July 2013 by McMahon Group

Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • July 2013 • Vol. 8, No. 7

INSIDE CURRENT PRACTICE Supreme Court rules on gene patenting case ........... 3 How I Manage... MGUS and Smoldering Multiple Myeloma: Robert Kyle, MD .................. 10 The Tumor Board: Conrad Simpfendorfer, MD ............. 24 Expert Forum: Controversies in breast cancer management ......... 26

SOLID TUMORS

IMAGES in ONCOLOGY

A Glimpse of Next-Generation Sequencing Study suggests broader screening for high-risk women Chicago—Next-generation comprehensive genomics screening in black women with breast cancer is providing an early look at how these tests are likely to be applied widely in routine care. Rather than testing only for BRCA1 and BRCA2 genes, the BROCA assay used in a recent study looked for mutations in 18 genes associated with increased breast cancer risk and found at least one inherited mutation in 22% of the women examined. “Modern genomics approaches see SEQUENCING, G page 8

“Walking,” squamous carcinoma cells go for a stroll. For more information see page 2.

ASCO Coverage Bevacizumab for advanced cervical cancer ...................... 4 Sorafenib for refractory thyroid cancer ...................... 14

HEMATOLOGIC DISEASE Improving hematopoietic stem cell transplant ............. 11 Minimizing Hodgkin lymphoma radiation treatment ................................ 12

COMING NEXT MONTH Special ASCO coverage issue

Counterfeit Chemo The second in a two-part special report on drug fraud in the U.S.

here are several ways in which fake and counterfeit drugs can get into the hands of physicians and patients. The Internet is probably the easiest way to access fakes because there is little to no oversight. Consumers may purchase drugs on the Internet for the convenience, to avoid potential embarrassment (as with Viagra) or to get what seems to be a good deal on costly drugs. However, if it seems too good to be true, it probably is, said Chris Vansteenkiste, the project manager of the Intellectual Property Crime Team at Europol. A study conducted by the European Alliance for Access to Safe Medications (EAASM) found, after analyzing a range of medications purchased from online pharmacies, that see COUNTERFEIT, T page 6

Drug Shortage Fosters Variety of Coping Strategies Chicago—The cancer drug shortage is forcing oncologists to cobble together a mix of coping strategies, some of which are raising costs, according to results of a survey of board-certified U.S. oncologists. Eightythree percent of oncologists have been confronted with drug shortages that affected treatment decisions, according to the survey. In 37% of cases, oncologists felt compelled to engage in a rationing process, selecting among patients to whom they offered a remaining quantity of a drug. “The vast majority of oncologists in this country are facing wrenching decisions about how to allocate lifesaving drugs when there aren’t enough to go around,” Keerthi Gogineni, MD, of Abramson Cancer Center at the University of Pennsylvania in see SHORTAGES, S page 8

by the

numbers Physicians’ Adaptations To Drug Shortages 79% 77%

Switch regimens

43% 37% 29% 20% 17%

Delay treatment

Substitute drug partway through therapy

Choose among patients Omit doses Reduce doses Refer patients to another practice

Source: J Clin Oncol. 2013;(suppl:abstr CRA6510).

RE VIE WS & COMMENTAR IES

Expert Insights From Levine Cancer Institute Chemo-N0 Study Confirms Utility of uPA/PAI-1 Biomarker ................. 17 Wendy Brick, MD

Similar Genetic Alterations Found in Primary and Metastatic NSCLC ..................... 18 Edward Kim, MD

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

EDITORIAL BOARD

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

Breast Cancer

Prostate Cancer

Charles F. von Gunten, MD

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

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

Oncology Nursing

Hematologic Malignancies

Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

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

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

Michele Neskey, MMSc, PA-C

Maura N. Dickler, MD

Harry Erba, MD, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

University of Alabama Birmingham, AL

Gastrointestinal Cancer

Mayo Clinic Rochester, MN

University of Pittsburgh Cancer Institute, University of Pittsburgh Pittsburgh, PA

Richard Stone, MD

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

Mary Lou Bowers, MBA The Pritchard Group Rockville, MD

Cindy O’Bryant, PharmD

Matt Brow

University of Colorado Cancer Center Denver, CO

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

Sara S. Kim, PharmD The Mount Sinai Medical Center New York, NY

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

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

On the Cover

Syed A. Abutalib, MD

ur cover features the artwork of Marie Sicari, MD, a pathologist, visual artist and performer whose digital art photography project focuses on imagery of human disease. Dr. Sicari specializes in the fields of anatomic pathology and dermatopathology. Dr. Sicari’s digital abstract art explores the fantastic imagery of microscopic pathology as a potential tool to access and explore the mind-body-spirit connection. Her work reflects the paradigm shift occurring in medicine toward the inclusion of holistic approaches and the role of creative arts in the healing process. If you are interested in purchasing this piece or other work from her collection, Dr. Sicari may be reached at www.behance.net/MarieSicari

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

Policy and Management

Pharmacy

Shaji Kumar, MD

Edward Chu, MD

Bioethics

University of California, San Diego, CA

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

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 Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

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

Mission Statement

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.

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.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Heard at

ClinicalOncology.com

In the NEWS

Clinical Oncology Newss readers frequently provide thoughtful comments online via the “Comment on This Article” tool at the end of every Clinical Oncology News story. We felt this one, by reader Debra Brown, merited reprinting in the magazine.

On June 13, the U.S. Supreme Court delivered a ruling in Association for Molecular Pathology v. Myriad Genetics, a landmark case on the practice of gene patenting. In brief, the court ruled that human genes cannot be patented. Because the case was based on Myriad Genetics’ BRCA gene diagnostic testing assay, the ruling sent shockwaves through the cancer community.

“In late March, I heard Dr. Peter Gotzsche from the Nordic Cochrane Institute speak at the Evidence Live Conference in Oxford. His opening sentence was ‘Breast screening is harmful and should be stopped.’

“A naturally occurring DNA segment is a product of nature and not patent eligible merely because it has been isolated, but cDNA is patent eligible because it is not naturally occurring.”

He then provided a compelling argument. Denmark has only been screening women in one region and so they have the perfect control group. The result: slightly more deaths from breast cancer in the screened group. Breast screening does not save breasts and it appears to save few lives, and even that benefit is compromised when you consider women who die as a result of over-treatment. Professor Michael Baum, a UK breast cancer surgeon, published some research in the BMJ J recently: 3-4 screened women per 10,000 will avoid death from breast cancer; 3-9 screened women per 10,000 will die from lung cancer and heart attacks as a result of radiotherapy/chemo. You reduce your risk of a breast cancer diagnosis by one-third by choosing NOT to screen. The NCI has produced an excellent summary of all of the evidence, it’s at their website. I think the continued white-washing of the evidence and a focus on screening targets with zero respect for informed consent is really quite shocking. I’m very pleased I took the time to do my own research. Sadly, women’s health care is loaded with political and vested interests and high emotion and there is little respect for women as individuals quite capable of making their own informed decisions. We’re told to screen with no real information....it’s time women were treated with the same respect and proper ethical standards we see in prostate screening. Men got risk information very quickly and doctors were reminded to obtain informed consent. It seems many are sticking their heads in the sand and ignoring the evidence for their own reasons. What happened to the motto ‘First, do no harm’?”

—Supreme Court Justice Clarence Thomas, delivering the majority opinion in Molecular Pathology v. Myriad Genetics

“Many academic labs, including our own, will soon be offering panel tests for dozens, or even hundreds of genes, for the same price Myriad historically charged for just two genes.” —Kenneth Offit, MD, chief of the clinical genetics service at Memorial Sloan-Kettering Cancer Center

“We have 24 patents, more than 500 patent claims, the vast majority of which are still valid and enforceable.” —Richard Marsh, general counsel for Myriad Genetics

“This is going to make a lot more genetic tests available, especially for rare diseases.” —Sherri Bale, managing director of GeneDx, a testing company

“The Supreme Court got it exactly right... It’s a great decision for patients, it’s a great decision for science, and I think it’s a great decision for the biotechnology industry.” —Eric Lander, PhD, president of the Broad Institute, a genetic research center at Harvard and M.I.T.

“It’s actually chilling to think about what would’ve happened had this gone the other way. Can you imagine if you had to go through this for every gene?” —Cy Stein, MD, PhD, chair of medical oncology and therapeutics research at City of Hope

TOP STORIES at ClinicalOncology.com Most-Read Stories

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Drug Shortages: A Serious Problem Requiring a Real Solution EDITORIAL BOARD COMMENTARY Maurie Markman, MD Senior Vice President of Clinical Affairs and National Director for Medical Oncology, Cancer Treatment Centers of America, Philadelphia

he terrible news and outcome of the large number of fungal meningitis cases resulting from improper compounding in the preparation of epidural steroid injections has sent shockwaves through the medical community.1,2 Although not dealing specifically with the oncology patient population, this experience highlights several extremely serious issues in the use of pharmaceutical products that are relevant to cancer management, including the skyrocketing cost of these agents, the desire to control costs by seeking alternatives to the normal channels of drug procurement and the ever-present problem of generic antineoplastics shortages. These shortages include drugs known to be life prolonging and even “curative” in their intent (e.g., cytarabine in the management of acute leukemia).3-5 The current drug development and procurement system can only be described as dysfunctional and chaotic. The effect of this system on providers of cancer

care—and far more importantly, on cancer patients themselves—has been, and continues to be, profound. One of the most disturbing features of the situation: There appears to be a widespread, even if extremely reluctant, acceptance by the oncology community (and more importantly oncology patients) that the current state of affairs is something we must be prepared to live with on a longterm basis, particularly when increasingly effective new anticancer agents are being introduced at a cost that is likely to routinely exceed $5,000 or even $10,000 per individual treatment (every threeto four-week) cycle, and where regular reports of “generic antineoplastic drug shortages” will be a permanent fixture of oncology care. I would like to address this latter issue. What effect has the more frequent absence of older, relatively inexpensive generic antineoplastics had on clinical outcomes? Is it not always possible to find an equally effective alternative, even possibly a far more expensive, newer nongeneric agent? There is no definitive answer to this question, but one reported experience with this issue will hopefully end any speculation that the drug shortage problem in oncology is simply not a major concern. Commenting on the effect of the mechlorethamine (nitrogen mustard) shortage initially identified in 2009, an agent specifically employed in the

treatment of Hodgkin lymphoma in the pediatric population, investigators in the Pediatric Hodgkin Lymphoma Consortium have documented an inferior outcome associated with a required substitution of cyclophosphamide for mechlorethamine.6 In this retrospective analysis involving 181 patients treated with mechlorethamine versus 40 patients managed over the past several years with cyclophosphamide, the two-year event-free survival was 88% among individuals receiving the older established regimen compared with 75% (P ( =0.01) for those treated with the alkylating agent substitution. Although overall follow-up in the cyclophosphamide-treated population remains limited (median 1.5 years compared with 4.7 years for the mechlorethamine-managed patients) and to date there has been no difference in overall survival, individuals who experience a relapse must undergo a dose-intensive (“rescue”) stem cell transplant with its recognized serious toxicity profile. The authors of this highly relevant manuscript concluded their report with the following statement, which might be equally appropriately applied in many adult cancer settings: “what might appear to be a suitable alternative regimen may result in an inferior outcome—an intolerable situation for young people with curable diseases.” The very specific point to be made here

is that the problem of shortages of vitally important generic antineoplastic regimens is an “intolerable situation” and a societal solution must be found. In fact, with the necessary political will it should not be difficult to develop and quickly implement an economic model acceptable to regulatory agencies, payers (governmental and private), as well as the generic pharmaceutical industry, that will provide a reasonable financial return for the manufacture of these “generic” medications and ensure that cancer patients are provided the best opportunity for a favorable clinical outcome.

References 1. Pettit AC, Kropski JA, Castilho JL, et al. The index case for the fungal meningitis outbreak in the United States. N Engl J Med. 2012;367:2119-2125, PMID: 23083311. 2. Drazen JM, Curfman GD, Baden LR, et al. Compounding errors. N Engl J Med. 2012;367:2436-2437, PMID: 23134355. 3. Gatesman ML, Smith TJ. The shortage of essential chemotherapy drugs in the United States. N Engl J Med. 2011;365:1653-1655, PMID: 22040130. 4. Kaiser J. Medicine. Shortages of cancer drugs put patients, trials at risk. Science. 2011;332(6029):523, PMID: 21527686. 5. Mitka M. FDA, US hospital and pharmacy groups report drug shortages a growing problem. JAMA. 2011;306:10691070, PMID: 21917568. 6. Metzger ML, Billett A, Link MP. The impact of drug shortages on children with cancer— The example of mechlorethamine. N Engl J Med. 2012; 367:2461-2463, PMID: 23268661.

SOLID TUMORS

Standard of Care Change for Cervical Cancer VEGF inhibitor improves PFS and OS in stage IVB/persistent cervical cancer patients Chicago—Adding bevacizumab to chemotherapy in patients with stage IVB recurrent or persistent cervical cancer improves overall survival by nearly four months, according to results from the Phase III GOG (Gynecologic Oncology Group) 240 trial. The study was presented in the plenary session at the recent annual meeting of the American Society of Clinical Oncology (abstract 3). “I think GOG 240 can be seen as a practice-changing study,” said Gottfried Konecny, MD, an associate professor of medicine at the David Geffen School of Medicine, University of California, Los Angeles, who was not involved with the study. Advanced cervical cancer kills 250,000 women worldwide. The current standard of care is cisplatin-paclitaxel, based on the GOG 204 trial (J ( Clin Oncol 2009;27:4649-4655, PMID: 19720909). The GOG 240 trial randomized 452 women to receive chemotherapy with or without bevacizumab (Avastin,

Genentech); the two chemotherapy regimens used were cisplatin-paclitaxel and cisplatin-topotecan, another commonly used regimen. The arms were well balanced for prognostic factors. No crossover was allowed during the study. Median overall survival (OS) was 17 months for women receiving chemotherapy plus bevacizumab compared with 13.3 months for women receiving chemotherapy alone (hazard ratio [HR], 0.71; P=0.0035). Patients who received bevacizumab also had a better response rate (48% vs. 36%; P=0.00807) and improved median progression-free survival (PFS; 5.9 vs. 8.2 months; HR, 0.6; P=0.0002). “The improvement in overall survival was not accompanied by a significant deterioration in health-related quality of life,” said Krishnansu Sujata Tewari, MD, a professor of obstetrics and gynecology at the University of California, Irvine, who presented the study. Adverse events (AEs) and toxicities

were characterized as manageable. The most common AEs seen more frequently in patients receiving bevacizumab were neutropenia (35% vs. 26%), hypertension (25% vs. 2%), thromboembolism (8% vs. 1%), gastrointestinal (GI) bleeding grade 3 or higher (1% vs. 0), genitourinary bleeding grade 3 or higher (3% vs. 0), GI perforation grade 3 or higher (2% vs. 0) and GI fistula grade 3 or higher (3% vs. 0). “The study results may not be applicable, in my opinion, regarding patients with metastatic disease as only 17% of patients had metastatic disease involvement and at this point, it is not known whether adenocarcinomas derive the same benefit as squamous histologies,” said Dr. Konecny. “The subset analysis did indicate that the hazard ratio was not as low as seen with squamous histologies.” The GOG 240 study is unique in showing that bevacizumab can improve both PFS and OS. In recent years, various clinical trials that have tested bevacizumab in breast, gastric, pancreas and prostate

cancers have demonstrated the drug improves PFS, but has no effect on OS. Dr. Konecny pointed out that the study answered a second important primary question. “The non-platinum regimen was not superior to the cisplatin-paclitaxel–containing chemotherapy backbone,” he said. “I think it is incredibly important to move bevacizumab into earlier disease stages, and to study it in those who possibly have positive lymph nodes or stage II to IVa, and it may be that this is a situation where the benefit of bevacizumab will translate into a reduction in mortality,” said Dr. Konecny. Both Drs. Konecny and Tewari pointed out that a cost-benefit analysis was needed. —Kate O’Rourke Dr. Tewari had no relevant disclosures. Dr. Konecny has received honoraria from Genentech and Sanofi and research funding from Amgen and Pfizer.

To participate in this FREE CME activity, log on to

www.CMEZone.com and enter keyword “MM111”

in Non-Hodgkin’s Lymphoma Evolving Treatment Paradigms 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 Nebraska Medical Center Omaha, Nebraska

Faculty

John P. Leonard, MD

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

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.NEWS

drugs in the United States directly to pharmacies and hospitals. However, some of the U.S. drug supply passes through the “gray market” of pharmaceutical trade, in which legal goods are sold outside direct distribution chan-

COUNTERFEIT continued from page 1

62% of the drugs were either substandard or fake. The investigators also uncovered that 90% of websites did not require a prescription for prescriptiononly drugs (“The Counterfeiting Superhighway,” EAASM report, May 2008). “This was from pharmacies that looked legitimate, not ones that you would immediately dismiss as fake websites,” added Mark Davison, the CEO of Blue Sphere Health Ltd. in Cambridge, England. “Anyone who buys drugs without a prescription over the Internet should have their head examined. It’s like the Wild West online.” Although the Internet may be the simplest, most common way for fakes to reach patients, it is far from the only way. Fake drugs also can seep through security gaps in the legitimate distribution chain. In the normal U.S. supply chain, three major wholesalers, AmerisourceBergen, Cardinal Health and McKesson Corporation, also called the “Big Three,” sell the bulk of prescription

country without facing prohibitions by the manufacturer. Wholesalers can pursue the “parallel trade” system to take advantage of lower drug prices in certain countries by buying them for less in one country and selling them

market, while fake drugs are put in the legitimate packaging,” Dr. Liang said. “A criminal might put legitimate medicines in the top layer of a package, so when an inspector pulls them out they only see the legitimate layer.”

