The April 2013 Clinical Oncology News Digital Edition by McMahon Group

Independent News on Advances in Hematology/Oncology clinicaloncology.com • April 2013 • Vol. 8, No. 4

INSIDE SOLID TUMORS Brachytherapy: More complications, less conservation than whole breast irradiation ............................... 14 Bevacizumab strikes out in latest breast cancer trials ............................ 15 Should chemotherapy be given routinely after breast cancer recurrence? ............. 24

HEMATOLOGIC DISEASE Ponatinib’s place in the leukemia armamentarium .................... 12 Cutting thromboembolic risk after warfarin ................ 13 By the Numbers: Leukemia risk after breast cancer ........................ 24

CURRENT PRACTICE Maurie Markman, MD: Maximizing novel technologies ........................... 9 Palliative care misunderstandings ‘astonishingly high’ ............. 19 Liability risks in a changing treatment landscape ............................... 26

BCI, Oncotype DX and IHC4 Face Off

Images in Oncology

BCI maintains prognostic performance into late recurrence time period San Antonio—The Breast Cancer Index (BCI, bioTheranostics) outperforms the Oncotype DX Recurrence Score (RS; Genomic Health) and the immunohistochemical (IHC)4 in accurately predicting breast cancer recurrence risk five to 10 years after a disease-free period, according to the TransATAC (Arimidex, Tamoxifen, Alone or in Combination) study, presented by Dennis Sgroi, MD, the director of Breast Pathology at Massachusetts see FACE OFF, page 25 

by the

Prostatic intraepithelial neoplasia, a microscopic prostate cancer precursor lesion, exhibiting telomere abnormalities (for more information, see page 8).

numbers Medical Billing

Science in Oncology

Drugging the Undruggable

n February, Time ran “Bitter Pill,” a feature story on medical bills in the U.S. that included the following costs for one patient’s care at MD Anderson Cancer Center:

Acetaminophen tablet

Patient’s Bill

Actual Cost

$1.50

$ 0.0149

Chest X-Ray

$283.00

$20.44*

Rituximab, 660 mg injection

$13,702

$4,000

$83,900 Cost of treatment plan and initial chemotherapy doses for a non-Hodgkin lymphoma patient at MD Anderson $2,050,000,000 MD Anderson’s 2010 . revenue, the latest figures available 26% MD Anderson’s 2010 profit margin Source: Brill, S.“Bitter Pill: Why Medical Bills Are Killing Us.” . Time. Feb. 20, 2013.

Liverpool, England—One of the most important avenues for drug discovery in cancer is to target genes considered “undruggable,” according to several experts at the 2012 National Cancer Research Institute (NCRI) Cancer Conference. This line of research is particularly relevant because “only one-quarter of patients derive any benefits from treatment,” said Ultan McDermott, MD, PhD, an oncologist and the career development fellow group leader in the Cancer Genome Project at the Wellcome Trust Sanger Institute in Cambridge, England. Compounding this, as much as 80% of the genome is thought to be “undruggable” and current drugs are only able to target 20% of all proteins, said Martin Drysdale, PhD, of the Beatson Institute for Cancer Research in Glasgow, Scotland. The intracellular molecules—p53, Myc and Ras—have long been deemed unfeasible targets for therapy, but drugging them would be a boon for cancer research and patient care. Aberrations in p53, Myc and Ras represent some of the most common events in human cancer, and experiments show that restoring normal function see UNDRUGGABLE, page 10 

* Cost based on amount Medicare routinely reimburses . for procedure.

Clinical Conundrums ......... 29

RE VIE WS & COMMENTAR IES

Expert Insights From Mayo Clinic Cancer Center Curing follicular lymphoma with stem cell transplantation........... 21

Beta-blockers improve survival in patients with NSCLC...........................20 Steven E. Schild, MD

Stephen Ansell, MD, PhD

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Clinical Oncology News wants to publish you! As part of the Clinical Oncology News inaugural writer’s contest, from now until June 30 the magazine will be accepting essays on the topic ‘Change in Medical Oncology or Hematology/Oncology’. Cash prizes!

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Essays can relate to the topic in any way the author sees fit — how medicine has changed for the worse, how it should be changed for the better, or simply a reflect on the process of change itself. Essays will be judged on their eloquence and persuasiveness and should be a maximum of 3,500 words. Winners will be announced in the August issue. First place will receive $1000, second place $500 and third place $250. All will receive recognition and prominent placement in Clinical Oncology News. Submissions should be emailed as a word document to Clinical Oncology News managing editor Gabriel Miller at gmiller@mcmahonmed.com.

Another Successful Year For the McMahon Group

2012

Once a year, the McMahon Group takes time out to recognize the best of an outstanding group of employees. Now into its fifth decade, the company continues to publish best-read medical newspapers and must-view medical websites covering several clinical areas, and also creates medical education platforms for physicians, nurses and pharmacists. All of which proves yet again that a company powered by talented people will necessarily generate success.

Here is a review of the winners of the 2012 employee awards: MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

MANAGEMENT/SUPPORT/IT/FINANCE/PRODUCTION

Each year employees are asked to select two outstanding members representing these diverse departments. The first winner was DIANE LODISE, who is both the director of facilities management, overseeing the facilities owned by the company, and the conventions coordinator, planning the many details of our extensive convention coverage.

The second winner was HYONG KWON, the company’s development manager for IT, for his continuing efforts in improving the company’s digital presence.

MAX GRAPHICS PERSON OF THE YEAR

MOST IMPROVED SALESPERSON OF THE YEAR

BLAKE DENNIS was recognized for her excellence as art director for Anesthesiology News as well as her graphic design of a variety of special projects. Blake is dedicated to creating the most visually appealing projects possible.

BRIAN HIGGINSON, publication director for Gastroenterology & Endoscopy News, was recognized for the increase in that publication’s sales in 2012, which in part led to one of its most profitable years ever. His dedication to his clients’ needs and understanding of their products ensure his continued success in sales.

