990 (if managed via minimally invasive surgery). Additionally, their analysis determined that if lymphadenectomy had been performed in the 305 patients managed with removal of the uterus and adnexa, the patients’ total health care costs would have increased by $1,418,189 (the increase in costs per patient was estimated at $4,650); conversely, the researchers noted, vaginal hysterectomy with salpingo-oophorectomy reduced the cost of primary surgery by more than 20%.

The authors of the Mayo Clinic study concluded that, given these findings, lymphadenectomy in lowrisk endometrial cancer, which accounts for more than one-fourth of all patients with endometrial cancer, is “not justifiable” and that hysterectomy and salpingo-oophorectomy, preferably via a minimally invasive approach, should be the standard of care for this patient population.

unique clinical situation, the data is known and patients at Mayo Clinic can be triaged immediately. This is not the case at any other institution in the United States. This technique also is controversial in that special stains cannot be performed in that setting either, and some information may be lacking in these patients.

This paper verifies other published information about endometrial cancer management. Unfortunately, at this time it cannot be applied to the general endometrial cancer population in a prospective manner. However, as we have become better at understanding the poor prognostic features involved with endometrial cancers, we can use these and other surrogates to manage patients who have not had complete surgical staging.

By the NUMBERS: Political Contributions

by Health Care Organizations

$166,669,314 Total amount the health care sector has spent in the 2012 election cycle

56 Percent given to Republicans

$17,540,800 Amount given by single largest contributor, the Adelson Clinic, owned by Dr. Miriam and Sheldon G. Adelson

100 Percent of this contribution that is unlimited, largely unregulated “soft money”

$1,017,312 Amount given by Amgen, the highest among cancerfocused pharmaceutical companies

51 Percent of Amgen’s contributions given to Democrats

$1,467,800 Political donations made by the American Academy of Orthopedic Surgeons

$651,800 Reference 1. Creasman WT, Morrow CP, Bundy BN, et al. Surgical pathologic spread patterns of endometrial cancer. A Gynecologic Oncology Group study. Cancer. 1987;60(8 suppl):2035–2041, PMID: 3652025.

Dr. Mutch reported no relevant financial disclosures.

Political contributions by US Oncology PAC

$0 Contributions made by the American Society of Clinical Oncology, which is prohibited from conducting political campaign activities as a 501(c) organization Data taken from the Center for Responsive Politics based on campaign finance totals for the current election cycle as released by the Federal Election Committee.

Accessed October 18, 2012.

18

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Treatment for Older Glioblastoma Patients Studied From Lancet Oncology

A

study designed to evaluate treatment options for older patients (aged ≥60 years) with glioblastoma (GBM) has revealed that chemotherapy with temozolomide (Temodar, Merck) or hypofractionated radiotherapy are both more effective than standard radiotherapy in this population.

The results of the study were published in the September issue of Lancet Oncology (2012;13:916-926, PMID: 22877848). The study was funded in part by Merck, manufacturer of the study drug.

According to the team of researchers from multiple hospital centers throughout Europe, the goal of the study was to rectify, at least in part,

a shortcoming of current guidelines governing the treatment of GBM, a cancer that carries a particularly poor prognosis (median survival is less than one year). Most published guidelines define treatment for patients between the ages of 60 and 70, but fail to address the subset of patients who are older than age 70, for whom guidelines do not exist due to a relative lack of data.

For the study, the authors enrolled 342 patients, 291 of whom were eventually randomized across three treatment groups—93 in the temozolomide arm (200 mg/m2 days 1-5 of every 28-day cycle for up to six cycles), 98 in the hypofractionated radiotherapy arm (34 Gy in 3.4-Gy fractions over two weeks) and 100 in the standard radiotherapy arm (60 Gy in 2.0-Gy

EXPERT INSIGHT David Tran, MD, PhD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Assistant Professor of Medicine, Washington University School of Medicine in St. Louis

T

he median age of diagnosis for GBM is 64 years. However, few large-scale prospective studies have been conducted to address the question of how to approach treatments for elderly patients with GBM. The specific issues are whether the standard six weeks of radiotherapy with concurrent temozolomide can be used safely in elderly patients, and whether temozolomide alone or hypofractionated radiotherapy would achieve comparable efficacy without excessive toxicity.

Although performance status, comorbidities and extent of resection are some of the main factors often used in treatment decisions, whether age also should be included as an independent

risk factor in this algorithm remains unclear given the current literature.

Yet age often is featured prominently in neuro-oncologists’ therapeutic decisions as it has been suggested to be a poor prognostic indicator.

In this respect this report from the Nordic Clinical Brain Tumor Study Group is the first major prospective, Phase III randomized trial that directly addresses the contribution of many of these factors, including age, to treatment outcomes in elderly patients with GBM. The original cut-off age for the study was 60 years old. However, four years into accrual, the age was increased to 65 due to positive results from the European Organisation for Research

fractions over six weeks). Another 51 patients were randomized across two groups—26 in the temozolomide arm and 35 in the hypofractionated radiotherapy arm. In the three-group randomization, median overall survival (OS) was significantly longer in the temozolomide group (8.3 months) than in the standard radiotherapy group (six months; P=0.01); however, the difference was not significant when the standard radiotherapy group was compared with the hypofractionated radiotherapy group (7.5 months; P=0.24).

For all patients who received temozolomide or hypofractionated radiotherapy (n=242), OS was similar, at 8.4 and 7.4 months, respectively (P ( =0.12).

Patients treated with temozolomide who had a methyl–ated O(6)-methylguanine-DNA methyltransferase

((MGMT T) gene promoter had significantly longer survival than those without MGMT T promoter methylation (9.7 vs. 6.8 months, respectively; P=0.02), but the researchers found no difference between patients with methylated and unmethylated MGMT T promoter who had been treated with radiotherapy (hazard ratio, 0.97; P=0.81).

Most importantly, given the aim of the study, survival among patients aged 70 years or older was better following treatment with temozolomide or hypofractionated radiotherapy than with standard radiotherapy.

According to the authors of the study, the hazard ratio for temozolomide versus standard radiotherapy was 0.35 ((P<0.0001), and the hazard ratio for hypofractionated versus standard radiotherapy was 0.59 ((P=0.02).

and Treatment of Cancer study, published in late 2004, that showed a survival benefit for patients younger than 65 years receiving combined chemoradiotherapy.1 Temozolomide or hypofractionated radiotherapy produced superior survival compared with standard radiotherapy, and this effect was further amplified and reached significance. One caveat is that the standard radiotherapy group did not start treatment until six weeks after surgery, compared with only three weeks for the temozolomide-alone arm. Whether such difference in treatment initiation confounds the final outcome in this age group is unclear. However, in younger patients, treatment initiation delay between three to six weeks postsurgery did not result in any significant differences in treatment effects.

Finally, MGMT T promoter methylation status also was incorporated into the Nordic trial. As expected, the presence of methylated MGMT T promoter in GBM was correlated with increased OS irrespective of treatment. However, surprisingly, patients with tumors

possessing a methylated MGMT T promoter had greater responses to temozolomide as predicted, yet no such benefit was observed in the standard radiotherapy arm. One possible explanation is the unplanned crossovers between these two treatment groups, confounding statistical analyses.

Overall, the Nordic study provided strong evidence supporting the use of either temozolomide alone or hypofractionated radiotherapy as the new treatment standard for elderly patients with GBM. All other factors being equal, the presence of methylated MGMT T promoter in the tumor could be used to decide between temozolomide and hypofractionated radiotherapy.

Reference 1. Stupp R, Mason WP, van den Bent MJ, et al. Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma.

N Engl J Med. 2005;352:987-996; PMID: 15758009.

Dr. Tran reported no relevant financial disclosures.

Having trouble keeping up with all of the oncology and medical journals that cross your desk?

On a monthly basis, Clinical Oncology News highlights key studies from the journals and provides guest clinician perspectives to help you stay up to date.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Dose-Dense Paclitaxel Improves Ovarian Cancer Survival Questions remain about best route of administration Chicago—After five years of follow-up, a dose-dense strategy of paclitaxel 80 mg/m2 every week is still providing an overall survival (OS) benefit compared with 180 mg/m2 every three weeks in the treatment of epithelial ovarian, fallopian tube or primary peritoneal cancer.

The long-term results of the study, in which both treatment arms also received an identical dose and schedule of carboplatin, reinforce this dosing strategy as a potential standard of care.

A total of 631 patients with stage II to IV ovarian cancer were randomized to either the dose-dense group (dd-TC; paclitaxel 80 mg/m2 on days 1, 8 and 15) or the conventional, triweekly group (c-TC; paclitaxel 180 mg/m2 on day 1).

Both groups received a carboplatin dose equivalent to AUC 6 on day 1.

At a median of 6.4 years of follow-up, there continues to be a highly statistically significant improvement in median progression-free survival (PFS) in favor of the dd-TC group compared with the c-TC group (28.2 vs. 17.5 months; hazard ratio [HR], 0.75; 95% confidence interval [CI], 0.62-0.91; P=0.0037; Figure). At the 2012 annual meeting of the American Society of Clinical Oncology (ASCO; abstract 5003), lead investigator Noriyuki Katsumata, MD, PhD, of Nippon Medical School in Kanagawa, Japan, stressed that the OS benefit was similar to that reported after the first data analysis published several years ago (Lancet ( t 2009;374:1331-1338, PMID: 19767092).

Whereas the PFS advantage of the dosedense regimen in the latest analysis was similar to that reported previously, the median OS in the dose-dense arm has not yet been reached in the follow-up period.

Overall, the OS advantage first reported with the initial results remains statistically significant for dd-TC (58.7% vs. 51.1%; HR, 0.79; 95% CI, 0.63-0.99; P=0.039).

“This is a major contribution in understanding dose-dense therapy

and whether it should be used,” said Jonathan Berek, MD, who directs the Stanford Women's Cancer Center, in Stanford, Calif. However, he noted that the greatest benefit appeared to be in the suboptimally resected group and that benefit was limited to serous histologic types. (The survival benefit has not yet reached significance in the optimally resected group.)