Unlike opioids or dangerous chemicals like uranium, the global supply chain for prescription drugs like Avastin is not cooperatively regulated by a global governing system. So a fake drug traveling from Turkey to the United States may move through the United Kingdom with minimal difficulty. nels. In the United States, this secondary trade goes on between wholesalers across state lines, with many intermediaries touching the drug and with limited state regulation. This setup has allowed suspect secondary wholesalers to introduce fakes into the U.S. legitimate supply chain (Figure). However, it’s not just weaknesses in the U.S. supply chain that make such trading possible. Globally, the problem is similar. For example, in Europe, licensed wholesalers can legally purchase prescription drugs in one country and import them to a second

for more in others. In both situations, during drug shortages, hospital pharmacists may purchase sought-after drugs from a gray market company, or through parallel trade, even though the prices are exorbitant and such trades can be perceived as profiteering, said Bryan Liang, MD, PhD, JD, the vice president of the Partnership for Safe Medicines and the director of California Western School of Law’s Institute of Health Law Studies in San Diego. “This system leaves opportunities for legitimate drugs in the supply chain to get pulled out and sold on the black

In fact, Dr. Liang conducted an experiment to see how easy it would be for a small wholesaler to sell fake drugs to oncologists in the United States. “I tried to see if I could find the name, address, fax number and email of every oncology clinic in the U.S. with a staff of more than 25 and how long it would take to compile that list. It took me approximately 25 minutes,” Dr. Liang said. “I could fax practically every oncology group in the U.S. and advertise cheap [fake] Avastin, and it would only take a few sales to become a multimillionaire.” Perhaps most problematic, however,

Drug Supply Chain Legitimate supply chain

National/Regional wholesaler (sells drugs)

Authentic manufacturing plant

Gray market/ Small wholesaler

Hospitals/pharmacies/ clinics

Patients

Infiltration of bad drugs

Illicit manufacturing plant

Internet

Patients

Gray market/ Small wholesaler (no authority to make drug)

Hospitals/pharmacies/ clinics

Patients

International wholesalers

China

Belgium

Figure. Threats to the drug supply chain.

England

Small wholesaler

Hospitals/pharmacies/ clinics

Patients

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

is the fact that international trade laws for prescription drugs are deficient, making it much easier for criminals to get away with manufacturing and selling fakes. Free trade rules open markets to narcotics like opioids and dangerous chemicals like uranium, but in these contexts, because the threats are well known, the international treaty to open trade is complemented by an international treaty to close trade in cases of criminal behavior, said Amir Attaran, PhD, JD, an associate professor in the Faculties of Law and Medicine at the University of Ottawa, Canada. However, for prescription drugs like Avastin (Genentech), the global supply chain is not cooperatively regulated by a global governing system. So, a fake drug traveling from Turkey to the United States may move through the United Kingdom with minimal difficulty. “Although we have laws that open borders to trade goods from abroad, we do not have laws that prevent trafficking bad medicines,” said Dr. Attaran, who also has a PhD in immunology from the University of Oxford in England. In fact, if a shipment of drugs is not earmarked for domestic populations (i.e., the country simply represents a post office destination), the U.K. and Canadian health regulatory authorities exercise little to no oversight of the drugs because they are only interested in the safety of their own populations, not those receiving the products, added Dr. Liang.

international criminal law and international trade law, Dr. Attaran said. “We’d like laws that properly target the moral offense.”

Stopping the Problem Counterfeit medications can be tough to identify, however. Some fake drugs are discovered because they have unusual or toxic side effects, which patients may report. In other instances, the pills may not look right, or they might be crumbly or have a strange smell or taste. More frequently, a distributor or pharmacy will report unusual changes in packaging, such as a typo or a logo that doesn’t look quite right, or perhaps a batch number is misprinted or inconsistent. Another warning sign is the medication instructions may not be in English or may appear in more than one language. “Nowadays the counterfeiters go as far as to reproduce logos, holograms and packaging, whereas in the past, we might see bad pills in a Ziploc bag,” said Connie Jung, RPh, PhD, the acting associate director for policy and communication in the Office of Drug Security, Integrity, and Recalls at the FDA’s Center for Drug Evaluation and Research. “These criminals have definitely become more sophisticated.” Despite this, there is a range of ways to prevent or police these crimes. The simplest is to not buy prescription medications on the Internet, Mr. Vansteenkiste said. Dr. Liang also advocates

‘Nowadays the counterfeiters go as far as to reproduce logos, holograms and packaging, whereas in the past, we might see bad pills in a Ziploc bag. These criminals have definitely become more sophisticated.’ —Connie Jung, RPh, PhD The law on fake prescription drugs in many countries is covered by intellectual property infringement where the penalty is essentially the same for faking a vital cancer drug as it is for faking a Nike T-shirt. “We do more to police fake trademark than fake medicines,” Dr. Attaran said. “And while trademark laws give us useful tools to go after fake medicines, it’s only in an oblique way.” Because almost 40% of the drugs Americans take are made overseas and about 80% of active pharmaceutical ingredients are imported, according to a February 2012 statement from Margaret A. Hamburg, MD, the commissioner of the FDA, the United States is potentially even more vulnerable to infiltration by organized crime. Now more than ever, the traffic in fake drugs should be closed, which requires a complete global package of

that all online sales of pharmaceuticals be presumed illegal unless the site is accredited by the National Association of Boards of Pharmacy Verified Internet Pharmacy Practice Site, the only online accreditation system recommended by the FDA. Other easy solutions are to educate patients, physicians and pharmacies. Educating patients by showing them what a bottle or pill should look like, for example, may help them feel more empowered. If patients, physicians, nurses or even billing agents find suspicious pills or packaging, they should know to report it to the FDA, their pharmacist and physician, and other relevant authorities. That way, the FDA can take prompt steps to notify patients and providers who may be affected and can remove the illicit product from shelves while also investigating the people involved, Dr. Jung said.

In many countries, prescription drug fraud is treated as intellectual property infringement—the penalty for faking a vital cancer drug is essentially the same as it is for faking a Nike T-shirt.

In terms of preventative measures, drug companies are working on technologies to make individual packs of medicines traceable and tamperproof. In California, new laws will soon require drug companies to put traceable codes on their packs starting in January 2015, and this will likely become a federal requirement. In Europe, initiatives like the Falsified Medicine Directive are helping companies implement traceability regulations and strategies while also creating new criminal offenses for counterfeiting. Along with making packs traceable, European regulators are mandating tamper-evident packs. Patient-specific packs, usually blister packs in Europe, will soon need to be sealed in such a way that it will be clear if a box has been opened, Mr. Davison said. Additionally, companies are working on anti-counterfeiting features like next-generation holograms and colorshifting inks, often used on bank notes. Pollen analysis, which detects patterns of pollen, can help investigators detect where counterfeit and substandard drugs have come from. Perhaps most important, however, are efforts to beef up international policing and laws. “Drug companies have teams of ex-cops or ex-Secret Service people whose job it is to investigate and hunt down these networks and work with local law enforcement to bring counterfeiters to justice,” said Mr. Davison. The House and Senate recently passed bills that expand the FDA’s power to inspect foreign manufacturing sites and increase penalties for counterfeiting drugs from three to 20 years in prison. Additionally, the FDA is setting up foreign offices. “That way, we have some boots on the ground in other countries to be our eyes and ears,” Dr. Jung said. The Council of Europe has drawn

up the first international treaty, called the MEDICRIME Convention, against counterfeit and fake medical products, which establishes that manufacturing, supplying and trafficking counterfeit medical products is illegal. And in 2012, several international entities, including the U.S. Immigration and Customs Enforcement, INTERPOL and the World Customs Organization, initiated Operation Pangea V, a global enforcement effort to stop the sale of illicit drugs online. The operation resulted in the seizure of 3.7 million doses of potentially life-threatening fake medicines worth an estimated value of $10.5 million, and took down about 18,000 websites selling fake or substandard drugs. “What we’re trying to do is raise the bar so that it is no longer time-efficient or cost-effective for criminals to go to counterfeit drugs as a way to make money,” Mr. Davison said. Dr. Attaran, however, believes there has not yet been sufficient time, effort or diplomatic muscle put into negotiating and agreeing on a treaty that criminalizes fakes in all countries and that obliges countries to cooperate. “Currently, we’re stuck at a primordial stage,” he said. “A true solution involves the world of diplomacy to create an international treaty and the world of law enforcement to make it stick. We have to be at the point where a pharmacist and a customs agent are willing to work together. For that to happen, you need a set of rules under which both operate.” —Victoria Stern This is the second article in a two-part special report on fraudulent drugs in the United States. Part I—which focused on the scope of the fraudulent drug problem— was published in the June issue of Clinical Oncology News and is currently available at www.ClinicalOncology.com.

SOLID TUMORS

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like BROCA will allow comprehensive screening of all genes involved in breast cancer risk at once, hopefully including BRCA1 and BRCA2 in the future, which will permit more efficient and cost-effective evaluations,” said Jane Churpek, MD, an assistant professor of medicine at the University of Chicago. The high yield of mutations in this study, presented by Dr. Churpek at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO; abstract CRA1501), came from a population in which 68% of the women had been referred for genetic counseling, most often because they had a family history of breast or ovarian cancer. Currently, the National Comprehensive Cancer Network (NCCN) guidelines largely limit breast cancer screening for high-risk patients to BRCA1 and BRCA2, but the current study provides a foundation for more ambitious genetic profiles. Although the NCCN guidelines accept additional screening in high-risk patients who do not carry BRCA1 and BRCA2 mutations, data like this supports the use of an expanded panel. The results also provide an opportunity to “increase awareness of and access to genetic counseling and genetic testing services, especially for underserved populations,” Dr. Churpek said.

In the study, peripheral blood from 249 unrelated black women from the University of Chicago Cancer Risk Clinic was extracted to perform BROCA, which uses targeted genomic capture and next-generation sequencing to examine all 18 genes currently associated with increased susceptibility to breast cancer. The definition of a damaging mutation was a genetic change associated with loss of protein function. Of the women screened, 56 (22%) carried at least one loss of function mutation. The proportions rose to 27% among women whose breast cancer developed at age 45 or younger, 30% in women with a close relative with breast or ovarian cancer, 30% in women with triple-negative breast cancer and 49% in women with a second breast primary. BRCA1 and BRCA2 were by far the most common genes affected, representing 45% and 34%, respectively, but mutations in the ATM, CHEK2 and PALB2 genes also were observed in multiple patients. Three of the women had more than one mutation. Almost all of the specific mutations in these genes were different. This genetic diversity among blacks makes a case for comprehensive genomic screening in similar high-risk populations. Although the ultimate goal is to prevent primary cancers, Dr. Churpek suggested this data is immediately relevant to secondary cancer prevention in higherrisk groups.

Although relevant to other high-risk groups, a focus on blacks is appropriate because black women have high rates of unfavorable breast cancer types, such as triple-negative, and more often they have onset at a young age. Although the data validates the importance of BRCA1 and BRCA2, the 21% of women with other mutations suggests a substantial contribution from other genes and indicates that “techniques that look at only a few sites in a few genes will not be adequate for this population,” said Dr. Churpek.

This study was conducted as part of an effort to understand the persistent and growing gap in breast cancer survival between black and white patients, which is especially marked in Chicago, Dr. Churpek said. The lower survival in blacks—even when care is comparable—has suggested potential differences in tumor biology. These results also suggest that a high prevalence of mutations in multiple susceptibility genes may play a role. “Comprehensive modern genomics approaches will allow a more efficient and cost-effective approach with

important implications for public health,” said Judy Garber, MD, MPH, the director of the Center for Cancer Genetics and Prevention at Dana-Farber Cancer Institute in Boston. Characterizing Dr. Churpek’s data as “clean and elegant,” Dr. Garber concluded that the findings underline the need to extend genetic counseling services to all high-risk groups. —Ted Bosworth

oncologists, representing 55% of those asked to participate, indicated that coping with drug shortages is done on an ad hoc basis. Seventy-eight percent reported treating patients with a different drug or regimen than they would have used in the absence of a drug shortage; 77% reported substituting a different agent partway through a regimen; 43% reported delaying treatment until the drug could be acquired; 29% reported omitting doses; and 20% reported reducing doses. Nearly 20% reported referring patients to a center where they thought patients could find better access to the drugs they needed. The direct effect of these improvised adaptations on patient outcomes is unknown, but even if treatment delays and substituted, second-choice therapies don’t have an adverse effect on response, they do increase costs, the survey suggested. Most shortages involve generic agents and survey results indicate that more expensive branded agents are typically substituted. In an example provided by Dr. Gogineni, 22% of respondents faced with a shortage of 5-fluorouracil (5-FU) substituted capecitabine, which is metabolized into

5-FU but is more expensive by several magnitudes. However, the substitution of more expensive but relatively equivalent agents may not pose nearly as great a problem as responding to drug shortages in which there is no clear alternative. According to the survey, most oncologists work at centers that offer no formal guidance for allocating drugs in short supply, and the problem is worse in community hospitals or small practices without the infrastructure to anticipate shortages, buy in bulk or pursue other strategies to minimize the problem. The ethical burden on oncologists weighs heavily because the survey suggests that most “lack formal guidance on how to address these shortages,” according to Dr. Gogineni. It is notable that the problem of shortages extends to antinausea agents, analgesics and IV fluids. These drugs are critical for patient support and the survey suggested these shortages frequently prevent clinical trial participation. The problem is not unknown to ASCO, which has undertaken multiple initiatives to reduce the shortages as well as to guide oncologists in coping with

Most shortages involve generic agents, with more expensive branded agents the typical substitution.

‘[Genetic screening] techniques that look at only a few sites in a few genes will not be adequate for this population.’ —Jane Churpek, MD

Dr. Churpek had no relevant relationships to disclose. Dr. Garber has received research funding from Myriad Genetics.

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Philadelphia, said. According to Dr. Gogineni, who presented data from the survey at the 2013 annual meeting of the American Society of Clinical Oncology (ASCO; abstract CRA6510), when physicians were asked about substitutions for several common generic agents, more than half ordered a more expensive agent.

More than one-third of oncologists have rationed cancer drugs. The persistent shortage of drugs is a public health issue spread across all areas of medicine, but the survey was designed to evaluate the effects specifically in oncology. The overrepresentation of sterile injectable generic drugs among those in limited supply affects oncology disproportionately because of the high proportion of anticancer drugs that come in this formulation. The survey, which included 250

these shortages, said Richard Schilsky, MD, ASCO’s chief medical officer. The most important initiative by ASCO has been to spur legislative changes that will address the regulatory and supply issues that underlie the shortages. “The drug shortage problem is a major issue for ASCO,” Dr. Schilsky said. Although some recent reduction in the noise about shortages has suggested amelioration, he said, “I am beginning to wonder whether or not we are really seeing an adaptation of oncologists more than any real change in the availability of generic injectables.” —Ted Bosworth Dr. Gogineri has received research funding from Pfizer. Dr. Schilsky has served as a consultant or advisor to GlaxoSmithKline and Merck.

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CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

How I Manage ...

Monoclonal Gammopathy of Undetermined Significance and Smoldering Multiple Myeloma M

onoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) disorders are characterized by the presence of a monoclonal protein (M-protein) without evidence of multiple myeloma (MM), Waldenstrom’s macroglobulinemia (WM) and light-chain amyloidosis (AL). Newly recognized SMM is associated with a higher risk for progression to symptomatic MM compared with MGUS. In both disorders the common denominator is absence of end-organ damage. The following is a brief review addressing some of the practically relevant issues important in the management of patients with MGUS and SMM.

What is monoclonal gammopathy of undetermined significance (MGUS)? Do all patients with MGUS require a bone marrow examination? Monoclonal gammopathy of undetermined significance (MGUS) is defined as having a serum M (monoclonal) protein less than 3 g/dL, less than 10% monoclonal plasma cells in the bone marrow and the absence of end-organ damage that is attributed to the plasma cell proliferative disorder.1 End-organ damage is characterized by CRAB features that consist of hyperCalcemia, Renal insufficiency, Anemia or Bone lesions related to the plasma cell proliferative disorder.2 MGUS is common, with an incidence of 3% of the population above the age of 50 years and 5% of persons 70 years of age or older.3 During long-term follow-up, the risk for progression is approximately 1% per year.4 A bone marrow examination is not needed if the serum M protein is less than 1.5 g/dL, is of the immunoglobulin (Ig)G subtype and the patient has a normal free light chain (FLC) ratio (lowrisk category), provided that the clinical evaluation, complete blood count (CBC), serum calcium and creatinine values are normal. Thus, almost onehalf of newly recognized patients with MGUS do not require a bone marrow examination. If one of the three just– mentioned risk factors is abnormal— and this occurs in one-third of patients with MGUS—the decision regarding a bone marrow examination must be made on clinical grounds. Patients with two or three abnormal risk factors, which account for about one-fourth of those with newly recognized MGUS, do

Robert A. Kyle, MD Professor of Medicine and Laboratory Medicine and Pathology, Mayo Clinic College of Medicine Rochester, Minnesota

require a bone marrow aspiration and a trephine biopsy. Performance of fluorescence in situ hybridization (FISH) on the bone marrow is strongly advised. Conventional cytogenetics also may be performed in addition to FISH. A bone marrow aspirate and biopsy as well as a radiographic bone survey are indicated in all patients with MGUS who have an M protein value of at least 1.5 g/dL and are of the IgA or IgM subtype and have an abnormal FLC ratio, or if they have CRAB features.5 A bone marrow examination also should be performed if there is any clinical suspicion of multiple myeloma (MM) or amyloid lightchain (AL) amyloidosis.

is no evidence of progression at four to six months, the patient should be evaluated at annual intervals. Patients in the low-risk category, as defined above, may be evaluated every three to five years. It must be emphasized to these patients that if they develop any symptoms such as bone pain, fatigue, constitutional symptoms, neurologic symptoms or bleeding, they must contact their physician immediately. If anemia, hypercalcemia or elevation of serum creatinine occurs, these patients must be evaluated for evidence of symptomatic MM or a related plasma cell dyscrasia. The physician should also be alert for the possibility of a second malignancy.

How do I follow patients with MGUS?

How do I suspect underlying AL amyloidosis?

The history and physical examination including CBC, calcium and creatinine, as well as measurement of the serum and urinary M protein, should be done four to six months after recognition of an MGUS. Occasionally it is found that a person has an early or evolving MM. If there

AL amyloidosis should be suspected in a patient with MGUS if there is a history of fatigue and unexplained weight loss, change in the voice or tongue, easy bruising particularly in the periorbital area, bleeding, dyspnea or peripheral edema. Paresthesias of the hands

AT A GLANCE Almost one-half of newly recognized patients with MGUS do not require a bone marrow examination. In newly recognized patients with MGUS, the physician should be alert for the possibility of a second malignancy. The risk for progression in smoldering MM is approximately 10% per year for the first five years and then decreases over time. Patients with high-risk smoldering MM should be encouraged to participate in a clinical trial.

may suggest carpal tunnel syndrome or peripheral neuropathy. Paresthesias or weakness of the feet suggest peripheral neuropathy involving the lower extremities. AL amyloidosis also should be suspected if physical examination shows macroglossia, periorbital purpura, unexplained ecchymoses, hepatomegaly, splenomegaly or evidence of edema. If AL amyloidosis is suspected, a bone marrow aspirate and biopsy with staining for amyloid and a subcutaneous fat aspirate are indicated. These two tests will recognize almost 90% of patients with AL amyloidosis.