ASSOCIATE/SENIOR/PROJECTS EDITOR OF THE YEAR

MANAGING EDITOR OF THE YEAR

Editorial director of the special projects division, KATHERINE REIDER was recognized for her contributions as an editor and for providing leadership and direction to the members of the department. Her diplomacy skills and focus on process have helped ensure that projects are developed with the highest level of accuracy and in a timely manner. Katherine also was recognized for her 10 years of service at McMahon.

GEORGE OCHOA was voted editor of the year for his efforts and dedication to McMahon Group through his exemplary writing and editing. His stories appear in every McMahon Group publication and on every website and provide the managing editors with articles that exemplify editorial excellence.

SALES ACHIEVEMENT AWARD

SALESPERSON OF THE YEAR

The publication director for General Surgery News, MICHAEL ENRIGHT, was selected for this award in recognition of his strong commitment to his clients and his innovative thinking to create unique marketing platforms, which included the publication’s first international edition as well as the initiation of a website video arcade.

For an unprecedented seventh year in a row, RICHARD TUORTO earned the salesperson of the year award. Unlike the other awards, which are decided by peer votes, this award is presented to the individual who brings in the most revenue in the calendar year. Richard manages the Anesthesiology News and Pain Medicine News teams as senior group publication director.

THE MCMAHON GROUP PERSON OF THE YEAR

PARTNERS’ AWARD

The top award each year is for the person of the year, which goes to the employee who goes above and beyond the call throughout the year. JEANNIE MOYER, associate director of human resources, received the honor this year. Jeannie oversees personnel and works tirelessly to provide the best possible atmosphere for employees each day. She is integral to helping McMahon Group continue to grow every year.

From time to time, the partner-owners of the company recognize the contributions of those who have had a significant effect on the company’s success through the years. The 2012 award was given to WARD BYRNE, who served as publication director for Anesthesiology News for several years, starting in the early 1990s. He was responsible for the excellent growth of that newspaper, which today dominates the market. Ward eventually left McMahon Group to start what would be an 11-year career working at a medical education company, after which he returned to his true love — teaching. Today, Ward teaches special education in the New Jersey school system.

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The Oncology Education Collaborative helps you identify educational activities in the learning formats YOU prefer. Select from a broad array of activities including live meetings, online programming, podcast downloads, mobile app education, print education, satellite radio broadcasts, and more. Learn more at OncologyCollaborative.org.

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CLINICAL ONCOLOGY NEWS

Clinical Oncology News • April 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 Betty Ferrell, RN, PhD

Paul J. Ford, PhD

City of Hope National Medical Center Duarte, CA

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

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

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

Richard Stone, MD

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

University of Colorado Cancer Center Denver, CO

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

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

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

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 work of Alan Meeker, PhD, an assistant professor of pathology at The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins University. The image is prostate intraepithelial neoplasia in which the telomeres have been stained red with a fluorescently labeled hybridization probe and prostatic basal epithelial cells have been stained green with an antibody specific for basal cell cytoskeletal proteins. Dr. Meeker’s lab is showing that these . morphologically abnormal cells also harbor molecular defects—the shortened telomeres—that are a hallmark of prostate cancer.

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

Cindy O’Bryant, PharmD

Edward Chu, MD

University of Texas, MD Anderson Cancer Center Houston, TX

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

Pharmacy

Shaji Kumar, MD Mayo Clinic Rochester, MN

Cathy Eng, MD

Bioethics

University of California, San Diego, CA

Michael J. Fisch, MD, MPH

Alan Meeker, PhD

University of Texas, MD Anderson Cancer Center Houston, TX

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

Gynecologic 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 and Head and Neck Cancers Edward S. Kim, MD Levine Cancer Institute, Carolinas HealthCare Charlotte, NC

Lung 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 News 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 • April 2013 • CLINICALONCOLOGY.COM

Maximizing Novel Technologies A strategy to improve cost-effectiveness in cancer management 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 financial impact of new technologies and novel pharmaceuticals in cancer management has become a major societal issue and the source of considerable debate. Currently, antineoplastic agents approved for non-research use by the FDA will routinely cost many thousands of dollars—if not much more—for each cycle delivered. Further, as a result of their effectiveness, treatments then can be extended, converting once rapidly progressive cancers into serious but more chronic conditions. Longer drug administration only heightens concerns over the costs of cancer management. Innovative imaging and laboratorybased technologies also add to growing individual, family, employer and governmental financial burdens associated with cancer care. And this occurs at a time when an aging population in the United States is increasing the potential number of patients who may benefit from their utilization. As a result, third-party payers including the government, private insurers and large employers are—reasonably—demanding ®

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

evidence of the value of a novel approach. Even if a Phase III trial demonstrates a “statistically significant” result, many are asking if the outcome is truly associated with clinical benefit. Further, these same payers increasingly are requesting, or requiring, cost–benefit analyses of new tactics before an approach is accepted as a component of standard of care. One unique strategy to optimize the benefit versus cost of a novel technology would be to employ the tool to satisfy more than a single relevant goal. Thus, the financial impact associated with the intervention can be shared between two or among more clinical outcomes, substantially increasing the benefit compared with the cost associated with the approach. Advanced radiographic imaging for lung cancer is a provocative, recently proposed example of this concept.1 While radiographic “screening” has been debated extensively for more than a decade, Phase III randomized clinical trial results demonstrating the potential utility of the approach in improving lung cancer–related mortality in a high-risk population has focused major attention on the cost-effectiveness of this strategy when employed outside of high-volume, academic centers.2 The proposal suggested that during radiographic screening for lung cancer, it might also be possible to evaluate the coronary arteries for the presence of calcium, a measurable clinical parameter that has been shown to predict the risk for future cardiovascular events.3 Thus, the costs—physician and other personnel,

equipment, space and maintenance—will be weighed against the goals of both early lung cancer detection and the assessment of cardiac risks leading to intervention.1 Other outputs that might be considered in this scenario include the presence and severity of chronic obstructive pulmonary disease, the existence and nature of aneurysms, and the bone density status of the individual. Another example in cancer relates to the rapidly evolving area of molecular testing for somatic abnormalities within cancers that may lead to specific therapeutic interventions. Although certain tests have become the standard of care in certain clinical settings (e.g., sensitizing EGFR mutation testing in advanced non– small cell non–squamous cell lung cancer; KRAS mutation testing in metastatic colon cancer), the overall utility of widespread molecular analysis still remains a matter of debate. As one example, consider adding an analysis of specific normal germline polymorphisms that have been shown in several studies to affect both therapeutic efficacy and toxicity to an analysis for the presence of molecular abnormalities in the cancer.4-6 The combined use of both a somatic tumor and germline molecular analysis might improve the cost-effectiveness of testing substantially in a number of clinical settings. Considering both the potential clinical benefits of novel, but clearly very expensive, technologies and the need for individuals, families and society to make extremely difficult health-related spending