No advantage was seen in clear cell or mucinous histologic types.

Dr. Berek noted that a similar OS advantage was seen when intraperitoneal administration of paclitaxel, which also increases area-under-the-curve pharmacokinetics, was compared with conventional administration. It is not known whether one strategy is better than the other. Although Dr. Berek

®

Now Available...

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM112” Release Date: October 22, 2012

Expiration Date: October 22, 2013

Chair

Learning Objectives

Linda T. Vahdat, MD

1 Appraise recent studies that may have clinically important therapy implications for patients with locally recurrent breast cancer or metastatic breast cancer (MBC).

Associate Professor of Clinical Medicine NewYork Presbyterian Hospital Weill Cornell Medical Center New York, New York

Faculty

Adam Brufsky, MD, PhD Assistant Professor of Medicine University of Pittsburgh School of Medicine Co-Director, Comprehensive Breast Cancer Center Medical Director, Women’s Cancer Center Magee Womens Hospital/UPCI Pittsburgh, Pennsylvania

William J. Gradishar, MD

in integrating this potentially practice-changing data. For these reasons, oncologists require education on clinically relevant recent studies, against a backdrop of evidence- and consensus-based treatment recommendations.

2 Describe a treatment algorithm that reflects evidence-based management of advanced HER2-negative and HER2-positive breast tumors and novel strategies for circumventing treatment resistance.

Course Format

3 Explain core guideline-recommended approaches to MBC management that take into consideration the heterogeneity of patient and tumor characteristics.

This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

4 Compare the mechanisms, synergies, and evolving roles of current and emerging targeted therapies with activity in MBC, particularly in terms of novel combinations and sequences.

Intended Audiences Oncologists

Statement of Need Complexities in the management of MBC are substantial, and the optimal approach to therapy remains unclear. Toxicity, resistance, and hypersensitivity reactions limit the use of cytotoxic drugs in mainstay treatment regimens, and improved therapeutic options are needed for this heterogeneous disease. There are encouraging data on novel treatment approaches, including combinations and sequencing regimens, but clinicians face challenges

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

JGOG, Japanese Gynecologic Oncology Group

Drs. Katsumata and Berek had no relevant financial relationships to disclose.

Individualizing Therapy in Metastatic Breast Cancer

Professor of Medicine Division of Hematology and Medical Oncology Department of Medicine Feinberg School of Medicine Northwestern University Chicago, Illinois

Figure. Progression-free survival in JGOG 3016.

indicated that both could reasonably be considered, he reported that several studies under way “will answer whether route of administration or specific drugs are important in addition to the dosedense regimen.”

—Ted Bosworth

Interactive Web-based monograph

Estimated Time for Completion: 60 minutes Accreditation Statement

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.0 AMA PRA Category 1 Credit™. t Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Method of Preparation To receive CME credit, participants should read the preamble, complete the pre-test, view the program, and complete the post-test and evaluation.

A score of at least 75% is required to complete this activity successfully. CME certificates will be issued immediately upon successful completion.

This activity is supported by educational grants from Genentech, Inc

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MM112”

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

SPECT/CT Effective in Obese, Head and Neck Region From JAMA

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entinel lymph node excision (SLNE) is an important diagnostic procedure for patients with melanoma. A recent study compared SLNE alone with SLNE assisted by preoperative lymphoscintigraphy using hybrid single-photon emission computed tomography/computed tomography (SPECT/CT). Findings revealed that this new imaging technology significantly improves metastatic node detection—particularly in the head and neck area—and disease-free survival (DFS) in patients with micrometastatic melanoma in regional lymph nodes.

The results of the study were published in the Journal of the American Medical Association (2012;308:1007-1014, PMID: 22968889).

The study, performed by a team of researchers from the University of Essen-Duisburg in Germany, compared the two approaches in more than 400 patients eligible for SLNE as identified by the hospital’s computerized melanoma database. In all, 254 patients between 2003 and 2008 underwent SLNE alone and 149 patients between 2010 and the conclusion of the study period in 2011 underwent SPECT/CT-assisted SLNE. All patients included in the final analysis had clinically negative lymph nodes.

Median follow-up was 22 months.

Overall, the authors found that the use of SPECT/CT allowed for increased use of SLNE in the head and neck region. Only 2% of the patients in the SLNE-alone cohort were able to undergo the diagnostic procedure

EXPERT INSIGHT Ryan Fields, MD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Assistant Professor of Surgery, Washington University School of Medicine in St. Louis

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elanoma is generally diagnosed from a skin biopsy. For lesions greater than 1 mm in depth (or for thinner lesions with certain high-risk features), SLN status is the single most predictive variable with respect to disease recurrence and melanoma-specific survival. The standard methodology for identifying SLN involves an SLN biopsy (SLNB), generally performed at the time of definitive excision of the primary melanoma. SLNB involves a preoperative lymphoscintigraphy with radiolabeled sulfur colloid, generally Tc-99m.

Dynamic images of the draining nodal basin are then obtained. Intraoperatively, a handheld gamma probe is used to localize the SLN, often with the addition of blue dye (i.e., isosulfan blue). In experienced hands, SLNB has an overall low false-negative rate. However, it can be quite high under certain circumstances, such as in the head and neck

area or in obese patients.

In this report, the ability of enhanced preoperative SLN imaging using SPECT/CT was compared with the aforementioned standard biopsy procedure, SLNE, in identifying SLN. Impressively, the authors found improved ability to identify SLNs in patients with head and neck melanoma and in obese patients. An increased number of SLNs also were identified in the SPECT/CT-assisted SLNE group, and these patients had decreased rates of nodal recurrence, which was associated with improvement in DFS. It is important to note, however, that this report was not a randomized trial. The authors compared two cohorts of patients treated from 2003 to 2011. The SPECT/CT cohort was treated after 2008 when this technique became available. There were differences between the two groups

in the head and neck region compared with 23.5% in the SPECT/CT group ( <0.001). The authors noted that (P with SPECT/CT-assisted SLNE, they were able to use smaller incisions and “alternative entry points” in the head and neck region because the anatomical location of the sentinel lymph node (SLN) had been precise.

Additionally, they determined that SPECT/CT-assisted SLNE detected more SLNs per patient than SLNE alone (2.40 vs. 1.87; P<0.001), and the number of positive SLNs per patient also was higher in the SPECT/CTassisted SLNE group (0.34 vs. 0.21; P=0.04). Interestingly, the study also showed that SPECT/CT-assisted SLNE was particularly effective in obese patients (defined as body mass index of at least 30 kg/m2): SPECT/CT-assisted

SLNE detected five of 20 positive SLNs in seven obese patients, whereas SLNE alone detected only four of 44 positive SLNs in 24 obese patients ((P<0.001).

Finally, and perhaps most importantly, the local relapse rate was far lower in the SPECT/CT-assisted SLNE group (6.8%) than in the SLNE-alone cohort (23.8%); thus, four-year DFS also was significantly higher in the former group (93.9% vs. 79.2%; P=0.02).

Based on these findings, the authors concluded that SPECT/CT-assisted SLNE enables physicians to determine the “exact location and visualization” of the SLN preoperatively, particularly in cases in which the tracer signal is “too weak for detection by the handheld gamma probe alone” or the SLN is “in the immediate vicinity of the remaining tracer depot.”

in tumor and SLN location and primary tumor ulceration (higher in the standard group). Also, as any group performs more SLNE procedures, an improvement in SLN identification would be expected, based on surgeon experience. Furthermore, because the SLNE procedure did not affect overall survival in the randomized MSLTI (Multicenter Selective Lymphadenectomy Trial-I),1,2 it would not be expected that the addition of SPECT/ CT would improve survival compared with standard SLNE. These factors are important to consider when interpreting the results of this study with respect to recurrence and survival.

However, the effect of SPECT/CT on the identification of SLNs is impressive and certainly merits further investigation. As the authors highlight, SPECT/CT showed improved ability to identify SLNs in obese patients and those with head and neck melanomas. In these patients, SPECT/CT may be a way to overcome the higher false-negative rate of the SLNE procedure. It is unlikely, however, that the addition of SPECT/CT would improve on the expected low false-negative rate of the SLNE procedure for trunk and extremity melanomas in nonobese patients when performed by an

experienced surgeon. Using SPECT/ CT in these cases would certainly increase the overall cost of the procedure with little diagnostic or therapeutic benefit.

This study demonstrates that SPECT/ CT can aid surgeons when planning an SLNE. It may be especially helpful in head and neck melanomas and in obese patients, which pose the biggest challenge in SLN identification and, consequently, have the highest false-negative rate. To define the ability of SPECT/ CT-aided SLNE to positively affect survival would require level I evidence in the form of a randomized clinical trial, which would certainly be feasible in a multi-institutional setting.

References 1. Morton DL, Cochran AJ, Thompson JF, et al. Sentinel node biopsy for early-stage melanoma: accuracy and morbidity in MSLT-I, an international multicenter trial. Ann Surg. 2005;242:302-311, PMID: 16135917.

2. Morton DL. Overview and update of the phase III Multicenter Selective Lymphadenectomy Trials (MSLT-I and MSLTII) in melanoma. Clin Exp Metastasis.

2012 Jun 24. [Epub ahead of print], PMID: 22729520.

Dr. Fields reported no relevant financial disclosures.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

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FDG-PET Comes Up Short in Lung Cancer Diagnosis Study For lesions less than 20 mm, accuracy less than 60% Chicago—Fluorodeoxyglucose positron emission tomography (FDG-PET) is a poor tool for diagnosing stage I non-small cell lung cancer (NSCLC), according to results of a study presented at the annual meeting of the American Society of Clinical Oncology (abstract 7008).

Specificity hovered around 30% in a study that involved community and academic practices.

“FDG-PET did not perform as well as previously published studies in clinical stage I patients with known or suspected non-small cell lung cancer undergoing surgical resection, “ said Eric Grogan, MD, MPH, an assistant professor in thoracic surgery at Vanderbilt-Ingram Cancer Center in Nashville, Tenn., who presented the study. Dr. Grogan said PET scan results “should be interpreted cautiously” in this patient population.

less than or equal to 10 mm.