How do I suspect underlying Waldenstrom’s macroglobulinemia? Waldenstrom’s macroglobulinemia (WM) should be suspected in patients with an IgM MGUS who develop constitutional symptoms including increased fatigue, unexplained weight loss, fever or night sweats. Hepatosplenomegaly or lymphadenopathy should also alert the physician to the possibility of WM. Blurred vision from hyperviscosity may be a presenting feature. Patients with WM may present with sensorimotor peripheral neuropathy. These patients must be evaluated for the presence of anemia or thrombocytopenia, as well as an increase in the serum and/or urine M proteins.

What is smoldering multiple myeloma (SMM)? How do I follow patients with SMM? Smoldering multiple myeloma (SMM) is characterized by the presence of an M protein level of at least 3 g/dL and/or 10% monoclonal plasma cells or more in the bone marrow but no evidence of end-organ damage. The risk for progression is approximately 10% per year for the first five years, 3% to 4% per year for the next five years, and then after 10 years the risk for progression falls to 1% to 2% per year. The major risk factors for progression of SMM are the size of the serum M protein and the number of monoclonal plasma cells in the bone marrow as well as the FLC ratio.6,7 The CBC, calcium, creatinine and serum M protein should be repeated in two to three months to exclude the possibility of evolving or symptomatic MM. If the results are stable, testing should be repeated every four to six months for one year and, if still stable,

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Minimizing Hodgkin Lymphoma Treatment With PET PET a ‘sufficiently robust biomarker’ after three cycles of ABVD Atlanta—Clinicians can use positron emission tomography (PET) to identify patients with stage IA and IIA Hodgkin lymphoma who can avoid radiation after three cycles of a standard course of ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine), based on results of the RAPID trial presented at the annual meeting of the American Society of Hematology (abstract 547). The United Kingdom National Cancer Research Institute RAPID trial was launched to examine whether a negative PET scan after ABVD therapy is a sufficiently robust biomarker of disease elimination to select patients who can forgo radiation without an unacceptable reduction in disease control. The study enrolled patients with stage IA or IIA Hodgkin lymphoma, who had no mediastinal bulk or B symptoms and no previous treatment. Patients received three cycles of ABVD, and if there was clear evidence of a response, a PET scan was performed. PET-negative patients then were randomized to receive either involved-field radiotherapy (IFRT) at 30 Gy or no further treatment. PET-positive patients received a fourth cycle of ABVD. Quality-controlled PET images were acquired at one of 30 PET centers and transmitted to St. Thomas’ Hospital in London, where the Core Laboratory assigned the images a score of 1 to 5. Randomization was based exclusively on the Core Lab– reviewed PET scores. A score of 1 to 2 was deemed negative and a score of 3, 4 or 5 was deemed positive. The noninferiority trial registered 602 patients with newly diagnosed Hodgkin lymphoma, with 139 having

stage IA and 281 having stage IIA disease. After three cycles of ABVD, 571 patients had a PET scan, and 74.7% had negative scores. In an intention-to-treat analysis of 420 patients with negative PET scans after three cycles, the median progression-free survival (PFS) at 48.6 months was 94.5% in patients who received IFRT and 90.8% in patients who did not receive radiation, a difference that was not statistically significant. A perprotocol analysis excluded 28 patients who were not allocated radiotherapy and two patients who received radiotherapy even though they were allocated not to receive it. In this analysis of 392 patients, the three-year PFS was 97% in patients who received IFRT and 90.7% in patients who did not receive radiotherapy (HR, 2.39; P=0.03). The PFS in patients who received no further treatment was nearly identical in the two analyses. “Using PET, it is possible to identify a population of patients with stages IA and IIA Hodgkin lymphoma who have an excellent outcome after three cycles of ABVD,” said John Radford, MD, a professor of medical oncology at the University of Manchester in England, who led the study. “Crucially, however, these results have been obtained in the setting of firstly, quality-controlled PET image acquisition; secondly, central review of PET images at the Core Lab in London; and thirdly, a conservative definition of PET-negative.” He said longer follow-up is required to establish the impact of a PET-directed approach on 10- and 20-year survival and cause of death.

the interval between evaluations can be lengthened to every six to 12 months. If there is any evidence of progression during follow-up, a bone marrow examination and a metastatic skeletal survey should be done in addition to the CBC, calcium, creatinine, serum and urine M protein values.

References

Should patients with SMM be encouraged to participate in a clinical trial? The answer is an enthusiastic yes! One current trial is the E3A06 ECOG randomized Phase III trial of lenalidomide versus observation for patients with high-risk SMM (ClinicalTrials.gov: NCT01169337). It is open through the Clinical and Translational Science Unit (CTSU) throughout the United States.

1. Kyle RA. Monoclonal gammopathy of undetermined significance. Natural history in 241 cases. Am J Med. 1978;64:814-826, PMID: 645746. 2. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;121:749-757, PMID: 12780789. 3. Kyle RA, Therneau TM, Rajkumar SV, et al. Prevalence of monoclonal gammopathy of undetermined significance. N Engl J Med. 2006;354:1362-1369, PMID: 16571879. 4. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis in monoclonal gammopathy of undetermined significance. N Engl J Med. 2002;346:564-569, PMID: 11856795. 5. Rajkumar SV, Kyle RA, Therneau TM, et al. Serum free light chain ratio is an

Hodgkin lymphoma stain.

‘If these findings are confirmed, I am more willing to discuss the omission of radiotherapy in selected patients with non-bulky disease who are PETnegative after three cycles of ABVD.’ —Nathan Fowler, MD Nathan Fowler, MD, an assistant professor in the Department of Lymphoma/Myeloma at the University of Texas MD Anderson Cancer Center in Houston, said the study will change his practice. “Although I would recommend interpreting these findings with caution until the results are published, if these findings are confirmed, I am more willing to discuss the omission of radiotherapy in selected patients with

non-bulky disease who are PET-negative after three cycles of ABVD,” he said. However, he added, he still feels “that a patient’s treatment should be individualized following a detailed discussion about the risks and benefits of each treatment modality.” —Kate O’Rourke Drs. Radford and Fowler have no relevant disclosures.

Series Editor Syed Abutalib, MD Assistant Director, Hematology and Stem Cell Transplantation Program Cancer Treatment Centers of America, Zion, Ill.

Coming soon How I Manage: Transplant-Eligible Patients With Multiple Myeloma by Kenneth Anderson, MD

independent risk factor for progression in monoclonal gammopathy of undetermined significance. Blood. 2005;106:812-817, PMID: 15855274. 6. Kyle RA, Greipp PR. Smoldering multiple myeloma. N Engl J Med. 1980;302:1347-1349,

PMID: 7374679. 7. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering (asymptomatic) multiple myeloma. N Engl J Med. 2007;356:2582-2590, PMID: 17582068.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.NEWS

Improving Hematopoietic Stem Cell Transplant New drugs and genomic insights to prevent GVHD, heart failure Atlanta—Hematopoietic stem cell transplant (HSCT) is a potentially curative therapy for many hematologic malignancies, but it is not without side effects and does not work in all patients. At the 2012 annual meeting of the American Society of Hematology (ASH), three studies reported findings on ways to fine-tune this therapy. One study identified a drug that can be used to reduce a common side effect of the treatment, graft-versus-host disease (GVHD). The second study identified genetic factors that can increase the likelihood of patients developing congestive heart failure (CHF) after HSCT. The third study showed that survival did not differ between children with malignancy who were transplanted with two units versus a single unit of partially HLAmatched umbilical cord blood (UCB). Bruce Blazar, MD, a professor of pediatrics in the Division of Blood and Marrow Transplantation at the University of Minnesota in Minneapolis, who highlighted the studies at a “Best of ASH” session at the annual meeting, said the three clinical trials “demonstrate ways we might improve the outcome of hematopoietic stem cell transplantation.”

Single Versus Double Previous studies suggested that a double unit might have advantages over a single-unit UCB transplant by providing more hematopoietic cells, leading to more rapid neutrophil recovery and potentially improving survival. Until now, however, randomized trials have not been conducted. In the Phase III Bone Marrow Transplant Clinical Trials Network 0501 trial, 224 children with acute leukemia were randomized to receive either a single- or a double-unit UCB transplant (abstract 359). After a median follow-up of 25 months, 92% of patients in both treatment arms were in remission. At one year post-transplant, no statistically significant benefits were seen in patients who received the double unit versus the single unit, in terms of overall survival (66% vs. 71%, respectively; P=0.13), disease-free survival (64% vs. 68%; P=0.22) and relapse rates (14% vs. 12%; P=0.37). Although both arms had the same overall

Table. Congestive Heart Failure Risk Based on Gene Variants Associated With Anthracycline-Related CHF Patient Characteristics

Odds Ratio

95% Confidence Interval

P Value

Male, <2 SNPs

1.0

N/A

Male, 2 SNPs

5.0

1.10–22.53

0.04

Female, <2 SNPs

2.4

1.11–5.16

0.03

Female, 2 SNPs

17.1

4.63–63.36

<0.01

CHF, congestive heart failure; SNP, single-nucleotide single nucleotide polymorphism polymorphism

‘Armed with these insights, we can now create better screening measures and perhaps even tailor intervention strategies based on a patient’s genetic makeup.’ —Saro Armenian, DO, MPH rate of acute GVHD (57%), patients who received a double cord blood transplant experienced a higher risk for grade 3/4 GVHD (23% vs. 14%; P=0.03). The incidence of platelet recovery was higher with the single than the double UCB transplant (76% vs. 66%), but this was not significant. “A single cord blood unit should be considered the standard graft for children, but for those who don’t have an adequate single unit, certainly a double cord blood transplant will serve as an adequate alternative to a single,” said John Wagner, MD, the lead author and the director of the Pediatric Blood and Marrow Transplant Program at the University of Minnesota in Minneapolis.

Reducing GVHD In another study, researchers demonstrated that histone deacetylase inhibitors (HDACi) can reduce the severity of GVHD in patients undergoing matched related donor reduced-intensity conditioning (MRD RIC) allogeneic HSCT (abstract 740). GVHD affects approximately 35% to 55% of patients who receive allogeneic HSCT. In the Phase I/II study, 47 patients undergoing MRD RIC HSCT at the University of Michigan and Washington University in St. Louis, received the oral HDACi vorinostat (Zolinza, Merck)

daily in addition to standard preventive treatments before, during and for 100 days after transplantation. The results were compared with those of 25 historical controls who had undergone an MRD RIC allogeneic HSCT using standard preventive treatments. Compared with controls, patients who received vorinostat had lower incidences of GVHD (22% vs. 42%; P=0.04), grade 3/4 GVHD (4% vs. 19%) and transplantrelated mortality at one year (13% vs. 19%). The two-year disease-free survival rate was 52% in the control arm and 66% in the vorinostat arm. There were no differences in rate of infectious complications or incidence of relapse, indicating that vorinostat helped reduce the risk for GVHD in patients without further compromising their immune systems. “This drug may potentially add to our armamentarium in preventing complications of hematopoietic stem cell transplantation, which would allow it to be used in a higher frequency of individuals with less severe complications,” Dr. Blazar said.

Congestive Heart Failure and HSCT In the third study, researchers examined genetic susceptibility to anthracycline-related CHF in survivors of HSCT (abstract 589). CHF is the leading cause

of morbidity and mortality after HSCT. The average time to CHF is 2.5 years from HSCT, and the average age is 55. Using a nested case-control approach, investigators evaluated the impact of several single-nucleotide polymorphisms (SNPs) in genes hypothesized to be associated with anthracycline-related CHF. Researchers identified individuals with CHF and with pre-HSCT germline DNA from 2,950 patients transplanted at City of Hope National Medical Center, between 1988 and 2007. Controls were matched on age at HSCT, type of HSCT (allo or auto), race, ethnicity, anthracycline dose and length of follow-up. Patients who had variations in the MRP2, RAC2 and HFE genes had up to a threefold higher risk for developing heart failure after transplant. These genes are responsible for key proteins that regulate the metabolism of anthracyclines and defense against oxidative stress. Compared with male patients who had less than two SNPs, female patients who had two or more of the genetic polymorphisms were at a higher risk for CHF than male patients who had two or more genetic polymorphisms, with an odds ratio (OR) of 17.1 ((P<0.01) compared with 5.0 ((P=0.04). The same pattern was seen for female and male patients who had less than two SNPs, but to a lesser extent (OR, 2.4 vs. 1.0; P=0.03 and N/A, respectively; Table). “Armed with these insights, we can now create better screening measures and perhaps even tailor intervention strategies based on a patient’s genetic makeup, minimizing long-term transplant-related toxicity and making a tremendous difference in the long-term health of these patients,” said Saro Armenian, DO, MPH, the study’s lead author, and an assistant professor of outcomes research and the medical director of the Pediatric Survivorship Clinic at City of Hope in Duarte, Calif. —Kate O’Rourke Dr. Blazar disclosed a consultancy with Athelos-NeoStem, Novartis and Acetylon Pharmaceuticals, and research funding from Novartis, Acetylon, Boehringer Ingelheim and Tarix. Drs. Wagner and Armenian had no relevant disclosures.

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Please send comments to Gabriel Miller at gmiller@mcmahonmed.com

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Testing Promising Therapies in Refractory MCL Role of lenalidomide and ibrutinib likely to continue expanding Atlanta—Lenalidomide (Revlimid, Celgene) and the investigational agent ibrutinib (Pharmacyclics) are effective as single agents in patients with relapsed and refractory mantle cell lymphoma (MCL), according to two studies presented at the 2012 American Society of Hematology (ASH) annual meeting (abstracts 904 and 905). The response rate was roughly 30% in patients receiving lenalidomide and 70% in patients receiving ibrutinib. According to Joshua Brody, MD, an assistant professor in hematology and medical oncology at Mount Sinai School of Medicine in New York City, who was not involved with the studies, some clinicians are already using lenalidomide in this setting based on results from smaller clinical trials, and the new study “will likely bring greater awareness and utilization of the agent in this setting.” He said several exciting studies at the ASH meeting showed ibrutinib is effective in various cancers, including chronic lymphocytic leukemia. “Ibrutinib will likely be approved for this and other types of lymphoma and its role will evolve over the next few years, first into combination regimens for relapsed/refractory patients and then into primary therapy,” Dr. Brody said. Relapsed/refractory MCL is characterized by frequent chemoresistance and limited treatment options. No standard therapy exists for patients who have failed bortezomib (Velcade, Millennium).

Lenalidomide Previously, the Phase II trials NHL002 and NHL-003 demonstrated that lenalidomide has activity in patients

with relapsed/refractory, aggressive non-Hodgkin lymphoma. EMERGE, a global, multicenter, single-arm, openlabel study, enrolled 134 patients with relapsed or progressive MCL. Patients had to have failed a prior anthracycline (or mitoxantrone), cyclophosphamide, rituximab (Rituxan, Genentech) and bortezomib. Patients received 25 mg lenalidomide on days 1 to 21 as part of a 28-day cycle. Patients were restaged every two cycles and treated until disease progression or toxicity. Andre Goy, MD, the chief of the Lymphoma Division and chairman of John Theurer Cancer Center at Hackensack University Medical Center in Hackensack, N.J., who presented the study, said the population was heavily pretreated with a median of four prior therapies (range, two to 10). Two-thirds were refractory to bortezomib, more than half had a high tumor burden, one-third had bulky disease, and one-third had received prior high-dose therapy and autologous stem cell transplant. Overall response rate was 28%, with 8% complete response (CR) and 20% partial response rates. The median duration of response was 16.6 months, and median progression-free survival (PFS) was four months. With a median followup of 9.9 months, median overall survival was 19 months. Similar response rates were seen across all subsets of patients, regardless of number of prior therapies, including in patients who had been refractory to their last prior therapy. Grade 3/4 adverse events included neutropenia (43%), thrombocytopenia (27%), anemia (11%), leukopenia (7%), febrile neutropenia (7%), fatigue (7%), diarrhea

‘This is the highest response rate ever reported, ever achieved, by one single drug in the history of relapsed mantle cell lymphoma.’ —Michael Wang, MD

A characteristic morphologic feature of mantle cell lymphoma is the monomorphic appearance of small to intermediate-sized cells.

Table. Response in Relapsed or Refractory MCL Patients Receiving Ibrutinib Bortezomib-naive, %

Bortezomib-exposed, %

Complete response

Partial response

Total response

‘If there is an unstated excitement about lenalidomide here, it’s the hint of evidence in other Phase II studies that rituximab not only adds to lenalidomide’s effect but really synergizes with it.’ —Joshua Brody, MD (6%), dyspnea (6%) and pneumonia (8%). Nineteen percent of patients discontinued because of adverse events. “Currently, many of us use [lenalidomide] in second-line therapy or beyond, and there are ongoing studies using it in first-line therapy, either as part of combination therapy or as a maintenance therapy,” Dr. Brody said. “If there is an unstated excitement about lenalidomide here, it’s the hint of evidence in other Phase II studies that rituximab not only adds to lenalidomide’s effect but really synergizes with it.”