Editorial Staff

Sales Staff

Kevin Horty, Group Publication Editor khorty@mcmahonmed.com

Julianna Dawson, Publication Director jdawson@mcmahonmed.com

Gabriel Miller, Managing Editor gmiller@mcmahonmed.com

David Nathanson, Account Manager dnathanson@mcmahonmed.com

Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com

Art and Production Staff

James Prudden, Group Editorial Director

Michele McMahon Velle, Creative Director, MAX Graphics

David Bronstein, Editorial Director Robin B. Weisberg, Manager, Editorial Services Elizabeth Zhong, Associate Copy Chief

Frank Tagarello, Senior Art Director/ Managing Director, MAX Graphics Dan Radebaugh, Director of Production and Technical Operations

decisions in the future, it is essential that major efforts are undertaken to objectively document the utility and optimize the value of new approaches. Rationally combining several relevant health-related goals resulting from new technologies may be one mechanism to accomplish this aim.

References 1. Mets OM, de Jong PA, Prokop M. Computed tomographic screening for lung cancer: An opportunity to evaluate other diseases. JAMA. 2012;308:1433-1434, PMID: 23047354. 2. National Lung Screening Trial Research Team. Reduced lung-cancer mortality with low-dose computed tomographic screening. N Engl J Med. 2011;365:395-409, PMID: 21714641. 3. Jacobs PC, Prokop M, van der Graaf Y, et al. Comparing coronary artery calcium and thoracic aorta calcium for prediction of allcause mortality and cardiovascular events on low-dose non-grated computed tomography in a high-risk population of heavy smokers. Atherosclerosis. 2010;209:455-462, PMID: 19875116. 4. O’Donnell PH, Ratain MJ. Germline pharmacogenomics in oncology: Decoding the patient for targeting therapy. Mol Oncol. 2012;6:251-259, PMID: 22321460. 5. Coate L, Cuffe S, Horgan A, et al. Germline genetic variation, cancer outcome, and pharmacogenetics. J Clin Oncol. 2010;28:40294037, PMID: 20679599. 6. Ramsey LB, Panetta JC, Smith C, et al. Genome-wide study of methotrexate clearance replicates SLCO1B1. Blood. 2013;121:898904, PMID: 23233662.

Comments or feedback on Dr. Markman’s column? Please write to Clinical Oncology News managing editor Gabriel Miller at

gmiller@mcmahonmed.com

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

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

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

CURRENT PRACTICE

UNDRUGGABLE continued from page 1 

to p53, Myc and Ras has strong, highly selective anti-tumor activity. However, “these [intracellular] proteins don’t seem to have good binding sites for conventional drugs, which is why we call them undruggable,” said Sir David Lane, PhD, the chief scientist at the Agency for Science, Technology and Research in Singapore, and winner of the UK Lifetime Achievement in Cancer Research Prize, who gave a keynote talk at the meeting. “These are the three horsemen of the cancer apocalypse,” said James Bradner, MD, a medical oncologist at the DanaFarber Cancer Institute and an assistant professor at Harvard Medical School in Boston, in a phone interview. “We can’t yet prescribe even one drug that targets these most common contributors to cancer pathogenesis.” But efforts in the last few years to develop drugs that target p53, Myc and Ras are yielding promising results. “We currently have just enough evidence that [drugging these targets] could work, enough to deploy new technologies to approach old fundamental problems,” Dr. Bradner said.

‘This is the first time it’s been demonstrated that Ras can be drugged.’ —Guowei Fang, PhD Investigators are currently working on several avenues to target these molecules, including peptide stapling to regulate p53, a pathway approach to pursue Myc and fragment-based drug discovery (FBDD) to regulate Ras (Table).

p53: Stapled Peptides Peptide stapling has emerged as an innovative way to target p53, which is mutated or overactive in about 50% of human tumors (Nature 2000;408:307310, PMID: 11099028). Gregory L. Verdine, PhD, the Erving Professor of Chemistry in the Department of Stem Cell and Regenerative Biology at Harvard University in Cambridge, Mass., developed the technique just over a decade ago. In 2000, Dr. Verdine and his colleagues found that creating an α-helix that binds peptides would allow potential therapeutic proteins to enter the cell without degradation (J Am Chem Soc 2000;122:5891). This method involves incorporating two novel amino acids synthesized in the lab into the peptides so they can form an additional crosslink to each other. “It is like a staple,” said Dr. Lane in