“FDG-PET accuracy improved with lesion size,” said Dr. Grogan. “The accuracy was less than 60% in lesions less than 20 mm and greater than 80% in lesions greater than 30 mm. [Greater than] 30 mm, the accuracy did not seem to improve.”

Ed Kim, MD, the chair of solid tumor oncology and investigational therapeutics at the Levine Cancer Institute at Carolinas

HealthCare System in Charlotte, N.C., said that, as the NCCN guidelines state, FDGPET should not be used alone to diagnose lung cancer. “Tissue is still the gold standard for diagnosis. However, I think it’s premature to conclude that PET scans are poor tests in this setting,” he said. “We need prospective randomized studies to answer this particular question.”

He pointed out that the study used data

®

from between six to eight years ago. “Back then, the biggest problem with FDG-PETs was the difficulty in performing them and reading them uniformly. Both methods and interpretation are better now due to standardization,” said Dr. Kim. —Kate O’Rourke Drs. Grogan and Kim do not have any relevant disclosures.

Now Available... on Breast and Ovarian Cancers

Integrating Data, Improving Outcomes To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN122” Release Date: October 22, 2012

FDG-PET/CT scan showing positive FDG uptake in tumor.

National Comprehensive Cancer Network (NCCN) guidelines recommend FDG-PET for the diagnosis of suspected NSCLC, but add that a positive FDG-PET finding needs pathologic or other radiologic confirmation.

In the current study, researchers used data from the previously reported American College of Surgeons Oncology Group Z4031 trial, which was designed to test proteomic analysis for detecting NSCLC. The study, involving 51 sites and 39 cities in the United States, included 969 patients with known or suspected stage I NSCLC who underwent surgical resection between 2004 and 2006. In addition to serum samples, investigators also collected imaging results, pathology reports, tissue and survival data.

In a secondary analysis of this prospective trial, investigators examined the records of 682 patients who had FDG-PET scans and compared the outcomes of the scans with the pathology reports. Of these patients, 83% were diagnosed with cancer. FDG-PET had an accuracy of 73%, a sensitivity of 82% and a specificity of 31%. Sensitivity varied by city, but the reason for this was unclear.

Of the 80 false-positives, 69% were granulomas. Of the 101 false-negatives, 62% were adenocarcinoma, and only 11 were

Chair

Stefan Glück, MD, PhD, FRCPS Sylvester Professor, Department of Medicine Division of Hematology/Oncology Sylvester Comprehensive Cancer Center Leonard M. Miller School of Medicine University of Miami Miami, Florida

Expiration Date: October 22, 2013

Faculty

Learning Objectives

Course Format

Ruth O’Regan, MD

1 Identify recent major findings in breast and ovarian cancer research.

2 Describe how recent findings may affect screening, diagnosis, and the use of biomarkers in breast and ovarian cancer.

3 Discuss the implications of recent research for clinical practice in treating breast and ovarian cancer.

Interactive Web-based monograph

Professor and Vice Chair for Education Department of Hematology/Medical Oncology Chief of Hematology/Medical Oncology Georgia Cancer Center for Excellence Grady Memorial Hospital Director, Hematology Oncology Fellowship Emory University Chair, Louisa and Rand Glenn Family Breast Cancer Research Director, Emory Breast Center Atlanta, Georgia

Robert A. Burger, MD Professor of Medicine and Oncology Professor, Surgical Oncology Section of Gynecologic Oncology Director, Women’s Cancer Center Fox Chase Cancer Center Philadelphia, Pennsylvania

Samer I. Schuman, MD, FACS, FACOG Assistant Professor, Obstetrics and Gynecology Associate Director, Gynecologic Oncology Fellowship Sylvester Comprehensive Cancer Center Leonard M. Miller School of Medicine University of Miami Miami, Florida

This activity is jointly sponsored by Global Education Group and Applied Clinical Education.

Intended Audiences Oncologists

Statement of Need Cancer is the second leading cause of death. Among women, breast and ovarian cancers are particularly common and have high mortality rates.

Clinical needs have been identified in the management of patients with these conditions, including the difficulty of translating the constant flow of newly presented data into daily physician practice; the quantity of information being released each year is considerably greater than the clinician can readily absorb.

To close these gaps, education is needed in reviewing the most important research in breast and ovarian cancers and clarifying how the new findings may improve screening, diagnosis, and treatment.

Estimated Time for Completion 90 minutes

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Applied Clinical Education (ACE). Global is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation Global Education Group designates this enduring activity for a maximum of 1.5 AMA PRA Category 1 Credits™. s Physicians should claim only the credit commensurate with the extent of their participation in the activity.

Method of Preparation To receive CME credit, participants should read the preamble, complete the pre-test, read the monograph, and complete the post-test and evaluation. A score of at least 75% is required to complete this activity successfully.

CME certificates will be issued immediately upon successful completion.

This activity is supported by educational grants from Genentech, Inc.

To participate in this FREE CME activity, log on to www.CMEZone.com and enter keyword “MN122”

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Doublet or Monotherapy for Metastatic Breast Cancer?

From Breast

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meta-analysis of the results of four Phase III clinical trials comparing combination chemotherapy with monotherapy for metastatic breast cancer in patients pretreated with anthracyclines and taxanes has yielded mixed results.

The analysis, which was published online in the journal Breastt (2012 Aug 14.

[Epub ahead of print], PMID: 22901442), reviewed four English-language, Phase III, randomized controlled trials culled from reviews of PubMed and the Cochrane Register of Controlled Trials, as well as from poster presentations at relevant society meetings. To be included in the final analysis, the studies had to

compare doublet cytotoxic agents with a single agent; include patients diagnosed with pathologically confirmed breast cancer who had previously been treated with an anthracycline and a taxane; and produce sufficient data for extraction.

The four selected trials—Martin M, et al ((Lancet Oncoll 2007;8:219-225, PMID: 17329192); Thomas ES, et al ((J Clin Oncol 2007;25:5210-5217, PMID: 17968020); Sparano JA, et al (J ( Clin Oncol 2010;28:3256-3263, PMID: 20530276); and Pallis AG, et al ((Ann Oncol 2012;23:1164-1169, PMID: 21937705)—included 2,373 patients (1,183 randomized to combination therapy groups and 1,190 randomized to monotherapy groups). Overall survival (OS) was the primary end point of the

EXPERT INSIGHT Michael J. Naughton, MD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Assistant Professor of Medicine, Washington University School of Medicine in St. Louis

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here are subjects of long-standing debate in the treatment of metastatic breast cancer. One of these subjects relates to the optimal timing and sequencing of the many available chemotherapy agents for the treatment of this disease. There are two general approaches: sequential single-agent

therapy and combination therapy.

Most breast oncologists feel sequential single-agent therapy is the preferred approach, as combination regimens have demonstrated improvements in short-term end points, such as relative risk and PFS, with little longterm effect, namely no improvement

meta-analysis; progression-free survival (PFS), overall response rate (ORR), and grade 3 or 4 toxicity were secondary end points.

The meta-analysis revealed that treatment of metastatic breast cancer with combination chemotherapy resulted in significant improvement in PFS (hazard ratio [HR], 0.79; P=0.000) and ORR (risk ratio [RR], 1.47; P=0.004) compared with monotherapy; however, there was no significant difference between the two groups with regard to OS (pooled HR, 0.96; P=0.356). Subgroup analysis found that capecitabine (Xeloda, Genentech)-based combination therapy led to improvements in PFS (HR, 0.77; P=0.000) and ORR (RR, 1.65; P=0.026), but that gemcitabine (Gemzar,

Lilly)-based doublet regimens demonstrated no clinical benefit. Additionally, there were more incidences of grade 3 or 4 anemia, neutropenia, thrombocytopenia, fatigue, and nausea and vomiting in the combination groups than in the monotherapy groups.

The team of Chinese researchers concluded that, given the “highly heterogeneous nature” of metastatic breast cancer and the limitations of their study (lack of individual data for patients in the four included trials and the heterogeneity of the four trials in terms of design and inclusion criteria, etc.), they were “still unable to clearly set the role of combination therapy in the treatment” of patients who had been pretreated with an anthracycline and a taxane.

in survival. Piccart-Gebhart et al demonstrated this in the front-line setting with adriamycin and paclitaxel.1 The meta-analysis reported by Qi and colleagues addresses the same question in patients previously treated with an anthracycline and a taxane for breast cancer. The major limitation of this meta-analysis is that the researchers were only able to identify four papers that were suitable for their study. Among these, one accounts for more than half of the patients in the meta-analysis, making it the largest driver of their findings. Additionally, the identified studies include only a few of the currently available agents for the treatment of refractory breast

cancer, with two of the studies using gemcitabine/navelbine as the doublet arm. That being said, their findings are consistent with the generally accepted belief that combination therapy may improve short-term outcomes, but does not affect the important goal of OS.

Reference 1. Piccart-Gebhart MJ, Burzykowski T, Buyse M, et al. Taxanes alone or in combination with anthracyclines as first-line therapy of patients with metastatic breast cancer. J Clin Oncol. 2008;26:1980-1986, PMID: 18421049.

Dr. Naughton reported no relevant financial disclosures.

HEMATOLOGIC DISEASE

Assessment Criteria Issued for Blast-Phase MPNs From Leukemia Research

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multicenter team of researchers has attempted to identify multiple clinical markers of leukemic transformation in the setting of antecedent myeloproliferative neoplasm in blast phase (MPNBP) in an effort to develop treatment response categories reflecting hematologic, clinical, pathologic, cytogenetic and molecular changes following therapeutic intervention. They have published their findings in the journal Leukemia Research (2012 Aug 28. [Epub ahead of print], PMID: 22938832) and plan to validate the proposed criteria through future multicenter clinical trials.