Ibrutinib Michael Wang, MD, an associate professor at the University of Texas MD Anderson Cancer Center in Houston, presented interim data from a Phase II study testing ibrutinib, a first-in-class, oral Bruton tyrosine kinase inhibitor, in patients with relapsed or refractory MCL. The study, conducted at 18 sites in the United States and Europe, enrolled 65 bortezomib-naive patients (89.2% totally naive and 10.8% less than two cycles of bortezomib) and 50 patients who had received at least two cycles of bortezomib. The median number of prior regimens was three for the entire study group; 53% had received three or more regimens. Patients received 560 mg ibrutinib daily until progression. Neutropenia, thrombocytopenia and anemia were seen in less than 20% of patients. “Most of the non-hematogenous toxicities were of grade 1 or grade 2,” said Dr. Wang, who characterized the drug as “well tolerated.” In the 110 patients evaluable for response at 9.2 months, 68% had a response, with a CR of 21% in bortezomib-naive patients and 23% in bortezomib-exposed patients (Table). In the 51 patients with a longer follow-up

of 14.7 months, 75% had a response, with a 40% CR rate in bortezomibnaive patients and 38% in bortezomibexposed patients. Partial response rates were 37% in bortezomib-naive patients and 33% in bortezomib-exposed patients. The median PFS for all evaluable patients was 13.9 months. “This is the highest response rate ever reported, ever achieved, by one single drug in the history of relapsed mantle cell lymphoma,” said Dr. Wang. Some patients achieved a response very fast, including three patients at 1.7 months, but in others it took four months to achieve a CR, said Dr. Wang, calling this “a phenomenon of incremental response.” “Beyond the remarkable response data, ibrutinib’s real promise is in its remarkable tolerability, in that it should be able to combine with other agents well, as has been the case for rituximab over the past decade,” added Dr. Brody. “Like rituximab, the real question is not whether ibrutinib is superior to other agents, but how best to use these agents in combination. Chemotherapies only achieve their curative potential in combination, and so there is room for optimism that combinations of these new targeted and immunomodulating agents can achieve long-term disease control and even cure.” —Kate O’Rourke Dr. Wang disclosed research funding and honoraria from Celgene, Millennium and Onyx, and research funding from Cellular Therapeutics, Janssen, Novartis and Pharmacyclics. Dr. Goy disclosed being on the speakers’ bureau for Celgene. Dr. Brody disclosed that his laboratory receives funding from Celgene and Gilead Pharmaceuticals, as well as reagent support from Pharmacyclics.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Sorafenib an Option for Refractory Thyroid Cancer Chicago—Sorafenib improves median progression-free survival by five months compared with placebo in patients with locally advanced or metastatic differentiated thyroid cancer that is refractory to radioactive iodine, according to a Phase III trial. The study is expected to change the standard of care for some patients with this disease. Treatment of differentiated thyroid cancer—97% of all thyroid cancers— includes surgery and thyroid-stimulating hormone suppression. If this is not successful, clinicians turn to radioactive iodine, but between 5% and 15% of patients will become refractory to this therapy. The patients then are usually referred to palliative care or a clinical trial, and median overall survival is between 2.5 to 3.5 years, said Marcia Brose, MD, PhD, the director of the Thyroid Cancer Therapeutics Program and an assistant professor at the Abramson Cancer Center and Perelman School of Medicine, at the University of Pennsylvania in Philadelphia. She presented the data, from the DECISION trial, at the American Society of Clinical Oncology’s 2013 annual meeting (abstract 4). To be included in the study, patients had to have disease progression within the preceding 14 months and to have not received prior chemotherapy, targeted therapy or thalidomide. The study randomized 417 patients to sorafenib (Nexavar, Bayer/Onyx; 400 mg) or placebo, both twice daily. After disease progression, patients on placebo were allowed to cross over to sorafenib, and individuals

receiving sorafenib were allowed to continue on the drug. Median progression-free survival (PFS) in patients receiving placebo (n=210) was 5.8 months compared with 10.8 months in patients receiving sorafenib (n=207; hazard ratio, 0.587; 95% confidence interval, 0.454-0.758; P<0.0001). There were no complete responses; 12.2% of patients had a partial response. Median overall survival has not been reached, but will be highly influenced by the fact that 71% of the placebo patients crossed over to receive sorafenib, according to Ezra Cohen, MD, an associate professor of medicine and an associate director for education at the University of Chicago Comprehensive Cancer Center, who was not involved with the study. “Grade 3/4 toxicities included primarily hand–foot skin reaction, hypertension and hypocalcemia,” Dr. Brose said (Table). Second cancers were more common in patients receiving sorafenib than placebo (4.3% vs. 1.9%, respectively), but the difference was due to squamous cell carcinoma of the skin, a known side effect of sorafenib, which is easily controlled, she said. Some clinicians in the United States already have been using sorafenib off-label for iodine-refractory, locally advanced or metastatic differentiated thyroid cancer. So, should sorafenib be the standard of care for this patient population? “Not all iodine-refractory patients need treatment,” Dr. Cohen said. “Even in a study such as DECISION, where

Table. Most Common Grade 3/4 Emergent Adverse Events of Sorafenib Sorafenib

Placebo

Hand–foot skin reaction

20.3%

Hypertension

9.7%

2.4%

Hypocalcemia

9.2%

1.4%

The study—the first Phase III trial of a targeted agent in this disease—suggests a change in standard care for iodine-refractory patients; however, not all of these patients require treatment. patients were required to have evidence of progressive disease within 14 months of enrollment and were required to be radioactive iodine–refractory, we still saw a quarter of the placebo-treated subjects who did not progress at 400 days.” Several Phase II trials have shown that other vascular endothelial growth factor receptor (VEGFR) inhibitors can improve outcomes in differentiated thyroid cancer, with response rates ranging from 15% to 50%, and median PFS of about one year. Dr. Cohen said, however, that data from Phase II and Phase III trials cannot be compared, and DECISION is the first Phase III trial of a targeted agent in this disease. None of the VEGFR inhibitors induce complete responses or offer a cure, he said. Dr. Cohen pointed out that most

radioactive iodine–refractory patients are asymptomatic, and one study has demonstrated that patients who are negative on 18-fluorodeoxyglucose positron emission tomography can have a median PFS exceeding three years (World J Surg Oncol 2012;10:192, PMID: 22985118). He recommended using sorafenib in refractory patients who have symptoms or are expected to have symptoms soon based on the location of their disease, as well as patients whose disease is progressing rapidly. —Kate O’Rourke Dr. Brose has been a consultant/advisor for Bayer and Onyx and received honoraria and research funding from Bayer. Dr. Cohen has been a consultant/advisor for Boehringer Ingelheim, Novartis, Primal Life Sciences and VentiRx, and received honoraria from Biodesix.

Genitourinary Cancers Symposium

Watch and Wait Works for Small Kidney Tumors For tumors less than 4 cm, no increase in risk for kidney cancer death Orlando, Fla.—A retrospective study of more than 8,000 older patients has concluded that surveillance of small kidney tumors is a safe alternative to surgery. “Surveillance of small kidney tumors did not increase the risk of dying of kidney cancer,” said William Huang, MD, a surgical oncologist at New York University Langone Medical Center in New York City. In contrast, “surgical treatment, particularly removal of the entire kidney, was associated with cardiovascular complications and poorer survival over time.” He presented the study at the 2013 Genitourinary Cancers Symposium (abstract 343). Nearly two-thirds of newly diagnosed kidney tumors are small (<4 cm); this group represents a heterogeneous group of tumors with varying malignant potential. Although surgery has

been the standard treatment for these cancers, emerging eviidence suggests that surgi-cal intervention in older orr morbidly ill patients may bee unnecessary and also mayy adversely affect non-oncologgic outcomes. In the current study, researchers set out to identify the effect of surveillance of small renal tumors on morbidity and mortal-ity compared with surgery. They used the Surveillance, Epidemiology, and End Results cancer registry data linked to Medicare claims data, to capture patient comorbidities, for diagnoses between 2000 and 2007. The retrospective cohort study included 8,300 patients who were aged 66 years or older with

kidneyy tumors less than 4 cm. Of thesse patients, 78% had surgery an nd 22% received surveillance. During a median follow-up of five years, patients in the o ssurveillance group had a 16% llower risk for death from any ccause compared with the surggical group (hazard ratio [HR], 0.84; 95% confidence interval, 0 0.775-0.94). Kidney cancer–specificc mortality did not differ significan ntly between the groups. “Surveillance ill is a reasonable option, particularly for patients who are older or have a limited life expectancy,” said Dr. Huang. He added that a small number of small tumors can become lethal over a period of time, and therefore if a patient has a normal life expectancy, surgery should still remain the

treatment of choice for these patients. Bruce Roth, MD, a professor of medicine in the Oncology Division at Washington University in St. Louis, who was not involved in the study, said the findings were important in showing that surveillance does not have a negative influence on kidney cancer mortality. He pointed out that today, more small lesions are being identified. “In 2013, it is difficult to go to an emergency room with chest pain or abdominal pain and not come out with a CAT [computed axial tomography] scan,” he said. “The more CAT scans you do, the more kidney masses you are going to find.” —Kate O’Rourke Drs. Huang and Roth have no relevant disclosures.

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REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.NEWS

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

T-DM1 Effective in First-Line Metastatic Breast Cancer From the Journal of Clinical Oncology

do-trastuzumab emtansine (Kadcyla, Genetech) proved more effective and better tolerated than trastuzumab (Herceptin, Genentech) plus docetaxel (Taxotere, Sanofi) in treating HER2-positive metastatic breast cancer. The results of this Phase II, openlabel, multicenter study (J ( Clin Oncol 2013;9:1157-1163, PMID: 23382472), led by Sara A. Hurvitz, MD, of the Jonsson Comprehensive Cancer Center in Los Angeles, confirmed results seen earlier in single-arm trials. Previously treated, eligible patients with

metastatic breast cancer were randomly assigned to one of two protocols. In the HT (trastuzumab plus docetaxel) arm, 70 patients were treated with IV trastuzumab (8 mg/kg loading dose, then 6 mg/kg every three weeks) plus IV docetaxel (75 or 100 mg/m2 every three weeks). In the second arm, 67 patients received 3.6 mg/kg every three weeks of IV ado-trastuzumab emtansine (T-DM1), a polymerization inhibitor that targets tumor cells, conjugated to trastuzumab. The T-DM1 arm experienced a clinically meaningful and statistically significant reduction in the relative risk for disease progression. The median

EXPERT INSIGHT Julie Fisher, MD Medical Oncology, Breast Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

reatment of patients with metastatic HER2/neu overamplified breast cancer has evolved over the past decade, and there are now numerous treatment options available for this group. This has translated into improved disease-free and overall survival times, with clinicians making treatment decisions in a constantly evolving landscape. Trastuzumab was FDA-approved in 1998, the same year the American Society of Clinical Oncology guidelines recommended routine HER2 testing of all breast cancers. Fifteen percent to 20% of invasive breast cancers manifest amplification of the HER2 oncogene. Although HER2 overexpression is associated with more aggressive disease, the addition of trastuzumab to treatment regimens has significantly improved

outcomes in this subset of patients. This has been an area of rapid development, and there are now four approved drugs for patients with HER2-positive metastatic breast cancer: trastuzumab, pertuzumab, lapatinib, and the newest on the horizon, T-DM1. T-DM1, an antibody-drug conjugate composed of DM1, a tubulin-binding agent conjugated to trastuzumab, is now approved in patients with HER2-positive metastatic breast cancer whose disease has progressed on HER2-targeted therapy. Now, Hurvitz et al report a Phase II study of T-DM1 versus HT as first-line treatment for metastatic breast cancer. Overall survival was similar in the two arms, but median PFS was significantly improved in the T-DM1 treatment arm. Moreover, there were fewer AEs with

progression-free survival (PFS) for the HT group was 9.2 months and for the T-DM1 group was 14.2 months (hazard ratio, 0.59; 95% confidence interval [CI], 0.36-0.97). Objective response rate (ORR) in the HT arm was 58% (95% CI, 45.5%-69.2%) and in the T-DM1 arm was 64.2% (95% CI, 51.8%74.8%). Three patients achieved complete remission (CR) in the HT arm and seven in the T-DM1 arm. For the 40 patients who responded to HT, the median duration of response was 9.5 months (95% CI, 6.610.6); the median duration of response for the T-DM1 group was not reached during the study (25th percentile of

duration of response was 8.8 months). There were more significant (≥ grade 3) adverse events (AEs) in the HT arm than in the T-DM1 arm, respectively: 90.9% versus 46.4%. AEs that led to treatment discontinuation also were more frequent in the HT arm (40.9% vs. 7.2%). Patient-completed quality-of-life surveys also favored the T-DM1 arm. This study gives compelling evidence that T-DM1 provides superior safety, efficacy and patient quality of life than HT in the treatment of HER2-positive metastatic breast cancer. Further study, the researchers believe, is warranted.

T-DM1, with no evidence of enhanced toxicity. Cardiotoxicity, a perennial concern with trastuzumab, was similar in both arms. This study represents another new era in metastatic breast cancer therapeutics. The introduction of conjugate drugs like T-DM1 that may have enhanced efficacy and better safety profiles than traditional two-drug regimens could open the door for additional conjugates. The 2012 EMELIA study established the role of T-DM1 in second-line treatment of metastatic breast cancer compared with lapatinib and capecitabine.1 The Hurvitz study demonstrates its promising activity as first-line treatment. That role will be defined more fully by the ongoing MARIANNE study, which examines T-DM1 versus T-DM1 plus pertuzumab versus trastuzumab plus a taxane.2 If studies continue to demonstrate benefit with decreased toxicity, the drug’s potential utility in all HER2-amplified breast cancer settings is compelling and merits further investigation. Based on the current data and experience, and pending the results of the MARIANNE study, T-DM1 is likely to soon become an attractive option

for front-line treatment of metastatic HER2-amplified breast cancer. This new paradigm will lead to considerations of what the appropriate second-line therapy is in HER2-positive patients after T-DM1 treatment. Clearly, further studies will be needed to identify the best treatment approach following disease progression. Beyond the scope of the breast cancer world, the question arises whether there is a role for T-DM1 in other HER2-overexpressing tumors, such as gastric and esophageal cancers. A future beckons in which cytotoxic agents are delivered directly to tumor cells, increasing efficacy and decreasing toxicity.

References 1. Verma S, Miles D, Gianni L, et al, for the EMILIA Study Group. Trastuzumab emtansine for HER2-positive advanced breast cancer. N Engl J Med. 2012;367:1783-1791, PMID: 23020162. 2. ClinicalTrials.gov: A Study of Trastuzumab Emtansine (T-DM1) Plus Pertuzumab/ Pertuzumab Placebo Versus Trastuzumab (Herceptin) plus a Taxane in Patients with Metastatic Breast Cancer (MARIANNE). www.clinicaltrials.gov/ct2/show/ NCT01120184. Dr. Fisher reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Chemo-N0 Study Confirms Utility of uPA/PAI-1 Biomarker From European Journal of Cancer

inal results of the Chemo-N0 study, the first prospective multicenter trial for women with node-negative (N0) breast cancer to evaluate the utility of a biomarker in deciding on a therapeutic course, have confirmed the prognostic utility of urokinasetype plasminogen activator (uPA) and its type 1 inhibitor (PAI-1). Using a standardized enzyme-linked immunosorbent assay (ELISA), 647 patients from 12 sites in Germany and the Netherlands were tested for uPA and PAI-1 levels. Groups were defined

EXPERT INSIGHT Wendy Brick, MD Medical Oncology, Breast Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

atients with node-negative, estrogen receptor (ER)-positive breast cancer are a heterogeneous group in which up to 70% will be cured by locoregional therapy alone. An important clinical question is how to identify those patients at low risk for recurrence who may be able to avoid adjuvant chemotherapy, and also how to identify patients at high risk who should receive adjuvant chemotherapy. Because not all patients benefit from adjuvant chemotherapy, rational management requires the availability of reliable prognostic and predictive markers. Medical oncologists use an array of information, including tumor grade and size, estrogen/progesterone receptor status, HER2 expression, proliferation markers such as Ki-67, and gene signatures like Oncotype DX (Genomic Health) and MammaPrint (Agendia), to determine which patients with N0 (and increasingly more often, nodepositive) disease should receive adjuvant chemotherapy. The plasminogen activator system has a complex role in the cell migration, angiogenesis, dissemination and metastasis of cancers. Large retrospective studies suggest that patients with high levels of tumor-invasion factors— uPA and its inhibitor PAI-1—in tumor tissue derive increased benefit from adjuvant chemotherapy over those containing low levels.1-4 The American Society of Clinical Oncology (ASCO) categorizes uPA and

as being low risk with uPA of 3 ng/mg or less and PAI-1 of no more than 14 ng/mg; high-risk patients were those with greater amounts. The first group (arm A) included 283 low-risk patients who were assigned to the observationonly group, in which adjuvant systemic therapy was not administered; 242 high-risk patients were randomized into either arm B1, and were treated with CMF (cyclophosphamide, methotrexate, 5-fluorouracil) therapy (n=117), or arm B2, and were observed without chemotherapy (n=125). A third group, arm B3, was comprised of 122 high-risk patients who declined randomization.

Of this group, 91 received CMF and 31 were treated with chemotherapy. The analysis, published in European Journal of Cancer (2013;49:18251835, PMID: 23490655), included 10-year results from the date of the last enrolled participant and 113 months of median follow-up. The study’s final conclusions validated earlier observations, among which are that low-risk patients had a 10-year disease recurrence rate of 12.9% (95% confidence interval [CI], 9.1%-18.1%), whereas the rate for patients with high-risk disease was 23% (95% CI, 16.9%-30.8%). Patients with high uPA/

PAI-1 experienced a 1.84-fold higher disease recurrence risk ((P=0.017) than patients with low-risk N0 breast cancer. Ten-year overall survival rates were 89.8% in low-risk patients and 79.1% in high-risk patients ((P=0.01; hazard ratio, 1.94; 95% CI, 1.16-3.24). The investigators concluded that nearly half of N0 patients could be managed adequately with observation alone, whereas those who possess higher levels of uPA/PAI-1 would benefit from adjuvant chemotherapy. The study supports the use of uPA/PAI-1 data for assessing individual risk and making therapeutic decisions.

PAI-1 as “clinically useful” and recommended biomarkers. The Chemo-N0 trial, reported here, is the first prospective, randomized multicenter trial to report long-term follow-up (10 years) confirming uPA/PAI-1 as an independent prognostic factor and that ERpositive node-negative patients with high levels of uPA and/or PAI-1 are at high risk for relapse and therefore should receive adjuvant chemotherapy. Risk assessment that includes uPA and PAI-1 can distinguish up to 55% of N0 ER-positive patients as low-risk and therefore allow them to avoid adjuvant chemotherapy and its inherent risks. The Chemo-N0 study also supports uPA/PAI-1 as useful in predicting response to systemic chemotherapy. Although clinically interesting and provocative, there are still questions to be answered with regard to the use of uPA/PAI-1. CMF, considered standard at the initiation of the Chemo-N0 study, was selected for the “systemic” treatment. It has been hypothesized that the predictive value of uPA/PAI-1 would be similar with current standard systemic regimens that include a taxane and/or an anthracycline. The currently maturing NNBC-3 (Node-Negative Breast Cancer-3) trial in Germany will help to address this question. The NNBC-3 trial randomized more than 4,000 N0 patients to determine the benefits of a sequential anthracycline-docetaxel regimen (FEC [5-FU, epirubicin and cyclophosphamide] × 3 docetaxel × 3) in high-risk NO breast cancer patients compared with a current standard of anthracycline-based chemotherapy (FEC × 6), after risk assessment was performed by either biological risk assessment using invasion factors uPA/ PAI-1 or a clinical-pathologic algorithm. Importantly, it also should be noted that no patients enrolled in the Chemo-N0 trial received hormone therapy.