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

a phone interview. “This additional hydrocarbon double bond makes the peptide more rigid; allows it to bind to its target better; makes it resistant to protease so it’s not broken down; and amazingly, permits it to go inside cells and act like a drug.” Several groups are developing stapled peptide inhibitors of MDM2 and MDM4, proteins that naturally bind to p53 and disrupt its protective, anticancer activity. “That’s where the stapled peptides look very promising,” Dr. Lane said. MDM2 is often overexpressed in human tumors, impairing p53 function, which means drugs that can inhibit the MDM2–p53 interaction may halt the spread of cancerous cells. To date, a particularly notable stabilized α-helix of p53, SAH-p53-8, has been shown to trigger cell death in cancer cells that overexpress MDM2, and restore normal activity in the p53 signaling pathway (J Am Chem Soc 2007;129:2456– 2457). Another study found that SAH-p53-8 also targets MDM4 and is toxic to cancer cells that overexpress MDM2, MDM4 or both (Cancer Cell 2010;18:411-422, PMID: 21075307). Although SAH-p53-8 will not be developed as a drug because of its low activity, a more potent stapled peptide based on the design of SAH-p53-8 shows promise in preclinical trials. On Nov. 7, Aileron Therapeutics, Inc., a biopharmaceutical company in Cambridge, Mass., in collaboration with Roche, announced the results of their preclinical study of ATSP-7041, the first stapled peptide drug candidate to regulate the p53 pathway by inhibiting both MDM2 and MDM4. The results, presented at the EORTC-NCI-AACR Symposium in Dublin, Ireland (abstract 226), showed that ATSP-7041 binds to MDM2 and MDM4 with high affinity, promotes p53-dependent cell death, reactivates the p53-dependent pathway and inhibits cell proliferation in multiple in vitro and in vivo cancer cell lines. Dr. Lane’s lab also has developed a stapled peptide, SM-Tide-O2, which appears to be a potent inhibitor of the p53-MDM2 and p53-MDM4 interaction, but uses a sequence different from ATSP-7041. “We are very close to peerreviewed publication and are in preclinical development,” Dr. Lane said.

‘The field has created a mystique around certain targets, regarding these challenges as insurmountable, but this is contrary to what the public trusts us to do. What the phrase means is “we haven’t drugged it yet”.’

—James Bradner, MD

mediators of the pathway. Such compounds don’t bind directly to the Myc protein, but inhibit the function of proteins, known as BET bromodomains, which act upstream of it. In a presentation at NCRI, Chun-Wa Chung, PhD, a research scientist in Molecular Discovery Research at GlaxoSmithKline (GSK) in Stevenage, England, described work at GSK that started in 2005, which prompted the discovery of a potent small molecule inhibitor, I-BET762, that can disrupt the function of BET bromodomains (BRD2, BRD43 and BRD4; Nature 2010;468:1119-1123, PMID: 21068722), and then through collaborative efforts with a group in Cambridge, England, showed that another such compound, I-BET151, indirectly inhibits MYC gene expression and function in mixed-lineage leukemia (Nature 2011;478:529-533, PMID: 21964340). Additionally, in 2011, Dr. Bradner and his team showed that JQ1, another small molecule inhibitor of BET

Table. Molecules in Trials To Target p53, Ras and Myc Molecule

Company

Trial

Cancer Targeted

AT-101

Ascenta

Phase II

Chronic lymphocytic leukemia; nonHodgkin lymphoma; prostate

AT-406

Ascenta

Phase I

Breast; pancreas; prostate; lung

MI-219

Ascenta/Sanfori/ UM

Phase I

B-cell lymphoma; prostate

MI-773

Ascenta/Sanfori/ UM

Preclinical

Prostate

MI-519-64

Ascenta/Sanfori/ UM

Preclinical

Prostate

RG7112

Roche

Phase I

Solid tumors, hematologic neoplasms

RG7388

Roche

Phase I

Solid tumors, hematologic malignancies

RO5503781

Roche

Phase I

ATSP-7041

Aileron/Roche

Preclinical

SM-Tide-O2

p53 lab A*Star Singapore

Preclinical

Myc

I-BET762

GSK

Phase I

NUT midline carcinoma

Ras

Salirasib

Concordia Pharmaceuticals

Phase II

Non-small cell lung

p53

Myc: Master Transcriptional Regulation Aberrations in the cancer-promoting gene MYC also represent some of the most common events in human cancer, occurring in up to 70% of cancers. “The MYC gene is fundamental to human cancer,” said Dr. Bradner. “It’s hard to find cellular models of cancer that don’t depend on MYC, yet there are no MYC inhibitors.” Recent investigations into targeting MYC have focused on epigenetic

bromodomains, regulates the function of MYC, reducing its expression and the expression of other genes that MYC targets. In mouse models of multiple myeloma, JQ1 inhibited cell proliferation and allowed treated mice to live significantly longer than their untreated counterparts (Cell 2011;146:904-917, PMID: 21889194). Collaborative study by Dr. Bradner and a team of investigators based at Cold Spring Harbor Laboratory in New York, found that BRD4 inhibition also was a promising therapeutic strategy in acute myeloid leukemia (AML), revealing, for instance, that JQ1 arrested the progression of mouse leukemia and lymphoma (Nature 2011;480:524-528, PMID: 21814200). With growing confidence in the druggability of MYC, Dr. Bradner, in collaboration with the Structural Genomics Consortium, has promoted an open-source approach to research, making JQ1 available to any lab and

GSK, GlaxoSmithKline; NUT, nuclear protein of the testis; UM, University of Michigan

CURRENT PRACTICE

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

working with the pharmaceutical industry and academic labs in the hope of expediting clinical development of drugs against MYC. “It’s become clear that it’s good for patients to have numerous molecules in clinical development against a difficult target because you never know which will be tolerated best,” Dr. Bradner said. “Together, we stand to make incredible progress in a short time.” So far, this collaborative approach has paid off. Dr. Bradner and his colleagues at the Dana-Farber Cancer Institute have worked with GSK on I-BET762 (GSK525762), and are now recruiting for Phase I trials targeting nuclear protein of the testis (NUT) midline carcinoma and other cancers (http://clinicaltrials.gov/show/NCT01587703). In 2011, Dr. Bradner launched the biotechnology company Tensha Therapeutics in Cambridge, Mass., to clinically develop more potent drugs that act as BET inhibitors. After screening more than 400 JQ1-like compounds, Dr. Bradner’s lab has completed optimization of a prototype of molecule, which is expected to transition into clinical trials this year.