In forming the so-called Post-Myeloproliferative Neoplasm Acute Myeloid Leukemia Consortium, the physicians

and researchers—from Mount Sinai Medical Center, Memorial Sloan-Kettering Cancer Center, the University of Pennsylvania, Weill Medical College of Cornell University, Yale University School of Medicine and the University of Texas MD Anderson Cancer Center— first met in 2011 to consolidate ongoing research efforts designed to identify molecular pathogenic mechanisms driving the disease and evaluate experimental therapies within clinical trials. The group worked to establish “viable and clinically relevant” criteria for determining therapeutic response across the participating institutions.

After a thorough review, the consortium identified response categories— including complete molecular response, complete cytogenic response,

acute leukemia response-complete, acute leukemia response-partial and progressive disease—that they believe “hold prognostic significance and [can] be validated in anticipated clinical trials.” For example, the group defined complete molecular response as “complete remission of both leukemia and myeloproliferative neoplasm without detectable molecular markers associated with” the disease. Conversely, complete cytogenic response was defined as “complete remission of both leukemia and myeloproliferative neoplasm” with “detectable molecular markers associated with either leukemia or myeloproliferative neoplasm.” Acute leukemia responsecomplete was defined as “complete remission of leukemia with residual myeloproliferative neoplasm features,”

and acute leukemia response-partial was characterized as a “decrease in leukemic burden but without resolution of peripheral blood or bone marrow blasts and residual myeloproliferative neoplasm features.” Finally, progressive disease was defined as progression of leukemia and/or background MPN. Hematologic profiles, clinical/pathologic parameters and molecular markers were identified for each of the categories.

The authors acknowledged that there are limitations to their proposed criteria.

For example, chromosomal and molecular diagnostics prior to leukemic transformation will not always be available, limiting the ability to distinguish between complete remission of the leukemic clone and the presence of the residual MPN clone in these cases.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Extracolonic Cancer Risk Rises With Lynch Syndrome From the Journal of the National Cancer Institute

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arriers of germline mutations in DNA mismatch repair (MMR) genes who have already had colorectal cancer (CRC) are at increased risk for genitourinary, breast, prostate and other cancers later in life, a new study has confirmed.

Using data from the Colon Cancer Family Registry for 764 carriers of a mutation of the MMR gene—including the 316 MLH1, 357 MSH2, 49 MSH6 and/or 42 PMS2 mutations—who had a previous diagnosis of CRC, the authors

calculated 10- and 20-year risk rates for the development of cancer in other organs following what has become known as Lynch syndrome cancer or hereditary nonpolyposis colorectal cancer (HNPCC). The results of the study were published in the Sept. 19 issue of the Journal of the National Cancer Institute (2012;104:1363-1372, PMID: 22933731).

The most common primary cancers following Lynch syndrome CRC were located in the urinary tract.

Over the 10 years following diagnosis of CRC, the cumulative risks for primary extracolonic cancers were

EXPERT INSIGHT Benjamin Tan, MD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Associate Professor of Medicine, Washington University School of Medicine in St. Louis

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pproximately 2% to 4% of all CRC cases are associated with Lynch syndrome. Consensus exists among experts regarding performance of immunohistochemistry or tumor microsatellite instability testing for newly diagnosed CRC to evaluate for possible HNPCC. Patients with pathogenic mutation in one of the MMR genes are also at risk for developing extracolonic

cancers. Caregivers, including medical oncologists, geneticists and gastroenterologists, need to discuss with the patient and their families such risks and also outline strategies for surveillance, possible prevention (if any) and treatment in the event that such cancers are detected.

This study represents one of the largest registries and adds to the growing literature detailing risk estimates for

EXPERT INSIGHT Stephen Oh, MD, PhD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Assistant Professor of Medicine, Washington University School of Medicine in St. Louis

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his report addresses the current lack of uniform criteria for response assessment in patients treated in clinical trials for MPN-BP. As patients with MPN-BP generally carry a poor prognosis, establishing formal criteria for response to treatment is critical for the advancement of therapeutic approaches in this area.

The authors’ six proposed response categories are appropriately devised and account for the key features that

indicate the presence or absence of disease activity.

However, as the authors readily acknowledge, there are several limitations to these criteria. In many cases, the leukemic clone may be in complete remission while the MPN clone persists. In the absence of specific cytogenetic or molecular markers for each clone, distinguishing the presence or absence of each clone may be difficult.

While mutations in several genes have

about 2% for cancers of the kidney, renal pelvis or ureter (the 20-year risk rate was about 5%), and the risk was about 2% for bladder cancer (20-year risk rate was 3%).

Standardized incidence ratios (SIRs), when compared with the general population, amounted to a 12.54fold increased risk for cancers of the kidney, renal pelvis or ureter; and a 7.22 SIR for urinary bladder cancer. The cumulative risk was approximately 1% for small-bowel cancer over the 10 years following CRC diagnosis (20-year risk rate was 4%; SIR was 72.68) and 0.7% for

gastric cancer (20-year risk rate was 1%; SIR was 5.65).

The most common primary cancer following Lynch syndrome CRC in women was endometrial (SIR of 40.23). Prostate cancer in men with Lynch syndrome amounted to an SIR of 2.05 compared with the general population. The authors observed no statistically significant differences in 10- and 20-year cumulative risk rates among individual MMR gene mutations and, in general, observed no differences in the SIRs based on the site of CRC, the gender of the carriers, or their age at diagnosis.

specific cancers in this population. The increased risks for breast and prostate cancers are not as widely known (these risks should be added to future versions of the National Comprehensive Cancer Network [NCCN] guidelines) compared with other cancers, such as urinary tract and upper gastrointestinal (GI) cancers.

The risk for dermatologic cancers was not even reported in this study.

Despite these risks, there are currently no clear recommendations for surveillance and prevention for any extracolonic malignancies except for endometrial cancer. The NCCN guidelines1 recommended “total abdominal hysterectomy and bilateral oophorectomy should be considered an option to reduce risk for patients who completed childbearing.” Although data

are limited, caregivers can offer transvaginal ultrasound and endometrial biopsy to screen for gynecologic cancers, annual urinalysis for urinary tract cancers and upper GI or capsule endoscopies for upper GI cancer screening. More data is needed to recommend earlier mammograms and prostate examinations for patients with Lynch syndrome.

recently been reported in both chronic and blast-phase MPNs (e.g., JAK2, MPL, TET2, LNK, ASXL1, IKZF1, SRSF2 and p53), these are largely not specific to MPN-BP, and therefore the utility of clinical testing for these mutations remains uncertain. Whether eradication of all molecular markers associated with chronic or blast-phase MPN is associated with improved outcome is also currently unknown. Ongoing research addressing the genetic basis of chronic and blast-phase MPNs will necessitate revision of these criteria in the near future. Despite these limitations, these recommendations represent a significant advance and should be incorporated into future clinical trials with MPN-BP patients.

Dr. Oh reported no relevant financial disclosures.

Reference 1. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology. Colorectal cancer screening.

Version 2.2012. Accessed October 16, 2012 at www.nccn.org.

Dr. Tan reported no relevant financial disclosures.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

New Pathways, Agents Break Ground in Hematology Experts highlight take-away messages from ASH and ASCO annual meetings Chicago—Personalized medicine and the integration of novel agents into existing treatment algorithms have been at the forefront of research presented at the most recent annual meetings of the American Society of Hematology (ASH) and the American Society of Clinical Oncology (ASCO).

In September, experts from leading U.S. cancer centers discussed the clinical implications of these studies at a symposium sponsored by Cancer Treatment Centers of America—CTCA Review: Advances and Controversies in Malignant Hematology and Oncology.

This article, with a focus on hematologic malignancies, is the first in a two-part series highlighting important advances in research and clinical care over the past 12 months.

based on that information. This is certainly not something that’s standard care today or available today, but something that we do need [large, randomized] trials for.”

Other studies are searching for potential backups to R-CHOP. One Phase III trial nearing completion randomized patients newly diagnosed with DLBCL to R-CHOP or dose-adjusted R-EPOCH (etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin and rituximab), an infusional therapy regimen that adds etoposide to the regi-

years and older who have undergone front-line treatment with bendamustine and rituximab either with or without bortezomib. Lenalidomide acts by disrupting cytokine-mediated interactions between tumor and stromal cells, enhancing immunologic synapse formation between rituximab-labeled cells and T/NK effector cells, and stimulating T- and NK-cell activity.

For younger patients with MCL, current efforts include improving outcomes, managing toxicity and inducing complete response with less intensive

Discoveries in genetic profiling are paving the way for a future in which molecular pathways begin to outweigh histology as the basis of clinical trials.

Targets and Agents in Lymphoma Discoveries in genetic profiling are paving the way for a future in which molecular pathways begin to outweigh histology as the basis for clinical trials, said Julie Vose, MD, a professor of hematology and oncology at the University of Nebraska Medical Center in Omaha. Dr. Vose urged clinicians to save tissue on biopsies to support research that might lead to new discoveries and improve outcomes.

“It’s very important to make sure we have adequate specimens [for research],” she said.

Over the past decade, treatment of diffuse large B-cell lymphoma (DLBCL) has incorporated rituximab into the CHOP (cyclophosphamide, daunorubicin, vincristine and prednisone) regimen and prognostic dissection via molecular profiling.

This work has led to the current proliferation of trials in DLBCL in which patients newly diagnosed with specific molecular subtypes are randomized to standard R-CHOP or similar therapy but with the addition of bortezomib (Velcade, Millennium).

It also has opened the Julie Vose, MD University of door for the use of gene Nebraska profiling as a strategy to personalize treatment, not only for lymphoma but also for many other types of malignancies, Dr. Vose said.

The current focus on DLBCL is to define those regimens and see which work best, she said. “Hopefully we’ll find an easier, faster, more economical way to do [gene profiling] than we have now, and then be able to choose therapy

Multiple myeloma (bone marrow smear).

‘Just as in tuberculosis or HIV or other cancers that have been cured with combinations, in myeloma we need to have biologically active agents and put them together the best we can. … Once relapse occurs, I don’t think we really have a curable disease.’

—Kenneth Anderson, MD men (ClinicalTrials.gov, NCT0018209).

Although the results won’t be available for several years, early data suggest the possibility of better outcomes with the R-EPOCH regimen, she said.