Current standard of care would be to consider hormone therapy for all patients in this trial with or without adjuvant cytotoxic chemotherapy. The Chemo-N0 trial, therefore, gives no indication of the benefit of hormone therapy in patients with either high or low levels of uPA/PAI-1. This question will certainly need to be evaluated before the use of these biomarkers becomes more clinically mainstream. Additionally, HER2 status was not considered in the Chemo-N0 trial. This is interesting in light of the fact that studies have shown more intense HER2 expression associated with lower uPA scores. This seemingly paradoxical observation may be due to the fact that stromal cells, rather than the epithelial cells of the tumor, produce most of the uPA. The Chemo-N0 trial did demonstrate that determination of uPA and PAI-1 in tumor tissue by ELISA is easily feasible in most laboratories. Core-needle biopsy material has been shown to allow reliable uPA/PAI-1 determination. Unfortunately, the test requires fresh or fresh-frozen tissue. Perhaps this is one reason that the measurement of uPA/ PAI-1 is limited in clinical use. This likely also is the case for the disparate use of MammaPrint rather than Oncotype DX. The use of Oncotype DX is firmly established in the United States as a predictor of high- or low-risk disease. Oncotype DX is available for paraffinembedded tissue, making timing with respect to tissue collection much less of an issue. It is based on mRNA expression of 16 tumor-specific genes and five control genes. It is widely used in the United States for N0, and more recently node-positive (one to three nodes), ER-positive patients. A high recurrence score is associated with a high probability of recurrence and benefit from adjuvant chemotherapy. ASCO guidelines

include recommendations for the use of Oncotype DX. The prospective WSG (West German Study Group) Plan B trial, which is evaluating efficacy of anthracycline-free chemotherapy in primary HER2-negative breast cancer following molecular-based risk assessment according to Oncotype DX and uPA/ PAI-1, has already recruited more than 2,500 patients. This is a provocative trial and its results will be eagerly awaited in countries where the use of Oncotype DX is not as deeply entrenched. Although clinically interesting, there are still questions to be answered with regard to the use of uPA/PAI-1. Additionally, although simple to obtain, the information is limited in comparison to microarray profiling and proteomics, where there is potential to gain significantly more clinical information regarding prognosis and predictive response to treatment.

References 1. Jänicke F, Schmitt M, Pache L, et al. Urokinase (uPA) and its inhibitor PAI-1 are strong and independent prognostic factors in node-negative breast cancer. Breast Cancer Res Treat. 1993;24:195-208, PMID: 8435475. 2. Annecke K, Schmitt M, Euler U, et al. uPA and PAI-1 in breast cancer: review of their clinical utility and current validation in the prospective NNBC-3 trial. Adv Clin Chem. 2008;45:31-45, PMID: 18429492. 3. Harbeck N, Thomssen C, Berger U, et al. Invasion marker PAI-1 remains a strong prognostic factor after long-term followup both for primary breast cancer and following first relapse. Breast Cancer Res Treat. 1999;54:147-157, PMID: 10424405. 4. Thomssen C, Harbeck N, Dittmer J, et al. Feasibility of measuring the prognostic factors uPA and PAI-1 in core needle biopsy breast cancer specimens. J Natl Cancer Inst. 2009;101:1028-1029, PMID: 19535782.

Dr. Brick reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.NEWS

Similar Genetic Alterations Found in Primary and Metastatic NSCLC From the Journal of Clinical Oncology

omparison of genetic sequencing of tumor samples taken during primary tumor resection and subsequent metastases in patients with lung cancer revealed few substantial genetic alterations. The researchers suggested that difficult biopsies of recurrent metastases might thus be avoided. It has been assumed that tumor recurrence often was the result of significant molecular alterations between the primary cancer and associated metastases. Although this is the case in some cancers, recent studies have shown concurrence in the genetic makeup of some primary tumors and

subsequent recurrent cancers. Stephane Vignot, MD, and colleagues conducted next-generation DNA sequencing on archived biopsy specimens from 15 patients with recurrent non-small cell lung cancer (NSCLC) and reported their findings in the Journal of Clinical Oncology (2013 Apr 29. [Epub ahead of print], PMID: 23630207). They noted that obtaining repeat biopsies might pose significant risks in this population. Common underlying smokingrelated comorbidities include chronic obstructive pulmonary disease and cardiovascular disease. DNA libraries were constructed for the 30 tumor samples (primary and

EXPERT INSIGHT

Edward Kim, MD

Kathryn F. Mileham, MD

Chair, Department of Solid Tumors and Investigational Therapeutics Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

Hematology, Medical Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

haracterizing patient subgroups by molecular testing and then directing appropriate targeted therapy is the present and future in cancer therapeutics. Following in the footsteps of infectious disease states, identifying sensitivities and resistances of various drugs help direct therapy and improve patient outcomes. Whereas multiple bacterial strains can all be sensitive to the same drug, other highly resistant strains can develop rapidly and become life-threatening. We have made these observations in cancer treatment: In ovarian cancer, platinums can be used several times for sensitive tumors, yet in refractory small cell lung cancer, relapse is quick and subsequent drugs fail precipitously. Identifying unique characteristics in cancers may help predict recurrence or guide treatments. As technology has progressed over time, chemotherapy combinations have resulted in dramatic outcomes in some tumors (testicular cancer) and frustration in others (NSCLC). The ability to determine

which tumors will be sensitive or resistant has been limited. Biomarker analyses with corresponding therapy have changed the management of cancers including HER2-positive breast cancer, c-kit-positive gastrointestinal stromal tumors, and in lung cancer, EGFR mutations and ALK translocations. However, once the treatments fail and the tumors acquire resistance, options remain poor. Next-generation sequencing has progressively become less prohibitive due to lower costs and greater availability. Since 1953 when Watson and Crick first characterized the double helix,1 technologies have improved to sequence DNA. However, there remains a lack of infrastructure to support clinical assessments in real time. The amount of data derived requires comprehensive bioinformatics analysis and reveals in many instances numerous mutations/alterations that are difficult to interpret. Vignot et al characterized 15 matched primary and metastatic tumor pairs, which yielded 311 genomic alterations,

associated metastasis), representing 3,230 exons in 182 cancer-related genes plus 37 introns from 14 genes often rearranged in cancer (19 genes total because seven genes were screened across both exons and introns). The goal of this study was to compare the two biopsies and to identify “driver” and “passenger” mutations. Somatic alterations were identified: 161 in primary tumors and 150 in metastases (n=311), of which 63 were known recurrent (32 in primary tumor, 31 in metastasis), and 248 were nonrecurrent and thus likely passenger mutations. TP53 mutations were present in 12 patients and were the most frequently observed recurrent

alteration. Epidermal growth factor receptor (EGFR) mutation was identified in one patient. The analysis found a high concordance of recurrent alterations between primary tumor and matched metastasis (94%) compared with likely passenger alterations (63%). Although further studies with a larger cohort of patients with NSCLC should be undertaken, the authors believe these results provide evidence that there is minimal advantage gained in a repeat biopsy and that comprehensive sequencing of the primary tumor specimen may provide the relevant genomic information needed to target patient treatment.

This scenario may be applicable if patients have a resected tumor and then a recurrence occurs years later, similar to the tissues used in this report. However, it is difficult to apply this principle to clinical practice. of which 63 were known recurrent. TP53 mutations were the most frequent, whereas a concordance rate of 94% was reported after comparative analysis. The results led the authors to conclude that the use of previous archived tissue can accurately portray the genomic alterations in recurrent/ metastatic lesions. This scenario may be applicable if patients have a resected tumor and then a recurrence occurs years later, similar to the tissues used in this report. However, it is difficult to apply this principle to clinical practice. If a new lesion were to appear years after a tumor resection, a biopsy is the clinical standard to prove the presence of malignant recurrence. In fact, we have proposed that biopsies be performed with larger amounts of tissue (core biopsies or inspected fine-needle aspirations) per studies like the BATTLE (Biomarker-integrated Approaches of Targeted Therapy for Lung cancer Elimination) trial.2,3 These biopsies can be performed safely in recurrent/metastatic patients, even after prior treatment. Furthermore, biopsies performed on tumors after

treatment, chemotherapy or targeted agents will potentially reveal different genomic alterations resulting from the treatment-stressed tumor. The application of high-throughput sequencing could lead to discovery of new targets or markers for predicting appropriate therapy in cancer patients. However, the clinical value of these platforms will be dependent on the real-time acquisition of adequate tissue in order to perform these tests and thus make the best judgment for treatment in each individual patient.

References 1. Watson JD, Crick FH. The structure of DNA. Cold Spring Harb Symp Quant Biol. 1953;18:123-131. 2. Kim ES, Herbst RS, Wistuba II, et al. The BATTLE trial: personalizing therapy for lung cancer. Cancer Discov. 2011;1:44-53, PMID: 22586319. 3. Tam AL, Kim ES, Lee JJ, et al. Feasibility of image-guided transthoracic core-needle biopsy in the BATTLE lung trial. J Thorac Oncol. 2013;8:436-442, PMID: 23442309.

Drs. Kim and Mileham reported no relevant financial disclosures.

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Post-Chemotherapy Sentinel Lymph Node Biopsy Value Assessed From Lancet Oncology

he detection value of sentinel lymph node biopsy (SLNB) in patients with breast cancer declines and the false-negative rate increases following completion of neoadjuvant chemotherapy, according to the SENTINA trial. The study confirmed the diagnostic reliability of SLNB before the administration of neoadjuvant chemotherapy, and concluded that this diminished accuracy should be considered when a biopsy is planned following neoadjuvant chemotherapy. The SENTINA trial was a large study conducted at 103 sites in Germany and Austria. Thorsten Kuehn, MD, and colleagues reported their findings

in Lancet Oncology (2013;14:609-618, PMID: 23683750). Women with breast cancer scheduled for neoadjuvant chemotherapy were placed into two groups: clinically node-positive and clinically node-negative, determined through palpation and ultrasound. SLNB was performed on the node-negative group, and two arms were formed: arm A consisted of patients (n=662) with node-negative SLNB and arm B consisted of patients (n=360) with node-positive SLNB. These patients underwent neoadjuvant treatment, a repeat SLNB and axillary lymph node dissection. In the cohort of patients with clinically positive nodes (N1 or N2), no pretreatment SLNB was performed. Patients

EXPERT INSIGHT

Richard White, MD

Teresa Flippo, MD

Surgical Oncology, Breast Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

he SENTINA trial recently published in Lancet Oncology demonstrates that SLNB can be performed routinely in patients who undergo neoadjuvant chemotherapy with results that are comparable to patients who undergo surgery as their first intervention. Furthermore, this paper, in combination with data from the NSABP (National Surgical Adjuvant Breast and Bowel Project) B27 Trial1 and the ACOSOG (American College of Surgeons Oncology Group) Z71 trial,2 moves the use of SLNB into the realm of neoadjuvant therapy, both in patients who are clinically node-negative and in patients who are clinically node-positive before initiating chemotherapy. This trial once again demonstrates that SLNB can be performed routinely in patients who are node-negative before the initiation of chemotherapy. This is no surprise. The trial further demonstrates that with proper attention to technical detail, including the use of both radioactive colloid and blue dye, SLNB can be performed in nodepositive patients who are clinically N0 at completion of chemotherapy. Finally, the trial confirms that the practice of performing an SLNB before chemotherapy and then attempting to repeat it after chemotherapy is fraught with

hazard and is not reliable. The surgical detection rate of 60.8% in arm B associated with a false-negative rate of 51.6% suggests transection of the major lymphatics at the time of the initial SLNB. This renders short-term repeat of the procedure after chemotherapy unreliable and is to be condemned. There is, however, data to support repeat SLNB in the setting of metachronous recurrence suggesting reconstitution of the lymphatic system over time.3 In patients with clinically node-positive disease, we have repeatedly demonstrated that neoadjuvant chemotherapy leads to a downstaging of the axilla. This trial aligns very nicely with the ACOSOG Z71 trial2 in demonstrating that SLNB can be accomplished with a reasonable false-negative rate (FNR) in patients who have N1 disease. It also points out some very important technical factors. In the NSABP B32 trial of sentinel node in clinically N0 breast patients, 9.6% of patients were found to have a false-negative SLNB in the setting of node-negative disease.4 It also demonstrated that the number of lymph nodes removed is directly associated with the false-negative rate (one node removed FNR=17.7%; two nodes removed=10.0%; three nodes removed =6.9%).4 In both the SENTINA and

had standard neoadjuvant chemotherapy and then were grouped by those who converted to either node-negative status (arm C, n=592), who then underwent a SLNB and axillary lymph node dissection, or those who remained clinically node-positive (arm D, n=123), who underwent axillary lymph node dissection without SLNB. Of 1,737 enrolled patients, 1,022 underwent SLNB before chemotherapy (arms A and B). The detection rate in this group was 99.1% (95% confidence interval [CI], 98.3%-99.6%). Patients in arm C had a detection rate of 80.1% (95% CI, 76.6%-83.2%) and a false-negative rate of 14.2% (95% CI, 9.9%-19.4%), including 24.3% in those patients who had a single sentinel node

removed and 18.5% in those who had two sentinel nodes removed. Overall accuracy improved when two or more sentinel lymph nodes were harvested. In patients who had a second SLNB procedure after neoadjuvant chemotherapy (arm B), the detection rate was 60.8% (95% CI, 55.6%-65.9%) and the false-negative rate was 51.6% (95% CI, 38.7%-64.2%). The researchers also noted that the false-negative rate was lower when both blue dye and radioactive colloid were used as tracers than use of a single-detection method. The study demonstrates the reliability of SLNB as a diagnostic tool, but shows that limitations arise when SLNB is used in a patient who has undergone neoadjuvant chemotherapy.

It is time to move the SLNB concept forward, embrace its role in patients who have undergone neoadjuvant chemotherapy, and take advantage of the reduction in morbidity associated with this technique. the ACOSOG Z71 trials, the FNR in patients who had only one lymph node removed was unacceptable (SENTINA=24.3%; ACOSOG Z71= 31.5%).2 The surgeon must strive to remove at least two nodes. Both trials demonstrate that the use of two tracers (both radioactive colloid and blue dye) is associated with an improvement in the falsenegative rate (SENTINA FNR=8.6%). In ACOSOG Z71, patients with two or more nodes removed using both tracers had an FNR of 10.8%.2 Future clinical trials will address the role of completion lymph node dissection in patients who have persistent small-volume nodal disease after neoadjuvant chemotherapy. We have demonstrated through the ACOSOG Z11 trial2 that a completion lymph node dissection is not associated with an improvement in overall survival or long-term disease-free survival in patients with low-volume nodal metastases.5 The question now is whether this applies to patients who undergo neoadjuvant therapy. These trials will be opening shortly. In summary, it is time to move the SLNB concept forward, in both clinically N0 and N1 disease, embrace its role in patients who have undergone neoadjuvant chemotherapy, and take advantage of the reduction in morbidity associated with this technique.

References 1. Mamounas EP, Brown A, Anderson S, et al. Sentinel node biopsy after neoadjuvant chemotherapy in breast cancer: results from National Surgical Adjuvant Breast and Bowel Project B-27. J Clin Oncol. 2005;23:2694-2702, PMID: 15837984. 2. Boughey JC, Suman VJ, Mittendorf EA, et al. The role of sentinel lymph node surgery in patients presenting with node positive breast cancer (T0-T4, N1-N2) who receive neoadjuvant chemotherapy: results from ACOSOG Z1071 trial. Cancer Res. 2012;74(24 suppl): abstract 94s. 3. Masskant-Braat AJ, Voogd AC, Roumen RM, Nieuwenhuijen GA. Repeat sentinel node biopsy in patients with locally recurrent breast cancer: a systematic review and meta-analysis of the literature. Breast Cancer Res Treat. 2013;138:13-20, PMID: 23340861. 4. Krag DN, Anderson SJ, Julian TB, et al. for the National Surgical Adjuvant Breast and Bowel Project (NSABP). Technical outcomes of sentinel-lymph-node resection and conventional axillary-lymph-node dissection in patients with clinically nodenegative breast cancer: results from the NSABP B-32 phase III trial. Lancet Oncol. 2007;8:881-888, PMID: 17851130. 5. Giuliano AE, Hunt KK, Ballman KV, et al. Axillary dissection vs no axillary dissection in women with invasive breast cancer and sentinel node metastasis: a randomized clinical trial. JAMA. 2011;305:569575, PMID: 21304082.

Drs. White and Flippo reported no relevant financial disclosures.

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Cetuximab Helpful for Patients With Unresectable Liver Metastases From the Journal of Clinical Oncology

atients with unresectable colorectal liver metastases (CLMs) benefited from the addition of cetuximab (Erbitux, Merck Serono) to standard chemotherapy, according to a new study. Patients with nonresectable CLMs were eligible for enrollment in this randomized study, which evaluated the resectability of liver metastases, tumor response and survival in patients treated with chemotherapy and cetuximab versus chemotherapy

alone. The investigators, who were based in Shanghai, China, and headed by Le-Chi Ye, MD, reported their interim results ((J Clin Oncol 2013:16:19311938, PMID: 23569301). From a population of 138 patients with KRAS wild-type synchronous unresectable CLMs who had undergone resection of their primary tumors, 70 patients were randomly assigned to arm A and treated with cetuximab (loading dose of 400-500 mg/ m2 and 250 mg/m2 weekly or 500 mg/ m2 biweekly) followed by chemotherapy comprised of either mFOLFOX6

EXPERT INSIGHT

Stuart Salmon, MD

Seungjean Chai, MD

Medical Oncology, Gastrointestinal Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

omplete surgical resection of hepatic metastases can lead to a 30% to 50% five-year survival in a subgroup of carefully selected patients with mCRC.1,2 Although the majority of patients do not present with initially resectable disease, studies show that patients who respond to systemic chemotherapy and are “downstaged” enough to undergo secondary hepatic resection have a similar chance at longterm survival.3 The largest prospective study to examine the interaction of chemotherapy with liver resection was a randomized European Organization for Research and Treatment of Cancer Intergroup trial, which tested the addition of six cycles of FOLFOX4 chemotherapy both before and after hepatic resection in 364 patients with resectable liver metastases.4 Chemotherapy led to an improvement in three-year disease-free survival (DFS), from 28% to 36%, but there was no statistically significant difference in five-year overall survival (OS).5 However, the optimal chemotherapy regimen in this situation remains uncertain. In the present study, Le-Chi Ye et al explored the addition of cetuximab to neoadjuvant chemotherapy in this small but well-designed randomized study. This trial showed a surprisingly robust clinical benefit for the addition of cetuximab in patients with KRAS wild-type CRC and unresectable liver-limited metastatic disease. The primary end point was the conversion rate to radical resection, which was significantly improved

by the addition of cetuximab to chemotherapy, and which reflected a similarly significant improvement in response rate. Overall, patients who received cetuximab had a superior progressionfree survival (PFS) and OS, which is largely explained by the much better outcomes for those patients who underwent successful resection. Although the benefits of cetuximab for those patients who did not undergo surgery were consistent with what would be expected by data from other randomized studies, there were no significant differences in outcome between arms for the group of patients who successfully underwent hepatic resection. How should we reconcile these very promising results with the recently reported preliminary data from the New EPOC study, which randomized 272 patients with KRAS wild-type colon cancer and operable liver metastases to perioperative chemotherapy with or without cetuximab?6 This study was stopped early after an interim analysis crossed the predefined futility boundary. With 45% of the expected events observed, PFS was significantly worse in the cetuximab arm. The obvious difference between these two studies is that the New EPOC patients were deemed to have surgically resectable disease at enrollment, which underscores the fact that the main benefit of cetuximab in the Ye study is due to its superior response rate in KRAS wildtype tumors and ability to downstage otherwise unresectable liver metastases.