Ras: Fragment-Based Discovery Researchers have been trying, unsuccessfully, to target Ras for more than 25 years. “I think Ras is one of the toughest drug targets,” said Guowei Fang, PhD, a research scientist at Genentech, in a phone interview. “It is the most frequently mutated oncogene in human tumors.” Mutations in Ras have been identified in 30% of all human cancers, and up to 90% of pancreatic, 50% of colon and 40% of lung cancers. In his talk at NCRI, Dr. Fang discussed Genentech’s preliminary success determining the druggability of Ras using nuclear magnetic resonance (NMR)-based fragment screening. “We analyzed the binding of molecules to the Ras protein itself, not yet asking whether those molecules could inhibit Ras, but seeing what molecules associated with Ras,” Dr. Fang continued. “This turned out to be a powerful approach to address the druggability of our target.” After screening 3,300 small molecules, NMR spectroscopy revealed that the 25 compounds were binding to the same location, a pocket on the protein (PNAS 2012;109:5299-5304, PMID: 22431598). Although binding only weakly to Ras, the 25 molecules were able to block activity of an enzyme called Son of Sevenless, which is required to activate the oncoprotein (Bioorg Med Chem Lett 22:5766-5776, PMID: 22902659). “This effort [to find an effective drug to target Ras] is still a long way off and will require extensive work; however, the fact that we found 25 molecules that can bind in the pocket of Ras represents

p53

a major breakthrough in the Ras therapeutic area,” said Dr. Fang. “This is the first time it’s been demonstrated that Ras can be drugged.” The next step for Dr. Fang and colleagues is to improve binding affinities and selectivity as well as increase the anticancer potency of these compounds. Dr. Fang suggested screening for compounds using a different, perhaps larger, chemical library, or using a

Myc

Ras

The Current State of Research The momentum toward validating viable candidates to drug p53, Myc and Ras has increased substantially in just the past three years. Stapled peptides, pathway approaches and fragmentbased drug discovery represent just three examples of promising avenues currently under investigation. Uncovering such targets is crucial for the health and progress of drug

The momentum toward validating viable candidates to drug p53, Myc and Ras has increased substantially in just the past three years. Stapled peptides, pathway approaches and fragment-based drug discovery represent just three examples of promising avenues currently under investigation. larger compound to target the molecule. Particularly promising in this area is that three research efforts—Genentech and two academic labs, the group directed by Stephen Fesik, PhD, at Vanderbilt University in Nashville, Tenn., and Dr. Martin Drysdale’s team at the Beatson Institute for Cancer Research in Glasgow—have independently and simultaneously reached the same conclusions about the Ras-binding pocket and are working toward the next step of finding preclinical candidates that target Ras. Moving forward, the labs are taking different approaches to uncover small molecule inhibitors. For example, after identifying small fragment molecules that interact with the surface of Ras (Angew Chem Int Ed 2012;51:6140– 6143, PMID: 22566140), Dr. Fesik’s lab has created x-ray crystal structures of the most promising fragments in order to create a larger and more potent molecule, or perhaps link the existing fragments together to obtain a high-affinity, biologically effective molecule. “Because the structure of the 25 molecules we found was quite diverse, it leads me to believe that there are multiple paths forward,” Dr. Fang said.

discovery. “Once one company has a molecule that works, in two years five companies have molecules that work, and that is when previously we had no effective molecules,” Dr. Lane said. “We used to have no inhibitors of MDM2, but the one discovered by Roche prompted the development of six or seven that are very good.” Researchers often refer to attempts to target p53, Myc and Ras as “drugging the undruggable”; however, Dr. Bradner feels this expression does not capture the spirit of research. “The field has created a mystique around certain targets, regarding these challenges as insurmountable, but this is contrary to what the public trusts us to do,” Dr. Bradner said. “What the phrase means is ‘we haven’t drugged it yet.’” —Victoria Stern

Patient Surveillance After Cancer Treatment Johnson, F.E.; Maehara, Y.; Browman, G.P.; Margenthaler, J.A.; Audisio, R.A.; Thompson, J.F.; Johnson, D.Y.; Earle, C.C.; Virgo, K.S. (Eds.) See page 32

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HEMATOLOGIC DISEASE

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

ASH 2012

Ponatinib Excels in Heavily Pretreated Population Following PACE trial, experts explore ponatinib’s place in the leukemia armamentarium Atlanta—The FDA has approved ponatinib (Iclusig, Ariad) for patients with chronic, accelerated, or blast phase chronic myeloid leukemia (CML) and Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL), when patients with these diseases are resistant or intolerant to prior tyrosine kinase inhibitors (TKIs). The accelerated approval was based on results from the PACE (Ponatinib Ph+ ALL and CML Evaluation) trial, presented at the American Society of Hematology’s annual meeting (abstract 163). “Responses happen regardless of the state of the disease, regardless of the presence or absence of mutations. The responses are very deep, rapid and sustained,” said Jorge E. Cortes, MD, the deputy chair of the Department of Leukemia at the University of Texas MD Anderson Cancer Center in Houston, who presented the study. Ponatinib has potent activity against native and mutated BCR-ABL and other kinases. The oral drug was designed specifically to overcome the resistance generated by the T315I mutation and also is effective in patients with other mutations. The study enrolled 449 heavily pretreated patients with CML or Ph+ ALL resistant or intolerant (R/I) to dasatinib (Sprycel, Bristol-Myers Squibb) or nilotinib (Tasigna, Novartis) or with the T315I mutation. Patients were assigned to one of six cohorts: chronic phase (CP)-CML R/I (n=203), CP‑CML T315I (n=64), accelerated phase (AP)-CML R/I (n=65), AP-CML T315I (n=18), blast phase (BP)‑CML/Ph+ ALL R/I (n=48), or BP‑CML/Ph+ ALL T315I (n=46). Five patients (3 CP-CML, 2 AP-CML) without confirmed T315I mutation and not resistant or intolerant to dasatinib or nilotinib were treated, but not assigned to a specific cohort.