Dr. Vose also highlighted advances on the horizon for mantle cell lymphoma (MCL). Although MCL represents only 5% to 10% of lymphomas, it is hard to treat, with a high relapse rate and a median survival of 30 months with the CHOP regimen. “Most of these patients are older, so we need to come up with new therapies that are not as toxic,” she said.

The goal of one trial is to determine whether adding the oral agent lenalidomide (Revlimid, Celgene) to rituximab as a maintenance strategy can improve outcomes in patients aged 60

therapy, Dr. Vose said. A Phase II trial by the Southwest Oncology Group is randomizing patients younger than age 65 years to induction therapy with R-CVAD (rituximab, cyclophosphamide, vincristine, daunorubicin and dexamethasone) versus the less intensive regimen of rituximab plus bendamustine, followed by consolidation with high-dose therapy and autologous stem cell transplantation (ASCT).

Dr. Vose also noted that several targeted trials are currently under way in peripheral T-cell lymphoma (PTCL), including a Phase I study of the JAKSTAT (Janus kinase and signal transducer and activator of transcription) pathway with the JAK 2 inhibitor ruxolitinib and a Phase I study of the angiogenesis pathway inhibitor lenalidomide.

Multiple Myeloma: Advances in Maintenance Therapy A better understanding of the genetic complexity of multiple myeloma (MM), even at diagnosis, suggests that combination treatment at the outset, and maintenance therapy to prevent further genetic evolution and progression, offers a more promising strategy for increasing progression-free survival (PFS) and overall survival, said Kenneth Anderson, MD, a professor and coleader of the Lymphoma and Myeloma Program at Dana-Farber Cancer Institute in Boston.

“We have a very complex disease right from the start, and if we let it evolve and progress, it actually only gets worse,” Dr. Anderson said. “That’s part of the Kenneth reason that we need to Anderson, MD do something to con- Dana-Farber Cancer Institute solidate and maintain an initial response to up-front therapy.

Just as in tuberculosis or HIV or other cancers that have been cured with combinations, in myeloma we need to have biologically active agents and put them together the best we can. … Once relapse occurs, I don’t think we really have a curable disease.”

A recent study by Dr. Anderson that included 71 patients with newly diagnosed MM, who were sequenced over time, found an average of 56 to 58 mutations per patient. “I’m not arguing that all of these are biologically significant, but the point is that [MM] is very heterogeneous,” he said. Additionally, as patients were followed, new mutations that were not present initially appeared at the time of relapse. “Some mutations come and some mutations go away as the patient’s tumor relapses,” and the exact significance of each of these mutations is not known, he said.

Current frontline treatment for MM typically yields responses of two to five years. “Unfortunately, there is a relapse, and we do have drugs that work for [an additional] year and a half or two years, but we still have an unmet medical need” for therapy that prevents or delays further relapses, he said.

A growing body of evidence indicates that integrating novel agents into consolidation and maintenance therapy is beneficial. With this strategy, “we can upgrade responses, we can get more complete responses in particular and we can get some molecular complete responses for the first time in our disease,” Dr. Anderson said.

A recent Phase III trial in which

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

patients were randomized three months after ASCT to bortezomib or observation showed significantly extended PFS in patients who received the consolidation monotherapy (median 27 vs. 20 months, respectively; P=0.037).

Dr. Anderson also noted studies in which a regimen of bortezomib added to thalidomide and dexamethasone (VTD) as consolidation therapy after ASCT yielded upgraded and more durable responses.

One investigation found no relapses in patients with molecular remission at a median follow-up of 42 months; another yielded a 39% response improvement; and a third showed a significant increase in molecular remission and reduction in tumor burden with VTD versus TD. Similar studies of lenalidomide and bortezomib-lenalidomide consolidation therapy have shown upgraded and more complete molecular responses. “So when we use intensification after we have incorporated novel therapies into—or even without—a transplant paradigm, we can get complete molecular responses,” Dr. Anderson said.

Those responses also can be maintained, although neither thalidomide nor interferon (IFN)-α appears to be the maintenance agent of choice, he said. Thalidomide after ASCT often causes irreversible peripheral neuropathy even at low doses. And although patients who received IFN-α as maintenance therapy gained 9.8 months of relapse-free survival and 5.8 months of overall survival in one study, the 4.1 months of toxicity they experienced suggested that the risks outweigh the benefits of this agent (J ( Clin Oncol 1998;16:2834-2839, PMID: 9704736).

Not so with lenalidomide. A low dose of the drug (10 mg daily) significantly extended time to progression (46 vs. 27 months; P<0.001) in a study of patients randomized to lenalidomide or placebo 100 days after ASCT. When the therapy’s benefits became obvious, control patients were offered treatment; 80% chose the therapy option ((N Engl J Med 2012;366:1770-1781, PMID: 22571201).

“At the end of the study, we have lenalidomide competing with lenalidomide. Despite that crossover, there was a survival advantage,” Dr. Anderson said.

Lenalidomide carries an increased risk for secondary cancers, but “the benefit of lenalidomide given in this fashion far outweighs the risk for relapse and progression and death from MM,” he said.

A second study of lenalidomide as a maintenance drug showed that 60% of secondary cancers occurred in the presence of multiple alkylating DNAdamaging therapies (N ( Engl J Med 2012;366:1782-1791, PMID: 22571202).

“The lesson here might not be to not use lenalidomide, but to not use a lot of DNA-damaging agents before you do ASCT,” Dr. Anderson said.

Emphasizing the need for collaborative research, Dr. Anderson noted that he and his colleagues in the United States and France have launched a trial that includes 1,000 patients newly diagnosed with MM. For the first time, the trial is looking at whether patients who are likely to respond well to combination therapy benefit further from ASCT. All patients receive a combination of bortezomib, lenalidomide and dexamethasone followed by harvesting of autologous stem cells. Half of patients receive high-dose therapy and ASCT and half do not. All patients receive maintenance therapy with lenalidomide.

Other promising agents and strategies currently being tested in Phase I and II clinical trials include oral proteasome inhibitors, monoclonal antibodies and vaccines. “If they have efficacy and are well tolerated, perhaps, for example, an oral proteasome inhibitor would be an ideal candidate to use alone or with lenalidomide in an attempt to improve on maintenance,” Dr. Anderson said.

Advances in Chronic Lymphocytic Leukemia Although the development of chemoimmunotherapy and the current combination treatment of choice, FCR

Chronic lymphocytic leukemia.

(fludarabine, cyclophosphamide and rituximab) have moved treatment for chronic lymphocytic leukemia (CLL) major steps forward in recent years, a regimen for those with the 17p deletion (TP53 mutation) and elderly patients remain a challenge, said Susan O’Brien, MD, a professor in the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston.

The most recent data from the CLL8 study, presented at ASH in 2011, showed median PFS rates of 57.9 and 32.9 months, respectively, in patients with untreated, active CLL and good physical fitness who were randomized to six courses of either FCR or FC (hazard ratio, 0.56; 95% confidence interval, 0.465-0.673;

P<0.0001; ASH 2011, abstract 977).

For patients in whom FCR is not the gold standard, a new class of drugs in clinical development is gaining popularity: B-cell receptor (BCR) signaling inhibitors, Dr. O’Brien said. These agents target kinases in the B-cell receptor pathway. One of them, the orally administered PCI-32765, forms a specific and irreversible bond with cysteine-481 in Bruton’s tyrosine kinase (BTK); inhibits BTK and CLL cell migration and adhesion; and is effective at very low concentrations.

Additionally, “it became evident very early on that these drugs are not myelosuppressive,” Dr. O’Brien said.

“This drug is one of the easiest drugs I’ve ever given. It even has less side effects than Gleevec [Novartis].”

Susan Trials with relapsed/ O’Brien, MD refractory CLL patients, University many who have cytopeof Texas MD Anderson nias, on doses of 420 Cancer Center or 840 mg, revealed a response rate of 68% and a response rate of 65% among patients with 17p deletion, Dr. O’Brien noted. Although eligibility criteria for the study originally included hematologic parameters for the 840-mg dose, those parameters were later dropped.

One interesting response pattern with the drug is a dramatic shrinking of lymph nodes with a simultaneous increase in blood lymphocytes, said Dr. O’Brien. About 70% of patients develop more lymphocytosis relative to baseline. Preclinical data show that the drug interferes with cytokines that normally cause cells to adhere to the stroma. Lymphocyte counts normalize in most patients about two months into treatment but can take substantially longer in a minority of patients. However, lymphocytosis is well tolerated and generally does not cause side effects, she said.

—Susan Birk Dr. O’Brien is a consultant/advisory board member for Bayer, Calistoga, Celgene, Cephalon, CLL Global Research Foundation, GlaxoSmithKline, MorphoSys, Pharmacyclics, Pfizer, sanofi Oncology, Seattle Genetics and Sigma Tau Pharmaceuticals, and has received research funding from Avila, Bristol-Myers Squibb, Calistoga, Genentech, Pharmacyclics and Talon. Dr. Vose has received research funding from Allos Therapeutics, BristolMyers Squibb, Celgene, Genentech, GlaxoSmithKline, Incyte Corporation, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Pharmacyclics, B Bio Pte Ltd., sanofi Oncology and U.S. Biotest, Inc. Dr. Anderson is a consultant/ advisory board member for BristolMyers Squibb, Celgene, Merck, Millennium Pharmaceuticals and Onyx Pharmaceuticals and a stockholder of Acetylon Pharmaceuticals and Oncope.

By the NUMBERS: Health Insurance PACs Large health insurers are often seen as a major beneficiary of the Affordable Care Act; however, an analysis of their campaign contributions suggests that they overwhelmingly support politicians seeking to repeal it.

$10.2 million Amount the political action committees (PACs) of the 11 largest health insurance companies have given to federal politicians in the last five years

35 Percent of the health insurance industry these 11 companies control

63 Percent of contributions that went to Republicans who oppose the law or support its repeal

37 Percent donated to Democrats

$1,775,599 Amount the highest contributor, WellPoint Inc., donated to Republicans

$614,900 Amount the company donated to Democrats

1 Rank of Republican House Majority Leader Eric Cantor among recipients of health insurance company donations Data courtesy of the Center for Public Integrity.