(modified fluorouracil, leucovorin, oxaliplatin) or FOLFIRI (fluorouracil, leucovorin and irinotecan). Arm B patients (n=68) were treated with mFOLFOX6 or FOLFIRI alone. The 14-day treatment cycles continued until disease progression, unacceptable toxicity or tumor response. A team of surgeons reviewed radiologic images and determined suitability for surgery after four treatment cycles and then after every two cycles. After a median 25 months of followup, patients in arm A had improved objective response rates—40 patients

(57.1%) versus 20 patients in arm B (29.4%; P<0.01); experienced prolonged median survival time—30.9 months (95% confidence interval [CI], 16.5-41.5) versus 21.0 months (95% CI, 16.7-23.4; P=0.013); greater overall survival (OS) at three years (41% vs. 18%; P=0.013); and increased CLM resection rates—25.7% (18 of 70 patients) versus 7.4% (five of 68 patients; P<0.01). Patients in arm A who underwent resection had a significantly improved median survival time compared with those who did not undergo surgery (46.4 vs. 25.7 months; P<0.01).

The New EPOC results simply mirror the negative experience of adjuvant cetuximab in the treatment of early-stage CRC. Many questions still need to be answered. Hopefully, these results by Ye et al can be confirmed in a larger trial; a comparison with bevacizumab-based therapy before hepatic resection also needs to be examined. We do not know if panitumumab and cetuximab are interchangeable, or whether these drugs partner better with irinotecan rather than oxaliplatin. Assuming tumor response is of paramount importance to convert unresectable tumors: could there be a role for monoclonal antibody therapy combined with more aggressive FOLFOXIRI chemotherapy? What is the potential role of hepatic arterial infusion chemotherapy or hepatic radioembolization in unresectable liver-only disease? Finally, recent data presented this month has demonstrated resistance to panitumumab in patients with RAS abnormalities other than the commonly tested K-ras codon 12 and 13 mutations.7 N-ras mutations and mutations in exons 3 and 4 of K-ras are individually uncommon, but together make up another 15% to 20% of patients who have resistance to epidermal growth factor receptor (EGFR)-antibody therapy. Differences in unmeasured RAS mutations between studies may explain some of the frustrating variability that we see across randomized trials of EGFR antibody therapy. Better selection of RAS wild-type patients may lead to even better outcomes with these drugs. Ye and colleagues should be congratulated for demonstrating that the addition of a biologic agent to chemotherapy in a properly selected population can increase the response rate and rate of hepatic resection in CRC. With these data, the use of first-line preoperative cetuximab-based chemotherapy can be justified in patients with KRAS wild-type unresectable liver metastases, but should not be used in patients

with operable liver metastases in whom surgical resection is planned from the beginning. Furthermore, these patient cases should all be reviewed in multidisciplinary settings that include experienced liver surgeons to maximize rates of resection, which is a primary driver for survival in this population.

References 1. Fong Y, Fortner J, Sun RL, et al. Clinical score for predicting recurrence after hepatic resection for metastatic colorectal cancer: analysis of 1001 consecutive cases. Ann Surg. 1999;230:309-318, PMID: 10493478. 2. Nordlinger B, Guiguet M, Vaillant JC, et al. Surgical resection of colorectal carcinoma metastases to the liver. A prognostic scoring system to improve case selection, based on 1568 patients. Association Française de Chirurgie. Cancer. 1996;77:1254-1262, PMID: 8608500. 3. Adam R, Delvart V, Pascal G, et al. Rescue surgery for unresectable colorectal liver metastases downstaged by chemotherapy: a model to predict long-term survival. Ann Surg. g 2004;240:644-657, PMID: 15383792. 4. Nordlinger B, Sorbye J, Glimelius B, et al. Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-1016, PMID: 18358928. 5. Nordlinger B, et al. EORTC liver metastases intergroup randomized phase III study 40983: Long-term survival results. J Clin Oncol. 2012;30(suppl):abstract 3058. 6. Primrose JN, et al. A randomized clinical trial of chemotherapy compared to chemotherapy in combination with cetuximab in k-RAS wild-type patients with operable metastases from colorectal cancer: The new EPOC study. J Clin Oncol. 2013; 31(suppl): abstract 3504. 7.

Oliner KS, et al. Analysis of KRAS/NRAS and BRAF mutations in the phase III PRIME study of panitumumab (pmab) plus FOLFOX versus FOLFOX as first-line treatment (tx) for metastatic colorectal cancer (mCRC). J Clin Oncol. 2013; 31(suppl): abstract 3511.

Drs. Salmon and Chai reported no relevant financial disclosures.

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Homoharringtonine Induction Therapy for Treatment-Naive AML From Lancet Oncology

omoharringtonine-based induction therapy offers an effective alternative to a daunorubicin plus cytarabine regimen in patients with de novo acute myeloid leukemia (AML), according to a first-ever multicenter randomized controlled trial (RCT). Homoharringtonine (HHT; omacetaxine mepesuccinate; Synribo, Cephalon) has been used in China as a treatment for leukemia for more than three decades. Previous published reports have demonstrated effectiveness for patients with relapsed or refractory leukemia, but no studies have assessed

HHT as a first-line treatment. Jie Jin, MD, PhD, and colleagues from 17 centers throughout China reported their findings from this Phase III study ((Lancet Oncol 2013;7:599-608, PMID: 23664707) in which newly diagnosed patients with AML, between the ages of 14 and 59, were randomly assigned to one of three study arms. Patients in the first arm (n=206) were treated with an induction regimen of HHT (2 mg/ m2 per day on days 1-7), cytarabine (100 mg/m2 per day on days 1-7) and aclarubicin (20 mg per day on days 1-7; the HAA arm). Patients in the second arm (n=198) were treated with the same doses of HHT and cytarabine, and were

EXPERT INSIGHT Jonathan Gerber, MD Hematology/Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

espite numerous attempts over the past several decades to improve on standard-induction chemotherapy regimens consisting of cytarabine combined with an anthracycline, outcomes for non-acute promyelocytic leukemia (APL) AML remain poor, with a fiveyear OS rate of less than 25% in adult patients.1 These disappointing results suggest that there may be a ceiling to the benefits of conventional chemotherapy for AML.2 In this study, Jin et al reported on a large, multicenter, blinded RCT that studied the addition of HHT to infusional cytarabine and an anthracycline. HHT is an inhibitor of protein translation; it was recently approved in the United States for adult patients with tyrosine kinase inhibitor (TKI)-resistant chronic myeloid leukemia (CML).

Mike Grunwald, MD Hematology/Oncology Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

The current study reveals promise for HHT in patients aged 14 to 59 with favorable, non-APL AML. Although there was no improvement in RFS or OS with either of the experimental regimens, the HAA regimen achieved higher CR and EFS rates without a significant increase in toxicity over the control (DA) arm. Interestingly, this benefit did not extend to the other HHT-containing regimen—HAD. The superior performance of HAA compared with HAD may reflect differences in the choice of anthracycline (i.e., aclarubicin vs. daunorubicin) and/or in the anthracycline dosing schedule. Interpretation of the trial results is somewhat limited by the mid-study change in daunorubicin dose in the DA control arm, which initially used a lower dose (40 mg/m2)

by the

numbers oncologists’ revenue Oncologists and hematologists are raising more revenue for the hospitals in which they work. Incidentally, it is not from their services—which have seen significant cuts in reimbursement— but rather from the rising cost of the drugs they prescribe. Here are a few figures from the 2013 Physician Inpatient/Outpatient Revenue Survey by physician placement firm Merritt Hawkins:

given daunorubicin 40 mg/m2 per day on days 1-3 (the HAD arm). The third arm (n=205) consisted of daunorubicin 40 to 45 mg/m2 per day on days 1 to 3 and cytarabine 100 mg/m2 per day on days 1 to 7 (the DA arm). End points compared survival and remission rates. Additionally, 480 of the study participants also were screened for known cytogenetic mutations and were categorized as having favorable, intermediate or unfavorable genotypes. Three-year results showed patients in the HAA arm had the best overall survival: 150 of 206 (73%) achieved complete remission (CR) versus 133 of 198 (67%) in the HAD group and 125

of 205 (61%) in the DA group. Eventfree survival (EFS) at three years in the HAA group was 35.4% (95% confidence interval [CI], 28.6%-42.2%); in the HAD group, 32.7% (95% CI, 26.1%39.5%) and in the DA group, 23.1% (95% CI, 17.4%-29.3%). Overall survival (OS) and relapse-free survival (RFS) did not differ among the groups for patients with unfavorable mutation status, but low-risk patients in the HAA arm had significantly more favorable results. The authors suggest that an HHTbased induction therapy should be considered an alternative treatment for young patients with AML, especially for those with favorable cytogenetics.

Unfortunately, the benefit from HAA did not apply to poor-risk patients, and elderly patients were excluded from this study. than is typically employed in Western regimens. Furthermore, the large variety of postconsolidation approaches used in this trial also made it challenging to draw definitive conclusions. Nevertheless, the HAA regimen performed comparably to recently reported high-dose daunorubicin regimens,3 and the durability of the responses in the HAA arm is encouraging. Based on this report, HHT may offer an alternative to high-dose anthracycline induction regimens for favorablerisk, non-APL AML patients with prior anthracycline exposure. However, it should be noted that cardiotoxicity in this trial was actually confined to the HHT-containing regimens. Future studies are needed to validate the benefits and toxicity profile of HHT in favorable-risk AML. Unfortunately, the benefit from HAA did not apply to poor-risk patients, and elderly patients were excluded from this study. These patient populations are currently the most underserved by

18.5% |

present AML therapies, and they are in desperate need of better therapeutic options. Novel approaches, such as those targeting leukemia stem cells, are likely needed to achieve better outcomes, particularly in poor-risk AML.

References 1. Pulte D, Redaniel MT, Jansen L, et al. Recent trends in survival of adult patients with acute leukemia: overall improvements, but persistent and partly increasing disparity in survival of patients from minority groups. Haematologica. 2013;98:222-229, PMID: 22929974. 2. Buchner T, Schlenk RF, Schaich M, et al. Acute Myeloid Leukemia (AML): different treatment strategies versus a common standard arm—combined prospective analysis by the German AML Intergroup. J Clin Oncol. 2012;30:3604-3610, PMID: 22965967. 3. Fernandez HF, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009;361:1249-1259, PMID: 19776406.

Drs. Gerber and Grunwald reported no relevant financial disclosures.

Increase in average revenue generated by oncologists/hematologists since 2010

annual revenue generated by an $1.76 million | Average oncologist/hematologist

$360,000 | 10 million |

Average salary of an oncologist/ hematologist Minimum number of current cancer survivors in the United States

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Pertuzumab Addition Improves HER2 Breast Cancer Regimen From Lancet Oncology

second interim analysis of results from the CLEOPATRA study confirms that the combination of pertuzumab, trastuzumab and docetaxel represents an effective advance for patients with HER2-positive metastatic breast cancer. Women with HER2-positive metastatic breast cancer were enrolled in this double-blind, two-arm study at 204 centers in 25 countries and treated with either pertuzumab, trastuzumab and docetaxel, or identical doses of placebo, trastuzumab and docetaxel. A

year ago, initial results of the CLEOPATRA (Clinical Evaluation of Pertuzumab and Trastuzumab) study revealed that progression-free survival (PFS) favored the inclusion of pertuzumab in the treatment regimen (N ( Engl J Med 2012;366:109-119, PMID: 22149875). European health authorities requested follow-up data, which is reported in the present study by Sandra Swain, MD, and her colleagues ((Lancet Oncol 2013;6:461-471, PMID: 23602601). Through the May 2012 cutoff date, 267 of 385 deaths needed for final analysis occurred. Specifically, 154 (38%) of 406 patients in the placebo group

EXPERT INSIGHT Steven Limentani, MD Medical Oncology, Breast Section Levine Cancer Institute Carolinas HealthCare System Charlotte, N.C.

n 1987, Slamon et al published their seminal work correlating HER2 overamplification with a worse outcome in patients with breast cancer.1 These observations ultimately led to the development of trastuzumab, an antibody directed against HER2. The FDA approved this agent administered in combination with chemotherapy for the treatment of stage IV HER2-overamplified breast cancer in 1998 and in the adjuvant setting in 2006. In the past year, the FDA has approved two new HER2-directed agents, pertuzumab and ado-trastuzumab emtansine. These agents join both trastuzumab and lapatinib as alternatives for patients with HER2-overamplified breast cancer. The CLEOPATRA trial—recently updated in Lancet Oncology by Swain et al, and extending the observations of Baselga et al published in The New England Journal of Medicine,2 provides additional data and further defines this major breakthrough in the treatment of women with stage IV HER2-overamplified

breast cancer who are being treated in the first-line setting. The addition of pertuzumab, which interferes with HER2/HER3 dimerization when combined with docetaxel and trastuzumab, leads to a significant improvement in both PFS and OS compared with the combination without pertuzumab. These benefits are obtained without an increase in AEs. The original publication described an improvement in PFS, but data on OS now exists. The median OS for patients treated with the control combination was 37.6 months; 154 of 406 patients had died in this cohort. The addition of pertuzumab was associated with a statistically significant improvement in OS ( =0.0008) and median OS has not yet (P been reached. In the experimental arm, only 113 of 402 patients have died. This leaves an interesting dilemma for the clinician treating a patient with HER2-overamplified stage IV breast cancer. The clinical experience is that some patients treated with chemotherapy plus trastuzumab may experience

died, as did 113 (28%) of 402 in the pertuzumab arm (hazard ratio [HR], 0.66; 95% confidence interval [CI], 0.520.84; P=0.0008). The median overall survival (OS) for the placebo group was 37.6 months and still had not been achieved in the pertuzumab group, although the researchers estimated OS for that group to be 48 months. The difference in objective response rate (ORR) between treatment groups has been judged to be significant. Frequency, severity and specificity of adverse effects (AEs) remain similar. Serious AEs were reported in 148 (36%) of the patients in the pertuzumab

group and 115 (29%) of the patients in the placebo group. In the new interim results, neutropenia, febrile neutropenia and diarrhea (at least grade 3) were increased by 2% in patients in the pertuzumab arm, suggesting no significant late or cumulative effects. In both groups, AEs fell considerably when docetaxel treatment was suspended. These additional data seem to confirm the hypothesis that pertuzumab and trastuzumab act synergistically on the HER2 blockade, and provide a meaningful improvement of current standard of care for this challenging group of patients.

The administration of docetaxel, trastuzumab and pertuzumab has now become the standard of care for patients with stage IV HER2-overamplified breast cancer treated in the first-line setting. prolonged remission, which is maintained with discontinuation of the chemotherapy and maintenance of the patient on trastuzumab alone. This agent is administered every three weeks with limited potential toxicity. These remissions or stable disease may last for years. This has caused some to become sanguine with the efficacy of this combination, wondering whether the addition of pertuzumab is truly “worth it.” The additional cost of a year of pertuzumab is estimated to be about $70,000.3 However, the recent publication by Swain et al argues strongly against treating patients without the addition of pertuzumab. In the control arm, there were approximately 40 additional deaths as well as a statistically significant decrease in OS if patients did not receive pertuzumab in addition to docetaxel plus trastuzumab. This finding shows not just a statistical difference but also a clinically meaningful benefit for patients who received the experimental combination. Furthermore, data on the addition of pertuzumab following failure of the control combination is lacking, and this approach is not FDA-approved.

Despite having a worse overall prognosis, the outcome for patients with HER2 overamplification has markedly changed for the better. The recent addition of ado-trastuzumab emtansine to the treatment armamentarium should further improve outcomes, as should the movement of these agents to the adjuvant and neoadjuvant settings. The administration of the docetaxel-trastuzumab-pertuzumab regimen has now become the standard of care for patients with stage IV HER2-overamplified breast cancer treated in the first-line setting.

References 1. Slamon DJ, Clark GM, Wong SG, et al. Human breast cancer: correlation of relapse and survival with amplification of the HER-2/neu oncogene. Science. 1987;235:177-182, PMID: 3798106. 2. Baselga J, Cortes J, Kim SB, et al. Pertuzumab plus trastuzumab plus docetaxel for metastatic breast cancer. N Engl J Med. 2012;366:109-119, PMID: 22149875. 3. http://www.fiercebiotech.com/story/ roche-wins-blockbuster-ok-combo-breastcancer-drug-pertuzumab/2012-06-09. Dr. Limentani reported no relevant financial disclosures.

Coming to Clinical Oncology News in October Expert Insights from Massachusetts General Hospital Cancer Center Commentaries on recently published, important studies by clinicians from top cancer centers.

makes all the difference

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The

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY 2013

Tumor Board

Ascites With Omental Mass And a History of Prostate Cancer Welcome to the July issue of The Tumor Board

his edition of The Tumor Board d focuses on peritoneal carcinomatosis. I am very honored to have Sricharan Chalikonda, MD, the director of hyperthermic intraperitoneal chemotherapy at Cleveland Clinic Foundation in Ohio, participate by providing an expert opinion. I hope our readers will enjoy this issue and I welcome all opinions and further comments on this topic. I also greatly welcome and encourage suggestions or submission of cases for future issues of The Tumor Board. Enjoy!