‘The more drugs we have for CML, the better it is, because we have different drugs for different patient profiles. … We are moving into an era of personalized therapy or “treatment à la carte.”’ —Elias Jabbour, MD

Table. Primary End Point Responses in PACE Chronic Phase CML

Advanced Phase CML

Blast Phase CML/Ph+ ALL

Primary end point

MCyR, %

MaHR, %

Resistant or intolerant to dasatinib or nilotinib

T315I mutation

Total

More than 90% of patients had received more than two prior TKIs. Sixty percent of patients with CP- or AP-CML and 53% of patients with BP-CML or Ph+ ALL had received at least three prior TKIs. The primary end point was major cytogenetic response (MCyR) in patients with CP-CML and major hematologic response (MaHR) in patients with more advanced disease. Fifty-six percent of CP-CML patients had a MCyR; 57% of AP-CML patients and 34% of BP-CML and Ph+ ALL patients had an MaHR (Table). Two-thirds of CP-CML patients

had any cytogenetic response, with 46% having a complete cytogenetic response (CCyR). Putting this into perspective, Dr. Cortes said that studies have shown that CML patients who take dasatinib or nilotinib after failing imatinib (Gleevec, Novartis) have a CCyR of 40%. Roughly one-third of CP-CML patients had a major molecular response, and 91% of CP-CML patients with MCyR are estimated to sustain response at 12 months. Responses occurred regardless of mutations, including F317L, F359V, E255K, G250E and others.

Grade 3/4 adverse events included rash (9%), hypertension (7%), increased lipase (12%), pancreatitis (5%), thrombocytopenia (34%), neutropenia (21%) and anemia (14%). The drug carries a black box warning regarding serious arterial thrombosis, which affected 8% of patients, and hepatotoxicity. Three fatal cases of acute liver failure occurred in the trial. According to Elias Jabbour, MD, an associate professor in the Department of Leukemia at MD Anderson Cancer Center who was not one of the study investigators, roughly one-third of clinicians start therapy with imatinib (Gleevec, Novartis) as first-line for CML and then move to dasatinib or nilotinib as secondline. Others use second-generation TKIs like dasatinib or nilotinib as first-line therapy. In that setting and upon failure, ponatinib is an appropriate choice. In addition to the use of nilotinib and dasatinib, in the second-line setting, clinicians may choose newly approved agents such as bosutinib (Bosulif, Pfizer), ponatinib, or omacetaxine (Synribo, Teva). The patient’s safety profile and mutation status should be taken into consideration when making this choice. “The more drugs we have for CML, the better it is because we have different drugs for different patient profiles,” said Dr. Jabbour. “If a patient has a T315I mutation, ponatinib and omacetaxine are the best choices. Physicians’ expertise, mutation profiles and patients’ comorbidities play a crucial role in selecting the best agent. We are moving into an era of personalized therapy or ‘treatment à la carte.’” —Kate O’Rourke Dr. Cortes disclosed receiving research support and serving as a consultant to Ariad, maker of ponatinib. Dr. Jabbour disclosed a consultancy with Bristol-Myers Squibb, Teva Oncology, Ariad and Pfizer.

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HEMATOLOGIC DISEASE

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

A Drug to Cut VTE Risk After Warfarin Apixaban use in cancer patients is controversial, requires further study Atlanta—One year of treatment with apixaban (Eliquis, Bristol-Myers Squibb/Pfizer) after six to 12 months of warfarin treatment for venous thromboembolism (VTE) decreased the risk for recurrent VTE and VTE-related deaths by 80% compared with placebo, according to results from the AMPLIFY-EXT trial (Apixaban After the Initial Management of Pulmonary Embolism and Deep Vein Thrombosis with First-Line Therapy–Extended Treatment). The study was reported at the American Society of Hematology’s 2012 annual meeting (LBA1). “The rates of major bleeding in the study were low and comparable to those in the placebo group,” said Giancarlo Agnelli, MD, the director of the internal and cardiovascular medicine/stroke unit at the University of Perugia in Perugia, Italy, who presented the results. In December 2012, the FDA approved apixaban for preventing stroke in patients with non-valvular atrial fibrillation, and experts say the drug most likely will be used off-label for VTE. The drug fills an unmet need—after discontinuing warfarin for VTE treatment, patients without reversible risk factors have a recurrence risk of between 6% and 10% per year. Some clinicians prolong treatment with anticoagulation, but this can increase bleeding. Apixaban is an oral factor Xa inhibitor given in fixed doses without routine coagulation monitoring. AMPLIFYEXT enrolled patients with deep vein thrombosis or pulmonary embolism who had completed six to 12 months of anticoagulant treatment and randomized them to either placebo therapy, or apixaban 2.5 or 5 mg twice daily, for one year. Approximately 810 patients comprised each arm. Symptomatic recurrent VTE or allcause death was lowest in patients receiving apixaban 2.5 mg (3.8%), compared with apixaban 5 mg (4.2%) and placebo (11.6%; P<0.001). Recurrent VTE or VTE-related death was 1.7% in both apixaban arms and 8.8% in the placebo arm. Major bleeding was 0.2% in the lower-dose apixaban arm, 0.1% in the higher-dose apixaban arm, and 0.5% in the placebo arm. The number needed to treat to prevent one episode of recurrent fatal or nonfatal VTE was 14. “Apixaban is definitely a very effective drug and appears to be safe for VTE patients,” said Agnes Lee, MD, the director of the thrombosis program at Vancouver General Hospital and an associate professor of medicine at the University of British Columbia in Vancouver, Canada, who was not involved with the study. She said two other fixed-dose

anticoagulants, rivaroxaban (Xarelto, Bayer) and dabigatran (Pradaxa, Boehringer Ingelheim), have shown results similar to those seen in the AMPLIFY-EXT trial, and many clinicians will choose to use one of the three drugs offlabel for long-term prevention of VTE. Only rivaroxaban has an indication for the treatment of deep vein thrombosis. Apixaban may be more appropriate for

patients who have renal impairment, she said, because it is the least dependent on renal function. Using these drugs in cancer patients, however, is a different story. “I would be hesitant to use these drugs in cancer patients. Experts in the field are also very much against it, because there could be potential interactions with chemotherapeutic drugs,” said Dr. Lee. Patients on chemotherapy tend to

have gastrointestinal problems leading to unpredictable absorption, and these drugs could increase the risk for gastrointestinal bleeding. “I would really like to see these drugs tested in a clinical trial of cancer patients,” Dr. Lee said. “It is desperately needed.” —Kate O’Rourke Dr. Agnelli reported relationships with Bristol-Myers Squibb and Boehringer Ingelheim. Dr. Lee reported honoraria from and advisory board involvement with Bristol-Myers Squibb, and honoraria from Bayer and Boehringer Ingelheim.