25

26

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

By the NUMBERS:

Study Suggests Thromboprophylaxis From Cancer

A

retrospective analysis of claims data among commercial insurers in the United States has confirmed high rates of venous thromboembolism (VTE) among patients with solid tumors, perhaps identifying the need for increased use of thromboprophylaxis in patients with bladder, colorectal, lung, ovarian, pancreatic or gastric cancers.

Historically, physicians have been reluctant to initiate thromboprophylaxis because of concerns about bleeding and the relative lack of data concerning the incidence of VTE in certain types of cancer. This analysis, headed by Alok Khorana, MD, and published in Cancer (2012 Aug 14. [Epub ahead of print], PMID: 22893596), reviewed claims data collected by IMS/PharMetrics PatientCentric Data between January 2004 and December 2009. The database

includes claims information of more than 58 million patients from more than 90 managed care organizations as well as Medicare. Funding for the study was provided by Sanofi-Aventis.

Adult patients (aged ≥18 years) who had an inpatient diagnosis of malignant neoplasm (lung, pancreas, gastrointestinal, colon/rectum, bladder or ovary) who received cytotoxic chemotherapy between January 2005 and December 2008 were selected from the database (N=17,284). To establish a control group, a matched cohort of noncancer patients was selected from the database and matched 1:1 to the cancer patients based on age, sex, geographic region, and medical and prescription coverage status. The mean age of the study population was 64 years; 51% of patients were women.

In analyzing both patient sets, the authors found that VTE occurred in 12.6% of the patients in the cancer cohort over 12 months after the initiation of chemotherapy compared

EXPERT INSIGHT Steven Sorscher, MD Staff Physician, Siteman Cancer Center at Barnes-Jewish Hospital and Washington University School of Medicine in St. Louis, and Associate Professor of Medicine, Washington University School of Medicine in St. Louis

T

his large retrospective study included more than 17,000 patients with solid tumors receiving chemotherapy and a matched patient cohort, representing a thorough and excellent confirmation identifying specific patients at high risk for developing VTE. Previous studies of risk and risk reduction in patients with cancer were appropriately cited by the authors. At issue now is the effect (e.g., on survival and morbidity) of developing a VTE in a highrisk patient electing no prophylaxis, the choice of prophylactic anticoagulant and whether one can “tease out” which specific patients derive enough benefit relative to risk to encourage anticoagulation. With the explosion of information in cancer care, the limitations of those studies and the challenges of a busy practice, how does the average medical oncologist possibly advise his or her patient?

The National Comprehensive

Cancer Network (NCCN) panel1 charged with maintaining guidelines for supportive care advises that “patients at high risk for VTE (based on Khorana risk assessment score 3 or higher2) should be considered for outpatient VTE prophylaxis on an individual basis,” and suggests discussing risks and benefits with patients, but it appears to conclude that, even with the risk-predicting models available, one should “await the results of randomized controlled trials.” However, in a very similarly challenging circumstance with limited data, an NCCN panel does more strongly endorse prophylaxis: myeloid growth factors for the prevention of febrile neutropenia in certain high-risk patients. For example, for patients receiving chemotherapy with a calculated risk for febrile neutropenia of 20% or greater, the panel “recommends” growth-factor support. Based on this and other studies, a patient

with 1.4% of the patients in the control cohort ((P<0.0001). Incidence of VTE was highest among those with pancreatic cancer (19.8%). The authors found that type of cancer; comorbidities (Charlson Comorbidity Index score or obesity); and treatment with commonly used specific antineoplastic or supportive care agents, such as bevacizumab (Avastin, Genentech), cisplatin and erythropoietin, were all predictors of VTE among patients with cancer.

The incidence figures reported in this analysis are significantly higher than those reported in previous studies, which ranged from 0.6% to 7.8% ((J Clin Oncoll 2009;27:4839-4847, PMID: 19720906; and Medicine (Baltimore) 1999;78:285-291, PMID: 10499070; and Thromb Haemostt 2002;87:575-579, PMID: 12008937), a fact the authors attribute to differences in patient population, clinical setting, duration of follow-up, receipt of chemotherapy, method of detecting VTE and time frame of analysis, among other factors.

with pancreatic cancer with certain comorbidities might have a VTE risk in the same range.

Obviously, I have compared different treatments to prevent different complications, but given the immense challenges and uncertainties of large prospective trials in these enormously complicated circumstances, the judgment of the VTE expert panel would be welcomed. I believe that the NCCN VTE panel should now apply the information in this study to expand on its recommendations under which patients might “consider” anticoagulation or even for which anticoagulation should be “recommended.” As in so many other instances, more specific endorsements resulting from consideration of the NCCN expert panel could lead to effective prevention of this very serious and common complication in many of our patients.

References 1. NCCN Guidelines Version 1.2012, Venous thromboembolic disease. www.nccn.org.

Accessed October 16, 2012.

2. Khorana A, Kuderer NM, Culakova E, et al. Development and validation of a predictive model for chemotherapy-associated thrombosis. Blood. 2008;111:4902-4907, PMID: 18216292.

Dr. Sorscher reported no relevant financial disclosures.

Pharma Reps Have Hard Time with Oncologists

1|

Rank of oncologists among the 20 most common medical specialties in terms of how restrictive they are toward pharma rep sales calls

61|

Percent of oncologists who have placed moderate to severe restrictions on visits from pharmaceutical sales reps

26|

Percent of all physicians who place the same restrictions on sales reps

79|

Percent of oncologists who see even their “best reps” only 12 times a year or less

981|

1|

Medicines and vaccines to fight cancer currently in testing by U.S. companies Place this ranks oncology in terms of market growth compared with other specialties

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

CRIZOTINIB continued from page 1

Therapeutics at the Levine Cancer Institute in Charlotte, N.C., who was not involved with the study, the results of the trial will encourage more practicing physicians to order ALK testing and treat patients who test positive with crizotinib.

“They will be testing more. Just as [with] EGFR [epidermal growth factor receptor] mutations, we need to test early and treat earlier,” Dr. Kim said. Roughly 5% of NSCLCs are ALK-positive. Last April, a survey of 80 oncologists conducted by BioTrends Research Group showed that roughly half were testing for ALK. In the PROFILE study, which involved 21 countries, 172 patients received crizotinib, 99 received pemetrexed (Alimta, Lilly) and 72 received docetaxel. Patients who received crizotinib had a PFS of 7.7 months compared with 4.2 months in the pemetrexed arm ((P=0.0004) and 2.6 months in the docetaxel arm (P ( <0.0001).

Pemetrexed’s performance was expected because the drug has prominent activity in adenocarcinoma NSCLC and almost all ALK-positive patients have this histology (Oncologist 2009;14:253-263, PMID: 19221167). Overall response rate

Table 1. Primary End Point: Progression-Free Survival Crizotinib (N=173)

Chemotherapya (N=174)

Events, N (%)

100 (58)

127 (73)

Median PFS, months

7.7

3.0 P value <0.001

PFS, progression-free survival a

Pemetrexed 500 mg/m2 or docetaxel 75 mg/m2 IV, day 1, 21-day cycle

—Kate O’Rourke

The median overall survival rate in the crizotinib arm, 20 months, was considered phenomenal in the second-line treatment of NSCLC.

Table 2. Comparison of Selected Grade 3/4 Adverse Events in PROFILE 1007 Trial Crizotinib Arm

Chemotherapy Arm

Elevated transaminases, %

16

2

Pulmonary embolism, %

5

2

Hypokalemia, %

4

0

Prolonged QTc, %

4

0

—Jean-Charles Soria, MD, PhD

also was improved in patients receiving crizotinib (65.3%) compared with chemotherapy (19.5%; P<0.0001). An interim analysis did not identify an improvement in overall survival (OS).

“I think the lack of overall survival advantage is explained first by the high rate of crossover—87% of the patients who experienced progressive disease in the chemotherapy arm crossed over to crizotinib,” said Jean-Charles Soria, MD, PhD, a medical oncologist at Gustave Roussy Cancer Institute in

Dr. Shaw disclosed an advisory relationship with Pfizer, as well as an advisory role with Ariad, Chugai, Daiichi-Sankyo and Novartis and research funding from AstraZeneca and Novartis. Dr. Soria has received consultancy fees from and served on the steering committee of Pfizer. He also disclosed consultancy fees from Abbott, Amgen, AstraZeneca, BMS, GSK, Lilly, Merck-Serono, MSD, Roche-Genentech and Sanofi, as well as an advisory role with AstraZeneca, Boehringer-Ingelheim, RocheGenentech and Servier. Dr. Kim disclosed an advisory role with Boehringer Ingelheim, Genentech, Lilly, and OSI Pharmaceuticals, and research funding from Genentech, Lilly, and OSI Pharmaceuticals.

AT A GLANCE ‘I think the lack of overall survival advantage is explained first by the high rate of crossover—87% of the patients who experienced progressive disease in the chemotherapy arm crossed over to crizotinib.’

A stain showing scattered ALK-positive neoplastic cells.

press time, the European Medicines Agency had failed to do so, insisting on a randomized trial. “While the U.S. treats, the EU [European Union] randomizes,” Dr. Soria said.

A Phase III trial, PROFILE 1014, currently is enrolling patients to test the value of crizotinib in the first-line setting of ALK-positive, locally advanced or metastatic non-squamous NSCLC. The comparator arm is pemetrexed plus cisplatin or pemetrexed plus carboplatin.

Villejuif, France. “Second, the data is immature. Less than 40% of expected events have happened.” Dr. Soria, who was asked to critique the trial at the ESMO meeting, pointed out that median OS was 20 months in the crizotinib arm, a phenomenal survival in secondline treatment of NSCLC. The ALK inhibitor is associated with toxicities that have been characterized as mild, but clinicians should be aware that 16% of patients experienced grade 3/4 liver toxicity (Table 2), and that the drug is associated with mild visual disturbances.