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

Case

69-year-old man presents with a two-month history of epigastric discomfort, distension and firmness of the abdomen. He denies any other associated symptoms such as nausea, vomiting, early satiety or weight loss. His appetite is preserved. He also developed mild pedal edema for which he had an echocardiogram performed. The cardiac echo was unremarkable, but mentioned the presence of ascites. He has no known history of chronic liver disease or risk factors for chronic liver disease. He denies any abdominal pain. He has a history of radical prostatectomy for prostate cancer many years ago. A total of 6.5 L of ascites was aspirated during paracentesis. Analysis of the ascitic fluid was consistent with nonâ&#x20AC;&#x201C;portal hypertensive ascites. A computed tomography (CT) scan reported moderate ascites with peritoneal and omental soft tissues density, highly suspicious for peritoneal carcinomatosis (Figures 1 and 2). Colonoscopy and esophagogastroduodenoscopy (EGD) were normal. The patient had a CT-guided biopsy of the omental mass, which reported a malignant mesothelioma, epithelioid type.

Figures 1 and 2. Computed tomography scans showing moderate ascites with peritoneal and omental soft tissues density, highly suspicious for peritoneal carcinomatosis.

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CLINICAL ONCOLOGY NEWS â&#x20AC;˘ JULY 2013

Case Challenge

Dr. Simpfendorferâ&#x20AC;&#x2122;s Commentary

alignant peritoneal mesothelioma is an aggressive neoplasm that arises from the mesothelial lining of the peritoneum. Selected patients with no extraperitoneal disease spread and a good performance status, and who can be predicted to achieve complete surgical cytoreduction, are referred for regional therapy using cytoreduction surgery and hyperthermic intraperitoneal chemotherapy (HIPEC). Median survival approaching five years has been reported from centers with expertise in this therapy.1-4

References 1. Sugarbaker PH, Welch LS, Mohamed F, Glehen O. A review of peritoneal mesothelioma at the Washington Cancer Institute. Surg Oncol Clin N Am. 2003;12:605-621, PMID: 14567020. 2. Feldman AL, Libutti SK, Pingpank JF, et al. Analysis of factors associated with outcome in patients with malignant peritoneal mesothelioma undergoing surgical debulking and intraperitoneal chemotherapy. J Clin Oncol. 2003;21:4560-4567, PMID: 14673042. 3. Chua TC, Yan TD, Morris DL. Outcomes of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for peritoneal mesothelioma: Australian experience. J Surg Oncol. 2009;99:109-113, PMID: 19016259. 4. Yan TD, Deraco M, Baratti D, et al. Cytoreductive surgery and hyperthermic intraperitoneal chemotherapy for malignant peritoneal mesothelioma: multi-institutional experience. J Clin Oncol. 2009;27:62376242, PMID: 19917862.

Second Opinion Expert Opinion by Sricharan Chalikonda, MD Sricharan Chalikonda, MD Assistant Professor of Surgery Director of HIPEC Program Cleveland Clinic Cleveland, Ohio

How would you further evaluate this patient? Preoperative evaluation should include contrast-enhanced CT of the chest, abdomen and pelvis, to exclude liver and other systemic metastasis. Also, the presence of tumor nodules greater than 5 cm, and loss of normal architecture of the small bowel, or findings of segmental small bowel obstruction, predict a poor outcome.1

36-year-old male presented to an outside hospital with abdominal distension, nausea and vomiting. A non-contrast CT scan showed a 16 cm pancreatic cyst (Figure 1). The patient had an endoscopic ultrasound that reported a complex cyst with thick fluid and solid components. Fine needle aspiration (FNA) reported blood and no malignancy. The patient had an endoscopic cystogastrostomy stent placement. The following day the patient developed peritonitis and pneumoperitoneum and was taken to surgery for emergency laparotomy. During surgery, the previously placed cystogastrostomy stent was discovered to be dislodged and there was contamination of the peritoneal cavity secondary to gastric perforation. The gastrostomy was repaired. The surgeon also described a large vascular mass in the lesser sac, which displaced all the surrounding organs. A follow-up MRI of the abdomen reported a 16.0 x 19.8 x 18.1 cm, thick-walled, complex mass versus collection (Figures 2 and 3). The mass abutted and partially compressed the inferior margin of the left lobe of the liver. This mass/collection demonstrated mass effect on the stomach and pancreas. The patient complained of abdominal discomfort, nausea and early satiety. The patient reports no history of pancreatitis or acute abdominal pain.

What is your differential diagnosis? How would you further evaluate and treat this patient?

What is cytoreductive surgery and HIPEC? Malignant peritoneal mesothelioma in the majority of cases remains confined to the peritoneal cavity. The peritoneal implants are typically superficial and do not invade the underlying tissues. Therefore, the disease is amenable to complete cytoreduction in the majority of cases. Direct administration of HIPEC allows for an increase in drug concentration to the peritoneum compared with systemic chemotherapy.2

Would the patient require additional systemic chemotherapy? To date, the role of systemic chemotherapy as a multimodality treatment, either as adjuvant or neoadjuvant, has not been studied for malignant peritoneal mesothelioma. Systemic chemotherapy is generally an option for patients who are not candidates for cytoreductive surgery and HIPEC.1,3

Figure 1: A non-contrast CT scan showing a 16 cm pancreatic cyst.

How do you follow these patients postoperatively? We see the patient at follow-up at one, three and six months, and then every six months thereafter. We repeat the imaging at the six-month follow-up.4

Figures 2 and 3: A follow-up MRI of the abdomen reported a 16.0 x 19.8 x 18.1 cm, thick walled, complex mass versus collection.

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CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.NEWS

On the Spot with Colleen Hutchinson

Breast Cancer P

art two of “On the Spot” continues the debate in breast cancer management, specifically the timing of radiation with respect to breast reconstruction and the benefits and oncologic risks of nipple-sparing mastectomy. In the first part, published in the June issue of Clinical Oncology News, experts debated surgical resection of the primary tumor for women

with metastatic breast cancer and the timing of sentinel lymph node biopsy. Once you’ve read what these experts have to say, look at your own practices and experience and see how their arguments measure up. Then it’s up to you to determine your own stance, which we’d love you to share with us. Your opinions are an important piece of the puzzle.

Thank you to this month’s contributors for their candid responses and for the time it took to share them. Please feel free to email me at colleen@cmhadvisors.com with any ideas for “On the Spot” debates, thoughts on this month’s column or general feedback, and comment online as well. I always like hearing from you! —Colleen Hutchinson

P ARTICIPANTS Marisa Weiss, MD, Founder and President of Breastcancer.org and Director of Breast Radiation Oncology and Breast Health Outreach, Lankenau Medical Center, Wynnewood, Pennsylvania

Tari King, MD, Associate Attending Surgeon, Breast Service, Memorial Sloan-Kettering Cancer Center, New York, New York

Seema Khan, MD, Professor of Surgery and Bluhm Family Professor of Cancer Research, Northwestern University, Chicago, Illinois

Mary Jane Houlihan, MD, Assistant Professor of Surgery, Harvard Medical School, Boston, Massachusetts

Susan Pories, MD, Associate Professor of Surgery, Harvard Medical School, Boston, Massachusetts

Cassann Blake, MD, Head, Section of Breast Surgical Oncology, Cleveland Clinic Florida, Weston, Florida

Grant Carlson, MD, The Wadley R. Glenn Professor of Surgery and Chief of Surgical Services, Emory University Hospital, Atlanta, Georgia

Mehran Habibi, MD, Assistant Professor of Surgical Oncology, Johns Hopkins University, Baltimore, Maryland

Larry Norton, MD, Deputy Physicianin-Chief for Breast Cancer Programs and Medical Director, Evelyn H. Lauder Breast Center, Memorial Sloan-Kettering Cancer Center, New York, New York

Statement

Timing of radiation with respect to breast reconstruction is controversial, given that issues such as healing and related cosmetic outcomes need to be balanced with efficacy of treatment and the potential for local recurrence. The preferred option for patients who will undergo mastectomy, desire reconstruction, and are suspected to be candidates for post-mastectomy radiation therapy is to pursue a two-stage implant-based reconstructive approach, inserting a tissue expander at the time of the mastectomy to preserve the breast envelope. Definitive reconstruction with either permanent implants or autologous tissue can then be performed once radiation has been completed.

Dr. Houlihan: Agree. We generally proceed with the second stage of reconstruction six or more months after completion of radiation therapy.

Dr. Pories: Agree. This approach preserves the skin envelope and avoids the complications of radiating a new flap or implant, which can compromise the cosmetic result.

Dr. Weiss: Disagree. The form of reconstruction that best tolerates radiation is autologous tissue.

If the patient is not a candidate for this approach (too thin or contraindicated by medical/surgical problems or other risks), then reconstruction with expander, then implant, or one-step implant procedure is still possible. The risk of capsular contraction and infection is higher when radiation is given after this form of reconstruction; however, many if not most women have a very good result without significant complication. There is no “right” way: two-step or one-step done before radiation or expander, then radiation, followed by implant swap. It depends a lot on the individual patient. What does not work well is treating with excessively large expanders or implants in place that stretch the skin,

flatten the chest wall, and leave no valley between the breasts—because each of these factors can substantially limit the ability to optimize radiation therapy, potentially increasing complications. Plastic surgeons need to resist the temptation or the patient’s desire to make mountains out of molehills—that is, don’t make the implant-reconstructed breast larger than the original natural breast. You’re just asking for trouble if you do.

Dr. Blake: On the fence. The timing of reconstruction, whether before or after post-mastectomy radiation therapy, is not a right or wrong decision. The skill and expertise of the managing team and the needs of the patient should be determining factors on when reconstruction should be performed. Cosmetic results are subjective. It has been argued that immediate reconstruction [results] for those who require post-mastectomy radiation are inferior; however, the psychosocial impact on an individual patient not having reconstruction for almost a year after mastectomy should be considered. Certainly postoperative complications may delay therapy, but overall the delay has not been shown to alter survival rates and a significant difference in local recurrence rate has not been established. I have worked with plastic surgeons on both sides of the fence,

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.NEWS

and I feel a discussion with the patient about the pros and cons of each approach is warranted to help guide in the decision-making process.

Dr. King: Agree. As indications for post-mastectomy radiotherapy (PMRT) continue to evolve, there remains considerable controversy among radiation oncologists as to which patients will benefit from treatment. While patients with a very high chance of loco-regional recurrence (LRR) failure who clearly need PMRT are easy to identify, such as those with bulky adenopathy or inflammatory disease, there are many patients in whom the indications are much less clear and may hinge on the absolute number of involved lymph nodes or the combination of other features, such as tumor grade and lymphovascular invasion. In cases where the need for PMRT is not clear, the best option is to pursue a two-stage, implant-based reconstructive approach, inserting a tissue expander at the time of the mastectomy to preserve the breast envelope and inframammary fold. Definitive reconstruction with either permanent implants or autologous tissue, according to the patient preference, can then be performed once adjuvant systemic therapy with or without radiation has been completed. If radiation is not deemed necessary, patients can proceed with their preferred method of reconstruction following systemic therapy. If radiation is deemed necessary, patients who desire implant reconstruction can undergo the exchange procedure and proceed with PMRT to the final implant. Alternatively, patients who desire autologous tissue reconstruction can proceed with PMRT with the [tissue expander] in place, and proceed with definitive tissue reconstruction once the acute radiation skin toxicities have resolved. This approach has several advantages. First, not all patients are candidates for tissue reconstruction, so allowing them to proceed with a two-stage implant approach and irradiating the implant may be their only option for reconstruction. Second, for patients who ultimately desire tissue reconstruction, it allows them to preserve the inframammary fold and undergo their definitive procedure once all treatment is complete, avoiding the potential morbidity of radiation damage to the tissue flap.

Dr. Carlson: Disagree. PMRT is increasingly used in primary treatment of breast cancer. It significantly reduces the risk of locoregional recurrence at the expense of potential cardiac and pulmonary morbidity. Meta-analysis has shown that PMRT can confer a survival benefit when used in patients with a 10% or greater risk of [locoregional recurrence]. Modern systemic therapy has significantly impacted [locoregional recurrence], further compounding the decision-making process. Preoperative workup including axillary ultrasound and possible lymph node biopsy provides valuable information for the surgical treatment planning. Radiation negatively impacts all forms of breast reconstruction. Most reconstructive surgeons feel the use of implants is contraindicated when PMRT is used and the majority will perform delayed breast reconstruction if the use of PMRT is planned prior to mastectomy. The concept of placing a temporary tissue expander under the mastectomy skin flaps has been proposed to compensate for the potential negative effects of PMRT. Some radiation oncologists feel the presence of the breast tissue expander can potentially interfere with the radiation fields and prefer the expander fluid be evacuated. This can result in seroma formation

CURRENT PRACTICE

around the expander, which results in a high incidence of infection in patients receiving radiation. Even if the expander is not deflated, the risk of expander loss is increased because of radiation. If successful, the radiated skin flaps frequently become fibrotic, which, if not resected at the time of reconstruction, can have a negative impact on the aesthetic outcome.

Dr. Habibi: Agree. This has several advantages. First, the radiation can be administered sooner; it is easier to coordinate the timing of surgery between surgical oncologist and the plastic surgeon to do a tissue expander than the full reconstruction. Second, the effect of radiation on reconstructed breast can be significant, especially autologous flaps like deep inferior epigastric perforator (DIEP) flaps. In our practice, we preferentially offer autologous flaps to patients with radiation. We feel that exchanging the tissue expander and bringing new healthy tissue with blood supply to the radiated field will be beneficial to the final cosmetic outcome.

Dr. Khan: Agree. For women who need mastectomy and desire reconstruction, placement of a tissue expander at the time of mastectomy does preserve more skin and lead to somewhat better reconstruction outcomes, although this is a matter of degree, and certainly deferred reconstruction can also provide good results. However, immediate expander reconstruction is associated with higher complication rates (hematoma, flap necrosis, infection and return to the operating room), and this fact should be discussed with patients whose tumors display adverse features that suggest a possibility of PMRT. Issues of radiation planning, particularly on the left side and particularly in older women or those at risk for cardiac disease, should also be discussed, and again a preoperative consultation with a radiation oncologist may be helpful. For most women, immediate expander reconstruction can be safely pursued, but an airing of all these issues is necessary. Another option to consider if the PMRT decision will be mainly driven by nodal findings is initial SLN biopsy as a separate procedure prior to mastectomy. Once the nodal status is confirmed, the radiotherapy plan can be clarified, and reconstruction planning can proceed accordingly.

Statement

Provided that certain oncologic and practical criteria are applied, nipple-sparing mastectomy provides the benefits of less invasive surgery and improved cosmetic outcomes without increased oncologic risk in appropriately selected patients.

Dr. Weiss: Generally agree. Current data show that cancer of the nipple ducts is exceedingly rare, and sparing the areola involves the same risk as regular skin sparing. If the cancer is close to the nipple, sparing the nipple is not worth the risk of leaving it intact.

Dr. Houlihan: Agree. In women with cancers or ductal carcinoma in situ (or DCIS) more than 2.5 cm from the nipple, nipple-sparing mastectomy is a reasonable option. The procedure is more difficult in the setting of a very large breast or if there is significant ptosis.

Women also must be informed of the fact that the nipple will be insensate.

Dr. Norton: On the fence. It depends heavily on the clinical presentation and the skill of the surgeon.

Dr. Carlson: Agree. The aesthetic results of nipple reconstruction after skin-sparing mastectomy and reconstruction can be disappointing. Data has shown that patient satisfaction with nipple preservation is much higher than if a nipple is reconstructed. A growing body of literature has shown a low incidence of nipple [cancer] recurrence after nipple-sparing mastectomy in the treatment of selected patients with early breast cancer. Despite this, long-term follow-up data is lacking. Sakurai et al recently published their experience with 788 therapeutic nipple-sparing mastectomies, which were compared with a cohort of 144 patients who were treated with conventional mastectomies (Med ( Oncol 2013;30:481, PMID: 23377926). The two groups were similar in disease stage and tumor size. None received radiation. In the nipple-sparing mastectomy group, nipple-areola complex recurrence was observed in 3.7%. At five and 10 years, disease-free survival was 86% and 83%, compared with 83% and 80% in the mastectomy group. The median follow-up for this study was 78 months.

Dr. Khan: Agree. Nipple-sparing mastectomy leads to improved cosmetic outcomes in appropriately selected patients, and there are emerging data that loco-regional outcomes are no different in women receiving this procedure compared with conventional mastectomy. The surgical series that have been reported are now of good size, ranging from several hundred patients upward, and although favorable long-term data have been reported from some groups, the overall follow-up period in a recent systematic review was only in the twoto three-year range. The conservative approach would therefore be to offer it only to women undergoing mastectomy for prevention, and those with early, favorable tumors where recurrence risk can be expected to be low. Other caveats are that it must be a complete mastectomy with no compromise in the extent of resection of breast tissue compared with conventional mastectomy procedures, and that tumor must not be located in the vicinity of the nipple, although the closest tolerable distance between tumor and nipple is not generally agreed upon. The benefit of base-of-the-nipple biopsy and frozen section during surgery is questionable since it can be associated with both false-positive and falsenegative findings. Inframammary fold incisions provide the best cosmesis and do not compromise nipple or flap viability, and therefore are my preferred approach.

Dr. Pories: Agree. Nipple-sparing mastectomies are appropriate for patients undergoing prophylactic surgery and can also be offered to breast cancer patients who have tumors that are at least 2 cm away from the nipple. However, the terminology “less invasive” is misleading, and patients must be aware that there is a chance that the nipple may have to be removed at a second procedure after the mastectomy if the blood supply is poor and there is necrosis of the nipple or if cancer is found in the nipple plug, which should be sent as a separate specimen. see ON THE SPOT, T page 28

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

ON THE SPOT continued from page 27

Dr. Habibi: Agree. Nipple-sparing mastectomy has changed the landscape of breast surgery in the last decade. One can make an argument that the breast is defined by the nipple-areola complex. With emphasis on oncologic and practical criteria, nipple-sparing mastectomy can improve the cosmetic outcome tremendously. I would not consider it a less invasive operation, as it is much more complex and difficult than regular skin-sparing mastectomy. The thickness

of the flaps and nipple-areola complex and the completeness of mastectomy are more complicated in nipple-sparing mastectomy; having said that, in the right hands the results can be oncologically safe and cosmetically outstanding.