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Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Worse Outcomes for Brachytherapy Compared With WBI A

retrospective, population-based, cohort study in older women has found evidence that brachytherapy is associated with poorer long-term breast preservation and increased complications than whole breast irradiation (WBI), although there is no difference in survival. In the study, published in JAMA (2012;307:1827-1837, PMID: 22550197), the authors, led by Grace L. Smith, MD, PhD, MPH, of the University of Texas

MD Anderson Cancer Center in Houston, used Medicare patient data from 92,735 women aged 67 years or older diagnosed with invasive breast cancer from 2003 to 2007, who were treated with lumpectomy followed by radiation therapy. After lumpectomy, 6,952 patients were treated with brachytherapy and 85,783 with WBI. Brachytherapy was associated with a higher risk for subsequent mastectomy, with a five-year cumulative

incidence of 3.95% (95% confidence interval [CI], 3.19%-4.88%) compared with 2.18% (95% CI, 2.04%-2.33%) in patients who received WBI (P<0.001). Brachytherapy was also associated with higher risks for infectious and noninfectious postoperative complications within one year of lumpectomy (brachytherapy 27.56% vs. WBI 16.92%; P<0.001). Brachytherapy was also associated with a higher risk for complications within five years of

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radiation (brachytherapy 24.96% vs. WBI 18.80%; P<0.001). Five-year overall survival was similar in both groups: 87.66% (95% CI, 85.94%-89.18%) of patients treated with brachytherapy compared with 87.04% (95% CI, 86.69%-87.39%) of those treated with WBI (P=0.02), a difference that did not persist with multivariable adjustment (HR, 0.94; 95% CI, 0.84-1.05; P=0.26). —George Ochoa

SOLID TUMORS

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Avastin Strikes Out in Latest Breast Cancer Trials Role of bevacizumab in breast cancer diminishes further San Antonio—Bevacizumab (Avastin, Genentech) has struck out in two additional Phase III trials, LEA and BEATRICE, in patients with breast cancer. The trial results were reported at the San Antonio Breast Cancer Symposium. “It is getting to the point where it is difficult to know the role of bevacizumab, if any, in breast cancer,” said Kent Osborne, MD, the director of the Lester

and Sue Smith Breast Cancer Center at Baylor College of Medicine in Houston, who was not involved with either study. “Bevacizumab is going to have a very limited role in breast cancer, unless ongoing studies show otherwise.” Investigators launched the LEA (Letrozole/Fulvestrant and Avastin) study because clinical data has suggested that downregulation of vascular endothelial

growth factor (VEGF) may overcome resistance to and improve the efficacy of hormonal therapies. Data from Phase II trials also has demonstrated that adding bevacizumab to endocrine therapy was safe and active. LEA randomized 380 patients with advanced breast cancer to receive firstline treatment with letrozole (Femara, Novartis) or fulvestrant (Faslodex,

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AstraZeneca) with or without bevacizumab. The study found that adding the VEGF inhibitor to endocrine therapy did not result in a statistically significant improvement in progression-free survival (PFS; 18.4 months [bevacizumab] vs. 13.8 months; P=0.14) and had no effect on overall survival (OS; abstract S1-7). Investigators launched the Phase III BEATRICE trial because there had been some hint that bevacizumab might work in patients with triple-negative breast cancer. The study randomized 2,591 patients with invasive, early triple-negative breast cancer in a 1:1 fashion to receive adjuvant therapy of four to eight cycles of an investigator’s choice of standard chemotherapy or four to eight cycles of standard chemotherapy plus bevacizumab plus one-year of bevacizumab monotherapy. Chemotherapy options were taxane-based (at least four cycles), anthracycline-based (≥4 cycles), or anthracycline plus taxane (three to four cycles each). The addition of bevacizumab did not improve invasive disease-free survival (DFS; hazard ratio, 0.87; 95% confidence interval, 0.72-1.07; P=0.1810). The researchers said that further follow-up was needed to assess any potential effect on OS (abstract S6-5). “[BEATRICE] is the first study in the adjuvant setting. If it is going to work, you would think it would work in this situation, in the sense that what we are dealing with at that stage are microscopic metastases that haven’t developed a sufficient blood supply yet, and if we can prevent that blood supply from forming, then you might have a more dramatic effect than in an already established tumor, like in metastatic breast cancer,” said Dr. Osborne. The results, he said, are “disappointing.” In the community, doctors are still using bevacizumab for some patients with breast cancer. John Finnie, MD, a staff hematologist and a medical oncologist at the David C. Pratt Cancer Center at St. John’s Mercy Medical Center in St. Louis, said he follows the National Comprehensive Cancer Network guidelines when deciding which patients with metastatic breast cancer will get bevacizumab. He added that he has not had any problem getting reimbursed, but he has spoken to colleagues who are not using it because they are not being reimbursed. —Kate O’Rourke Dr. Osborne disclosed that he is a consultant for AstraZeneca, Genentech and Novartis. Dr. Finnie has no relevant disclosures.

REVIEWS & COMMENTARIES

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.NEWS

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

Clofarabine–Busulfan Regimen for ALL Needs Larger Study From Biology of Blood and Marrow Transplantation

llogeneic hematopoietic stem cell transplantation (SCT) is an effective treatment for acute lymphoblastic leukemia (ALL) but has been associated with significant mortality in those patients receiving a standard total body irradiation (TBI) regimen. Equivalent disease control has been achieved with busulfan and melphalan to replace TBI’s toxicity, but longer-term non-relapse mortality (NRM) remains substantial because of graftversus-host disease (GVHD). Fludarabine, a nucleoside analog,

and busulfan were used to good effect in patients undergoing SCT for ALL, achieving overall survival (OS) of 63% at two years and long-term NRM of only 18% at two years. Clofarabine, a second-generation purine nucleoside analog, and pharmacokinetically (PK) dosed busulfan were given to patients undergoing SCT in ALL to reduce toxicity and enhance antileukemic activity. Partow Kebriaei, MD, and colleagues at the University of Texas MD Anderson Cancer Center, in Houston, reported their results in Biology of Blood and Marrow Transplantation (2012;12:1819-1826, PMID: 22750645).