“Importantly, in patient-reported outcomes, crizotinib was associated with

significantly greater improvement from baseline in both lung cancer symptoms and quality of life,” said Alice Shaw, MD, PhD, a thoracic oncologist at Massachusetts General Hospital Cancer Center in Boston, who led the PROFILE trial.

Most researchers say the study establishes crizotinib as the standard of care for this patient population.

According to Dr. Soria, multiple ALK variants exist and researchers need to sort out whether different variants predict different benefits from crizotinib.

He expressed frustration that although crizotonib has been approved in the United States for more than a year, at

Crizotinib In NSCLC, ALK K is activated by chromosomal rearrangement leading to constitutive kinase activation Crizotinib targets ALK, ROS1 and MET ALK testing in NSCLC should increase and allow earlier treatments In the PROFILE 1007 trial, all subgroup analyses favored crizotinib The trial establishes crizotinib as a standard of care for patients with advanced previously treated ALK+ NSCLC

If you missed any recent issues of Clinical Oncology News, visit www.clinicaloncology.com.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Clinical Conundrums

Prepared by

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

Focus on NEJM, JCO and Blood

QUESTIONS

1. True or False. In patients with

newly diagnosed multiple myeloma (MM), progression-free survival (PFS) and overall survival (OS) are significantly improved with the addition of lenalidomide (Revlimid, Celgene) maintenance therapy.

2. True or False. In the trial by Ceci-

lia Becattini, MD, PhD, and her colleagues from the University of Perugia in Italy, aspirin reduced venous thromboembolism (VTE) recurrence by nearly half following the completion of six months of anticoagulation therapy for unprovoked VTE in patients without underlying cancer.

3. True or False. The a multicenter

particularly in those with follicular lymphoma refractory to rituximab.

4. True

or False. In chronic lymphocytic leukemia (CLL), with the development of newer novel therapeutics such as immune-modulating agents, B-cell receptor and adhesionrelated kinase inhibitors, it is prudent that progressive disease (PD) is not misinterpreted, leading to inadvertent dismissal of active agents.

5. True or False. The randomized

Phase III HOVON-65/GMMG-HD4 trial clearly showed no benefit from maintenance bortezomib (Velcade, Millennium) in patients with MM who present with high-risk disease, myeloma-related renal failure and del(17p).

therapy and autologous transplant (HDT/ASCT) in patients with untreated ALK-protein positive anaplastic large cell lymphomas (ALCLs).

7. True or False. Combining the MD 9. True or False. In the prospective Anderson low-risk prognostic scoring system (LR-PSS) with EZH2 mutation status identifies 29% of patients with International Prognostic Scoring System (IPSS) low- and intermediate 1-risk (“lower-risk”) myelodysplastic syndromes (MDS) with a worse-thanexpected prognosis who may benefit from earlier initiation of more aggressive therapies.

Phase I study by Anas Younes, MD, and his colleagues at the University of Texas MD Anderson Cancer Center in Houston, demonstrated that SAR3419 has promising clinical activity in patients with relapsed B-cell lymphoma,

6. True or False. A prospective Phase II study (NG-T-01) on behalf of the Nordic Lymphoma Group demonstrated excellent outcomes with dose-dense induction therapy followed by high-dose

8. True or False. In patients with

ANSWERS

thromboembolism. N Engl J Med. 2012;366:19591967, PMID: 22621626.

subgroups that correlate with outcomes.

In CLL, with the advent of newer targeted therapies with unique effects, it has become evident that these definitions may not faithfully predict outcome. In particular, the current definition of PD may not adequately serve as a surrogate marker for poor outcome and thus CLL experts are discussing the refinement of current clinical end points. It is important to recognize that this issue is not just restricted to one disease.

1.

False. Three recently published studies in The New England Journal of Medicine support the use of lenalidomide maintenance therapy in MM. Lenalidomide has concrete evidence for improvement in PFS but its role in improving OS is not firmly established. There are hints that this strategy may improve OS, but longer follow-up of current studies will answer this question more precisely.

Palumbo A, Hajek R, Delforge M, et al. Continuous lenalidomide treatment for newly diagnosed multiple myeloma. N Engl J Med. 2012;366:17591769, PMID: 22571200.

McCarthy PL, Owzar K, Hofmeister CC, et al.

Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:17701781, PMID: 22571201.

Attal M, Lauwers-Cances V, Marit G, et al.

Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:1782-1791, PMID: 22571202.

2. True. Dr. Becattini conducted a

double-blind, controlled trial comparing 100 mg of aspirin daily with placebo over a two-year period in 402 patients who had completed at least six months of oral anticoagulant therapy for a firsttime, unprovoked VTE. No difference was found in the incidence of major bleeding or death.

Becattini C, Agnelli G, Schenone A, et al. Aspirin for preventing the recurrence of venous

3. True.

The maximum tolerated dose of SAR3419 administered every three weeks for six cycles is 160 mg/m2.

The majority of clinical responses with SAR3419 were seen in patients with follicular lymphoma, including those who were rituximab refractory. SAR3419 (huB4-DM4) is a humanized immunoglobulin G1 anti-CD19 monoclonal antibody. A second Phase I/II study to evaluate a once-per-week administration schedule of SAR3419 was recently initiated in an attempt to assess the feasibility and the potential benefits of dosedense therapy by reducing the time between drug administrations.

Younes A, Kim S, Romaguera J, et al. Phase I multidose-escalation study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered by intravenous infusion every 3 weeks to patients with relapsed/refractory B-cell lymphoma. J Clin Oncol. 2012;30:2776-2782, PMID: 22753910.

Coiffier B, Ribrag V, Dupuis J, et al. Phase I/II study of the anti-CD19 maytansinoid immunoconjugate SAR3419 administered weekly to patients (pts) with relapsed/refractory B-cell non-Hodgkin lymphoma (NHL). J Clin Oncol. 2011;29(suppl 15;abstr 8017):508s.

4. True. In oncology, the defined

criteria complete response (CR), partial response, stable disease and PD have assisted in stratifying patients into

and then again periodically is prudent in order to properly gauge prognosis and select the optimal treatment strategy, respectively.

primary myelofibrosis (PMF), risk stratification at the time of diagnosis

Cheson BD, Byrd JC, Rai KR, et al. Novel targeted agents and the need to refine clinical end points in chronic lymphocytic leukemia. J Clin Oncol.

2012;30:2820-2822, PMID: 22778323.

5. False. Bortezomib maintenance

significantly improved the near complete response plus CR rate from 31% to 49%. The subgroup analyses showed that the superior outcome with maintenance bortezomib is predominantly accomplished in patients with highrisk disease, myeloma-related renal failure and del(17p). It should be noted that these and any other data pertaining to maintenance therapy should be interpreted in the context of front-line therapy and its outcome.

Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and maintenance treatment in patients with newly diagnosed multiple myeloma: results of the randomized phase III HOVON-65/ GMMG-HD4 trial. J Clin Oncol.

2012;30:2946-2955, PMID: 22802322.

PT-1 trial, Peter Campbell, PhD, and his colleagues at the Wellcome Trust Sanger Institute in Cambridgeshire, United Kingdom, demonstrated a significant association between leukocytosis and risk for thrombosis in patients with essential thrombocytosis.

10. True or False. Treatment out-

comes for adult acute lymphoblastic leukemia (ALL) have not improved over the past three decades.

6.

False. Patients with ALK protein-positive ALCL, primary cutaneous and primary leukemic subtypes were excluded from this study. Conventionally, PTCLs, with the exception of ALK protein-positive ALCL, have poorer outcomes than their B-cell counterparts. In this study, an induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide and prednisone) was administered (in patients aged >60 years, etoposide was omitted). If in complete or partial remission (n=131), patients proceeded to consolidation with HDT/ASCT. At 60.5 months of median follow-up, 83 patients were alive. Consolidated fiveyear OS and PFS were 51% (95% confidence interval [CI], 43%-59%) and 44% (95% CI, 36%-52%), respectively. d’Amore F, Relander T, Lauritzsen GF, et al.

Up-front autologous stem-cell transplantation in peripheral T-cell lymphoma: NLG-T-01. J Clin Oncol. 2012;25:3093-3099, PMID: 22851556.

7. True. In this study the MD Ander-

son LR-PSS successfully stratified patients with “lower-risk” IPSS MDS into three risk categories with significant differences in OS (20% in category 1 with median of 5.19 years [95% CI, 3.01-10.34 years], 56% in category 2 with median of 2.65 years [95% CI, 2.183.30 years] and 25% in category 3 with see CONUNDRUMS, S page 30

29

30

CURRENT PRACTICE

CONUNDRUMS continued from page 29

median of 1.11 years [95% CI, 0.82-1.51 years]), thus validating the MD Anderson LR-PSS. Furthermore, the EZH2 mutation was a highly significant predictor of OS, with a hazard ratio of 2.84 or greater in all three categories, and neither the IPSS nor LR-PSS prognostic models captured its effect.

Bejar R, Stevenson KE, Caughey BA, et al. Validation of a prognostic model and the impact of mutations in patients with lower-risk myelodysplastic syndromes. J Clin Oncol. 2012;30:3376-3382, PMID: 22869879.

8. True. Risk stratification in PMF

requires using the IPSS at the time of diagnosis and then the Dynamic IPSS (DIPSS) periodically to capture the evolving nature of the disease. The DIPSS-Plus has not been validated to date in another independent data set.

Gupta V, Hari P, Hoffman R. Allogeneic hematopoietic cell transplantation for myelofibrosis in the era of JAK inhibitors. Blood. 2012;120:1367-1379, PMID: 22700718.

Cervantes F, Dupriez B, Pereira A, et al. New

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ NOVEMBER 2012

prognostic scoring system for primary myelofibrosis based on a study of the International Working Group for Myelofibrosis Research and Treatment.

Blood. 2009;113:2895-2901, PMID: 18988864.

Passamonti F, Cervantes F, Vannucchi AM, et al.

A dynamic prognostic model to predict survival in primary myelofibrosis: a study by the IWG-MRT (International Working Group for Myeloproliferative Neoplasms Research and Treatment). Blood.

2010;115:1703-1708, PMID: 20008785.