Dr. Blake: Agree. A nipple-sparing mastectomy can have great cosmetic results without increasing oncologic risk; however, I question describing it as a less invasive surgery. The incision for a nipple-sparing mastectomy is frequently on par with that of a skin-sparing simple mastectomy. I am comfortable with recommending this procedure for risk reduction, but I am very

selective in offering a nipple-sparing mastectomy for a patient with breast cancer. Publications on the oncologic safety of nipple-sparing mastectomy have made me more comfortable with offering this to patients with breast cancer than I was a few years ago. I am optimistic that the American Society of Breast Surgeons Nipple Sparing Mastectomy Registry will provide helpful information on this procedure’s utilization and cosmetic and oncologic outcomes. Colleen Hutchinson is a medical communications consultant based in Philadelphia and can be reached at colleen@cmhadvisors.com.

Table. Questions and Answers From Leading Surgical Oncologists Specializing in Breast Cancer Contributor

Biggest obstacle to cure

Most overblown cancer discovery in recent years

Most valuable cancer discovery in recent years

The current administration’s approach to health care

2009 U.S. Biggest Preventive misconception Services Task about breast Force mammog- cancer raphy screening guidelines changes

The relationship between breast cancer oncologist and surgeon is:

The ideal breast cancer patient understands that:

Tari King, MD

Research funding; limited availability of metastatic tissue samples for study

Breast MRI detecting occult contralateral breast cancer

Anti-HER2 therapy

Necessary change; expected outcome unclear

Problematic; unrealistic; limited

Only occurs in women with a family history of the disease

A two-way street

Treatment is a process and requires patience and persistence

Mary Jane Houlihan, MD

The complexity of the disease itself

Angiostatic agents

Genomics

Well-meaning but politicized

Not followed by me

Public’s perception that this is the greatest risk for dying

In my setting, wonderful

We are not the enemy, we are part of her team

Grant Carlson, MD

Participation in randomized trials

Single-agent targeted therapy in solid tumors

Trastuzumab

Unrealistic, shifting social engineering to health care

Appropriate

That it is a fatal disease

Occasionally contentious

Treatment is a process

Seema Khan, MD

Understanding “Personalized biology; medicine” equitable access to care

Cancer cell metabolism can be exploited for therapeutic gain

Right direction; timid; needs more attention to cost control

Evidence-based; thought-provoking; prompt new research

Mastectomy means “I will never have to deal with this again”

Collaborative; mutually respectful; productive

Breast cancer is largely curable; [treatment] should include avoiding overtreatment as much as embracing necessary treatment

Larry Norton, MD

Insufficient research funding

High-dose chemotherapy

Molecular pathology

Nuanced

Clinically naive

Stage IV is incurable

Partners

Knowledge is power

Cassann Blake, MD

Inadequate clinical trial participation

Bevacizumab for breast cancer

Gene expression profiling

Proceed with caution

Possibly appropriate for some women

Extensive imaging affects survival

It’s complicated

We don’t have all the answers

Marisa Weiss, MD

Human behavior

Thermography

Trastuzumab

One step forward but oversimplified

Huge setback for early detection for most women

That it only runs in families

Best with respectful dialogue but often tense

She needs to take a proactive role

Mehran Habibi, MD

Cancer cells’ adaptability and resilience

Oncotype DX for DCIS

Sentinel node biopsy, breast tomosynthesis

Steps in the right direction

Right message at the wrong time

That we have had great improvement in advanced breast cancer

A close partnership is vital

The surgeons also want to have the surgery done yesterday

Susan Pories, MD

Funding mechanism for scientists

I try to keep an open mind—today’s crazy idea might turn out to be tomorrow’s cure

Angiogenesis; HER2/neu, genomic proﬁling

Laudable; health care should be a right, not a privilege

Misguided; early detection saves lives and improves outcomes

Patients fear it is a death sentence

Important to work together very closely

She needs a coordinated team working together on her care

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights from NEJM, Blood, JCO and ASCO QUESTIONS

characterized by MYC/ BCL2 protein coexpression have a poor clinical outcome with a five-year overall survival (OS) and progression-free survival (PFS) of less than 30% and are subclassified as “double-hit B-cell lymphoma.”

1. True or False.

In advanced Hodgkin lymphoma, plasma EpsteinBarr virus (EBV) DNA levels had no bearing on the prognosis in the recent North American cooperative group trial.

True or False. In the Australasian LeukaeTrue or False. A mia & Lymphoma Group single mismatch at the CML8 trial, two factors— Primum non nocere. DRB3 loci is associatfemale sex and BCR-ABL1 (First, do no harm.) ed with worse outcomes in hematopoietic cell value of ≤0.10% at three months—were recognized to be inde- transplantation (HCT). pendently associated with a higher probability of achieving at least two years of True or False. Currently, there undetectable BCR-ABL1 (“stable MR”) is no standard first-line regimen for with frontline imatinib (Gleevec, Novar- peripheral T-cell lymphomas. tis) therapy. True or False. On behalf of True or False. Patients with dif- the Japanese and Korean Lymphofuse large B-cell lymphoma (DLBCL) ma Study Group, bendamustine plus

rituximab (BR) is a promising salvage regimen for relapsed or refractory DLBCL in patients who are not eligible for, or have undergone, autologous stem cell transplantation.

True or False. In the TRAP (Trial to Reduce Alloimmunization to Platelets) study, 17% to 21% of recipients of leuko-reduced or ultraviolet-irradiated platelets developed new antibodies against HLA antigens.

8. True or False. On June 5, 2013, the

FDA approved lenalidomide capsules (Revlimid, Celgene) for the treatment of patients with mantle cell lymphoma whose disease has relapsed or progressed after two prior therapies, one of which included bortezomib.

True or False. At the 2013 annual meeting of the American Society of Clinical Oncology (ASCO), the updated results of a Phase I/II study of

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

elotuzumab (HuLuc63, Bristol-Myers Squibb) in combination with lenalidomide and low-dose dexamethasone showed significant activity in patients with relapsed/refractory multiple myeloma (MM).

10. True or False. At ASCO 2013, a

study on behalf of the Spanish Myeloma Group showed that minimal residual disease (MRD) assessment using multiparameter flow cytometry (MFC) has no prognostic value in patients newly diagnosed with MM.

for answers see CONUNDRUMS, S page 30

SOLID TUMORS

S-1 Has Dramatic Effect in Japanese Trial Adjuvant S-1 is noninferior, and potentially superior, to gemcitabine San Francisco—The oral chemotherapy drug S-1 (Taiho Pharmaceutical) l substantially increases overall survival rates compared with gemcitabine in patients with resected pancreatic cancer, according to a Phase III trial in Japan. As a result, the safety and efficacy committee monitoring the trial recommended early reporting of the results to speed adoption of S-1 as the new standard postoperative treatment for patients with pancreatic cancer in Japan. “Our survival data were much stronger than expected. Based on these results, we hope that guidelines for standard postoperative therapy for pancreatic cancer in Japan will be changed to replace gemcitabine with S-1 as single-agent therapy,” said lead author Katsuhiko Uesaka, MD, PhD, the medical deputy director at Shizuoka Cancer Center Hospital in Shizuoka, Japan. He presented the study at the 2013 Gastrointestinal Cancers Symposium (abstract 145). Experts stress that the results are only relevant in Japan and major studies are needed in white, black and Hispanic patients. Previous small studies have shown that S-1 has more harmful gastrointestinal side effects in white patients than in Asian patients (Cancer

Sci 2011;102:478-483, PMID: 21143703), necessitating lower doses of the drug. In the current JASPAC-01 trial, investigators randomly assigned 385 Japanese patients to postoperative treatment with gemcitabine or S-1. All patients had histologically confirmed ductal adenocarcinoma of the pancreas, R0 or R1 resection and pathologic stage I, II or III disease with resection of the celiac axis. Patients had no chemotherapy or radiotherapy in the three years before the study and had adequate organ function. An interim analysis found that patients who received S-1 had a 44% lower risk for death than patients who received gemcitabine (P ( =0.0001). The two-year survival rates were 70% and 53% for S-1 and gemcitabine, respectively. Relapse rates also were lower for S-1 patients: The relapse-free survival rate was 49% in the S-1 arm compared with 29% in the gemcitabine arm. S-1 was well tolerated with more than 70% of the patients completing therapy. Grade III or IV toxicities were found in less than 5% of S-1 patients. Fatigue and anorexia were more frequent among patients in the S-1 arm than in the gemcitabine group (5.4% vs. 4.7%; 8.0% vs. 5.8%, respectively). But S-1

‘It is hard to think that S-1 will not be the future standard of care in Japan and certain other countries.’ —Philip Agop Philip, MD, PhD was associated with significantly lower rates of leukopenia (8.6% vs. 38.7%), thrombocytopenia (4.3% vs. 9.4%) and elevated aspartate aminotransferase (1.1% vs. 5.2%). “It is hard to think that S-1 will not be the future standard of care in Japan and certain other countries,” said Philip Agop Philip, MD, PhD, the director of gastrointestinal oncology at Karmanos Cancer Institute and a professor of oncology at Wayne State University in Detroit. He noted that the study population consisted of very well-selected patients, with many having R0 resection or lymph node–negative disease. Patients underwent preoperative laparoscopy to rule out peritoneal disease. “In my opinion, non-Japanese studies are needed to define the role of S-1 at a

lower dose, and in early- as well as latestage disease,” Dr. Philip said. S-1 is a dihydropyrimidine dehydrogenase inhibitory fluoropyrimidine composed of tegafur, gimeracil and oteracil potassium. It is currently prescribed in Japan to treat stomach, colorectal, pancreatic, biliary, head and neck, nonsmall cell lung and metastatic breast cancers. Although not yet approved in the United States, several Phase III trials are exploring S-1 for treatment of patients with stomach cancer. —Christina Frangou Dr. Uesaka receives honoraria from Lilly and Taiho Pharmaceutical. The trial was sponsored by Pharma Valley Center, Shizuoka Industrial Foundation, and funded by Taiho Pharmaceutical. Dr. Philip reported no relevant disclosures.

CURRENT PRACTICE

CONUNDRUMS continued from page 29

ANSWERS

1. False. Plasma EBV DNA has prog-

nostic significance in Hodgkin lymphoma, both prior to and at six months following therapy. A cutoff of more than 60 viral copies per 100 μL plasma was used in the North American cooperative group trial. Pretreatment plasma EBV positivity was an independent predictor of treatment failure on multivariate analyses. At month 6, plasma EBVpositive patients (n=7) had inferior failure-free survival with a hazard ratio of 3.8 compared with plasma EBV-negative patients (n=125), log-rank P=0.007. Kanakry JA, Li H, Gellert LL, et al. Plasma Epstein-Barr virus DNA predicts outcome in advanced Hodgkin lymphoma: correlative analysis from a large North American cooperative group trial. Blood. 2013;121:3547-3553, PMID: 23386127.

2. True. The findings of this retro-

spective study emphasize rapid reduction of BCR-ABL1 as a strategy to maximize potential suitability for future tyrosine kinase inhibitor discontinuation studies. Branford S, Yeung DT, Ross DM, et al. Early molecular response and female sex strongly predict stable undetectable BCR-ABL1, the criteria for imatinib discontinuation in patients with CML. Blood. 2013;121:3818-3824, PMID:23515925.

CLINICAL ONCOLOGY NEWS • JULY 2013 • CLINICALONCOLOGY.COM

Hu S, Xu-Monette ZY, Tzankov A, et al. MYC/ BCL2 protein co-expression contributes to the inferior survival of activated B-cell subtype of diffuse large B-cell lymphoma and demonstrates high-risk gene expression signatures: a report from The International DLBCL Rituximab-CHOP Consortium Program. Blood. 2013;121:4021-4031, PMID: 23449635.

adequately to move forward to consolidative stem cell transplantation.

ly expressed HLA-A, -B, -C and -DRB1 loci (HEL) is associated with worse outcomes in HCT, whereas less is known about the cumulative effect of mismatches in the lesser expressed HLA loci DRB3/4/5, DQ and DP (LEL). The Center for International Blood and Marrow Transplant Research (CIBMTR) showed that patients with seven of eight matches at HEL and with three or more mismatches at LEL in the graft-versus-host vector had a significantly higher risk for mortality (1.45 and 1.43) and transplant-related mortality (1.68 and 1.54) than the subgroups of patients with none or one mismatch at LEL. In the eight of eight–matched group, LEL mismatches were not associated with any adverse outcome. Prospective evaluation of matching for LEL loci is warranted to reduce post-transplant risks in donor–recipient pairs matched for seven of eight HEL.

[CI], 25%-50.9%) and median PFS of 6.7 months (95% CI, 3.6-13.7 months) was reported with the BR regimen.

True. In this Phase II study, a CR 4. False. A single mismatch in high- 6. rate of 37.3% (95% confidence interval

Fernández-Viña MA, Klein JP, Haagenson M, et al. Multiple mismatches at the low expression HLA loci DP, DQ, and DRB3/4/5 associate with adverse outcomes in hematopoietic stem cell transplantation. Blood. 2013;121:4603-4610, PMID: 23596045.

3. False. Although it is true that 5. True. Multiple alternative regi-

patients with DLBCL characterized by MYC/BCL2 protein coexpression have inferior outcome with R-CHOP (rituximab [Rituxan, Genentech], cyclophosphamide, doxorubicin, vincristine, prednisone) therapy, MYC/BCL2 double-hit B-cell lymphoma is defined genetically, not via immunohistochemical expression. It is possible that additional molecular abnormalities or levels of MYC and BCL2 protein expression may distinguish these two groups.

Lunning MA, Moskowitz AJ, Horwitz S. Strategies for relapsed peripheral T-cell lymphoma: the tail that wags the curve. J Clin Oncol. 2013;31:1922-1927, PMID: 23630204.

mens to frontline CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) have been studied. The addition of etoposide to CHOP (CHOEP) has been studied by the German HighGrade Non-Hodgkin Lymphoma Study Group and Nordic Lymphoma Group as part of a first-line autologous strategy. In the Nordic study, CHOEP had an overall response rate of 82%, with 51% of patients attaining complete response (CR) and about 70% responding

Ohmachi K, Niitsu N, Uchida T, et al. Multicenter phase II study of bendamustine plus rituximab in patients with relapsed or refractory diffuse large B-cell lymphoma. J Clin Oncol. 2013;31:2103-2109, PMID: 23650408.

7. True. In contrast, 45% of recip-

the Phase II cohort, with a higher rate observed with elotuzumab 10 mg/kg versus 20 mg/kg (92% vs. 76%). The overall median time to response was one month (range, 0.7-19.2 months) with the best response within approximately 2.6 months (range, 0.7-32 months). The median duration of objective response was 17.8 months (range, 1-37.1 months). The most common grade 3/4 adverse events included anemia, thrombocytopenia, lymphopenia and neutropenia. These findings prompted two Phase III trials of elotuzumab 10 mg/kg with lenalidomide-dexamethasone. These include ELOQUENT-1 in previously untreated MM and ELOQUENT-2 in relapsed/ refractory MM.

ients of non–leuko-reduced platelets developed new antibodies against HLA antigens. Interestingly, of the 530 participants included in the study, 101 developed platelet refractoriness without evidence of HLA antibodies, as measured by the lymphocytotoxicity assay.

Lonial S, Jagannath S, Moreau P, et al. Phase (Ph) I/II study of elotuzumab (Elo) plus lenalidomide/dexamethasone (Len/dex) in relapsed/ refractory multiple myeloma (RR MM): Updated Ph II results and Ph I/II long-term safety. J Clin Oncol. 2013;(suppl):abstract 8542.

Jackman RP, Deng X, Bolgiano D, et al. Lowlevel HLA antibodies do not predict platelet transfusion failure in TRAP study participants. Blood. 2013;121:3261-3266, PMID: 23393051.

10. False. Relapse in most MM

The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. N Engl J Med. 1997;337:1861-1869, PMID: 9417523.

8. True. The recommended dose and

schedule for lenalidomide is 25 mg orally once daily on days 1 to 21 of repeated 28-day cycles. Lenalidomide should be taken at about the same time each day, with or without food. FDA. Full Prescribing Information. http://www. accessdata.fda.gov/drugsatfda_docs/label/ 2013/021880s034lbl.pdf. Accessed June 9, 2013. American Society of Hematology. FDA approves lenalidomide for mantle cell lymphoma. http://www.hematology.org/News/2013/10723. aspx. Accessed on June 9, 2013.

True. The study reported an overall response rate of 84% among

patients is due to persistence of MRD, which is not adequately accounted for by traditional measurement of CR and is associated with poor prognosis. The current study compared the prognostic value of traditional response criteria and MRD measurement by LymphoSIGHT sequencing with MFC in a cohort of patients treated in Spanish Myeloma Group trials. Bone marrow samples were obtained from 68 patients treated with the same agents in two clinical trials (GEM00 and GEM05). Both PFS and OS were significantly longer in patients without MRD, whether determined by LymphoSIGHT sequencing or MFC. Martinez-Lopez J, Garcia-Sanz R, Pepin F, et al. Prognostic value of deep sequencing method for minimal residual disease (MRD) detection in multiple myeloma. J Clin Oncol. 2013;(suppl): abstract 8511.

LOOK AHEAD Next month’s issue of Clinical Oncology News will feature in-depth and expanded coverage of practice-changing studies from the 2013 ASCO Annual Meeting And coverage of the 17th International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas and Myeloma

—————————— New Columns —————————— The August issue will also feature How I Manage: Transplant-Eligible Patients With Multiple Myeloma by Kenneth Anderson, MD

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Medical Practice Management in the 21st Century: The Handbook

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New Challenges in Communication with Cancer Patients

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Proteomic Applications in Cancer Detection and Discovery

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Current approaches to lung cancer treatment include radiation, surgery and chemotherapy/targeted therapy, all of which are intended to target the tumor. Through our ongoing clinical program, BMS is investigating an entirely new way to treat lung cancer by targeting the immune system. Our research is focused on transforming the way tumor cells and the immune system communicate, including checkpoint pathways; we hope to find new ways to stop lung cancer from evading the immune system, thereby restoring the body’s natural ability to fight it. If you’re interested in learning more about BMS investigational studies in lung cancer, including a list of study sites, please visit BMS Study Connect to search for lung cancer studies near you. http://www.bms.com/studyconnect/Pages/Home.aspx

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