Gangat N, Caramazza D, Vaidya R, et al. DIPSS plus: a refined Dynamic International Prognostic Scoring System for primary myelofibrosis that incorporates prognostic information from karyotype, platelet count, and transfusion status. J Clin Oncol. 2011;29:392-397, PMID: 21149668.

9.

True. In this study, Dr. Campbell investigated the relationship between vascular complications and 21,887 longitudinal blood counts in a prospective, multicenter cohort of 776 patients with ET. Additionally, they validated the finding by Tiziano Barbui, MD, of the Ospedali Riuniti di Bergamo in Italy, of the increased risk for hemorrhage, not bleeding, with clonal thrombocytosis.

Campbell PJ, MacLean C, Beer PA, et al. Correlation of blood counts with vascular complications in essential thrombocythemia: analysis of the prospective PT1 cohort. Blood. 2012;120:1409-1411, PMID: 22709688.

Send us your news

10. False. Treatment results in adult

ALL have improved over the past three decades with CR rates increasing to 85% to 90% and OS rates to 40% to 50%.

However, it is important to note that 40% to 50% of patients, including those with standard risk, still relapse, which is associated with an extremely poor survival rate of less than 10%. Reduction of relapse rate, therefore, is the main goal of treatment optimization for this subset of adult patients with ALL.

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

Fielding AK, Richards SM, Chopra R, et al. Outcome of 609 adults after relapse of acute lymphoblastic leukemia (ALL); an MRC UKALL12/ECOG 2993 study. Blood. 2007;109:944-950, PMID: 17032921.

gmiller@ mcmahonmed.com

Bassan R, Hoelzer D. Modern therapy of acute lymphoblastic leukemia. J Clin Oncol. 2011;29:532543, PMID: 21220592.

Barbui T, Carobbio A, Rambaldi A, Finazzi G. Perspectives on thrombosis in essential thrombocythemia and polycythemia vera: is leukocytosis a causative factor? Blood. 2009;114(4):759-763, PMID: 19372254.

Dr. Mohammed Aziz assisted in preparing this column.

CLASSIFIEDS

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CLINICAL ONCOLOGY NEWS • NOVEMBER 2012

Fibulin-3 May Be Biomarker for Mesothelioma Blood test holds potential for earlier diagnosis

F

ibulin-3 may be useful for determining the diagnosis and prognosis of pleural mesothelioma, according to a study in the New England Journal of Medicine (2012;367:1417-1427). Plasma fibulin-3 levels proved capable of distinguishing healthy individuals who had been exposed to asbestos from patients with mesothelioma. In conjunction with levels of fibulin-3 in effusions, plasma fibulin-3 levels could distinguish mesothelioma effusions from other malignant and benign effusions.

“Mesothelioma has no way of being detected early,” lead author Harvey Pass, MD, a professor of thoracic oncology and division chief of general thoracic surgery at NYU Langone Medical Center, in New York City, told Clinical Oncology News.

“We need to have a marker to diagnose the disease at an earlier stage—a blood test to say there’s something brewing.

That’s what the hopes are for this test.”

In two geographic cohorts, Detroit and New York City, plasma and effusion samples were obtained from patients with mesothelioma (n=142), plasma samples from persons who had been exposed to asbestos but did not have mesothelioma (n=136), and plasma and effusion samples from patients with pleural effusions not due to mesothelioma (n=93). In addition, a Toronto cohort included unidentified, blinded plasma samples from patients with mesothelioma (n=48) and asbestosexposed, cancer-free persons (n=96).

There was a significant difference in mean plasma fibulin-3 levels between patients with mesothelioma and asbestos-exposed, cancer-free persons, with elevated levels indicating mesothelioma. For example, in the Detroit cohort, mean plasma fibulin-3 levels in patients with mesothelioma were 105.0±7.1 ng/ mL compared with 13.9±1.2 ng/mL in asbestos-exposed persons ((P<0.001). In an overall comparison of patients with and without mesothelioma, plasma fibulin-3 levels had a sensitivity of 96.7% and a specificity of 95.5% at a cutoff value of 52.8 ng/mL. A blinded validation study in the Toronto cohort showed strong discrimination between controls and patients with mesothelioma (area under the curve = 0.87).

“This paper is important because it identifies a potential tumor biomarker that can detect malignant pleural mesothelioma,” said Lawrence Feldman, MD, an associate professor of hematology/ oncology at the University of Illinois Cancer Center, in Chicago, who was not involved with the study. “A tumor biomarker that has sufficient specificity and sensitivity for this disease is potentially very helpful to diagnose

this disease early and could be used to follow the patient post treatment for detecting early relapse.”

Fibulin-3 has not been proven as an early detection marker for mesothelioma, according to the authors. “We have a signal that fibulin-3 might be an early detection marker, since it detects stage I as well as later stages,” said Dr. Pass. “But we would need a prospective

trial to show that fibulin-3 could detect mesothelioma in asbestos-exposed individuals before they have symptoms.”

Dr. Feldman said, “The limitations of this paper include the fact that it is a cohort analysis and not a prospective study. This study also lacks a scientific rationale for why fibulin-3 levels are selectively elevated in pleural mesothelioma as compared with other cancers.”

HALAVEN® (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays t Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm 3 – Grade 3 or 4 non-hematological toxicities. t The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions t If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1. t Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose Permanently reduce the 1.4 mg/m2 HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias.

Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1. Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503). Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: t /FVUSPQFOJB t 1FSJQIFSBM OFVSPQBUIZZ t 25 JOUFSWBM QSPMPOHBUJPO The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 MedDRA ver 10.0 HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders 35% 8% 16% 2% Peripheral neuropathyb Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1% Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders 10% NAc Alopecia 45% NAc

Dr. Pass noted that fibulin-3 does not have immediate practical applications.

“This study uses an ELISA [enzymelinked immunosorbent assay] offered by one company for research purposes.

It has not been tested in a CLIA [Clinical Laboratory Improvement Amendments] setting.”

—George Ochoa

Dr. Pass has submitted a patent on fibulin-3 for mesothelioma diagnosis and prognosis.

Dr. Feldman reported no relevant financial conflicts of interest.

Table 2 (cont'd) MedDRA ver 10.0

HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: y p Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colony-stimulating factor) was used in 19% of patients who received HALAVEN. Peripheral p Neuropathy: p y In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVENtreated group: t Eye Disorders: increased lacrimation t Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth t General Disorders and Administration Site Conditions: peripheral edema t Infections and Infestations: upper respiratory tract infection t Metabolism and Nutrition Disorders: hypokalemia t Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness t Nervous System Disorders: dysgeusia, dizziness t Psychiatric Disorders: insomnia, depression t Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen.

Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. Therefore, a lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment For patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.3 Pharmacokinetics Specific Populations Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment.

Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function.

Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that geometric mean dose-normalized systemic exposure is similar for patients with mild renal impairment (CrCl 50-80 mL/min) relative to patients with normal renal function. However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dosenormalized systemic exposure increased 2-fold compared to patients with normal renal function.

12.6 Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitroo bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivoo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling t Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination. t Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. ––– –– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– ––– –– HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved. Printed in USA / March 2012 ERI 346

31

DISCOVER OVERALL SURVIVAL HALAVEN: The FIRST and ONLY single-agent therapy proven to significantly extend OVERALL SURVIVAL after 2 prior lines of MBC therapy1-9

P R O P O R T I O N O F PAT I E N T S A L I V E

UPDATED OVERALL SURVIVAL (OS) ANALYSIS (UNPLANNED): MEDIAN OS, MONTHS (95% CI)1,10,a

The updated OS analysis was consistent with the primary analysis1 The primary analysis, conducted when ~50% of events (deaths) had been observed, demonstrated a median OS for Halaven vs TPC of 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR*=0.81 (95% CI: 0.66, 0.99) (P=0.041)1,10 Results from an updated, unplanned survival analysis of the Phase III, randomized, open-label, multicenter, multinational EMBRACE† trial of Halaven versus TPC in patients with metastatic breast cancer (MBC) (N=762), conducted when 77% of events (deaths) had been observed. The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen. All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxanes [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracyclines, 10% other chemotherapy), and 3% hormonal therapy.

Halaven is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia

t Monitor complete blood counts prior to each dose, and increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days t Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels t Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy t Patients should be monitored closely for signs of peripheral motor and sensory neuropathy t Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less t Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days) t Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

Please see accompanying brief summary of Halaven full Prescribing Information.

To learn more about Halaven, visit www.halaven.com

HALAVEN® is a registered trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2012 Eisai Inc. All rights reserved.

Printed in USA/August 2012 HALA0042 R1

25% (2.6 month)

(n=508)

13.2

INCREASE

(12.1, 14.4)

IN MEDIAN OS

Deaths=386

Treatment of Physician’s Choice (n=254)

10.6 (9.2, 12.0) Deaths=203

TIME (MONTHS) Number of patients at risk

a

Indication

Halaven

508 254

406 178

274 106

142 61

54 26

11 5

0 Halaven 0 TPC

CI=confidence interval; Treatment of Physician’s Choice (Control arm)=TPC. Conducted in the intent-to-treat (ITT) population.

Pregnancy Category D t Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation t In an uncontrolled ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities t Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy. Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment t For patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Most Common Adverse Reactions t Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%) t The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) References: 1. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2012. 2. Saad ED et al. J Clin Oncol.

2010;28(11):1958-1962. 3. Slamon DJ et al. N Engl J Med. 2001;344(11):783-792. 4. Geyer CE et al. N Engl J Med. 2006;355(26):2733-2743. 5. von Minckwitz G et al. J Clin Oncol. 2009;27(12):1999-2006. 6. Miller K et al. N Engl J Med. 2007;357(26):2666-2676. 7. Robert NJ et al. J Clin Oncol. 2011;29(10):1252-1260. 8. Sparano JA et al.

J Clin Oncol. 2010;28(20):3256-3263. 9. Jones SE et al. J Clin Oncol. 2005;23(24):5542-5551. 10. Cortes J et al.

Lancet. 2011;377(9769):914-923.

*HR=hazard ratio. † EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice versus E7389 (Eribulin).