EXPERT INSIGHT Mrinal Patnaik, MD Consultant, Division of Hematology, and Assistant Professor of Medicine and Oncology, Mayo Clinic

dult ALL is a hematologic malignancy associated with high mortality and morbidity. Combination chemotherapy, including targeted agents such as tyrosine kinase inhibitors (imatinib, dasatinib) and monoclonal antibodies (rituximab, blinatumomab, inotuzumab), has been used to achieve induction remissions. However, for most adult patients, the only long-term curative option remains allogeneic stem cell transplantation (Allo-SCT). Allo-SCT is limited by a high NRM rate, limited donor pool, post-transplant disease relapse, and complications such as acute and chronic GVHD. Younger and fitter patients are generally selected for TBI-based myeloablative (MA) conditionings [increased NRM and reduced relapse rates]; whereas older and less fit patients are selected for reduced

intensity conditionings [lower NRM, higher relapse rates]. The rationale for TBI use has been its immunosuppressive properties and the protective effect in reducing the incidence of post-transplant central nervous system (CNS) relapse, given the limited penetration of most chemotherapeutic agents across an intact blood–brain barrier. Clofarabine is a novel second-generation purine nucleoside analog that has demonstrated good activity in refractory ALL (20%-30% response rates as a single agent in refractory pediatric ALL) and acute myeloid leukemia (AML). Its current U.S. FDA approval is restricted to refractory pediatric ALL only. Clinical trials have demonstrated activity in adult AML and as an MA conditioning agent for AML patients undergoing AlloSCT. Side effects of clofarabine include

This prospective Phase II study began in October 2009 with findings through October 2011. Fifty-one patients received either a matched sibling (n=24), syngeneic (n=2) or matched unrelated donor (n=25) transplant. Patients (median age, 36 years; range, 20-64 years) were either in first complete remission (n=30), second complete remission (n=13) or active disease (n=8). PK-guided busulfan allows for tight systemic drug exposures. The target median daily doses were area under the curve 5,500 µ M per minute for patients under the age of 60 years and 4,000 µ M per minute for those over. The regimen was well tolerated with a 100-day NRM

rate of 6%. At the time of this report, 33 patients were alive, with a median follow-up of 14 months. Overall, patients had a oneyear OS of 67% (95% confidence interval [CI], 55%-83%) and a two-year OS of 50% (95% CI, 34%-75%). For patients undergoing SCT in first remission, the one-year OS was 74%. Disease-free survival and NRM are uniformly better for the first remission and become worse with second remission or active disease. Clofarabine combined with busulfan offers a compelling safety profile and effective disease control for use in SCT for the adult ALL patient, according to the authors.

myelosuppression, hepatic transaminitis, skin rashes, hand–foot syndrome and acute kidney injury. In this study, the authors have combined clofarabine with IV targeted busulfan in 51 patients with ALL undergoing Allo-SCT. With a median follow-up of 14 months, the 100-day NRM was 6%, whereas the one-year OS, disease-free survival (DFS) and NRM were 67%, 54% and 32%, respectively. Importantly, 100% of patients who had minimal residual disease (MRD) going in to the transplant had no detectable disease post-transplant. Grade III hepatic transaminitis was seen in 25% of patients, whereas only one patient had a grade III elevation in his creatinine. Despite clearing MRD, the major limitation remained disease relapse; two-year DFS was 32% in a high-risk cohort. Although this is a good study exploring an important concept, it needs further evaluation in a larger cohort of patients. The fact that the conditioning includes a novel agent with activity in relapsed/refractory ALL and is effective in clearing MRD is encouraging. The lower NRM with comparable engraftment and GVHD rates makes this an acceptable alternative. The major limitation is the small and

heterogenous sample size. The outcomes have been historically compared with TBI-based conditioning regimens, and ideally it would be good to see a randomized head-to-head comparison. Patients with known CNS disease would specifically need to be followed for late CNS relapses. In current practice most of these patients are selected for TBI-based regimens, with or without additional external beam craniospinal radiation (CNS boost). To substitute this with the current regimen would require specific analysis of this subgroup of patients with a longer follow-up. The high rate of liver injury and mucositis are areas of concern. Hepatic transaminitis after Allo-SCT can limit or alter administration of important medications (antifungals, immunosuppressive agents) and can affect outcomes, although it was encouraging that none of the patients developed hepatic veno-occlusive disease. In summary, this study, although not ready for clinical practice changes, offers an exciting platform for a larger analysis to test a novel conditioning regimen in adult patients with ALL. Dr. Patnaik reported no relevant financial disclosures.

REVIEWS & COMMENTARIES

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

SEER Data: Preoperative Radiotherapy Better for Esophageal Cancer From Cancer

comparison of patients with esophageal cancer who received preoperative versus postoperative external beam radiation therapy (RT) has revealed that overall survival (OS) and cause-specific survival (CSS) were best in those undergoing RT preoperatively. Because of the location of the radiation exposures, a second aspect of the analysis was to determine if patients who received RT were more likely to die from a cardiopulmonary event than patients with esophageal cancer who did not receive RT. The study did not find this to be the case. Andrzej Wojcieszynski, MD, and

colleagues from the University of Wisconsin and the University of Pennsylvania abstracted patient records from the National Cancer Institute’s SEER (Surveillance, Epidemiology and End Results) database. They collected demographic information and tumor characteristics from 5,512 individuals treated for adenocarcinoma or squamous cell carcinoma of the esophagus between 1988 and 2007. Patients who died within 90 days of surgery were excluded. The findings were reported in Cancer (2013 Feb 7. [Epub ahead of print], PMID: 23400669). Patients were mostly male (80%) and white (86%), and median age was 63 years. Follow-up was from diagnosis to date of death or the end of the

James Martenson, MD Radiation Oncologist, Mayo Clinic

linical trials performed over the last approximately 20 years have shown that selected patients with esophageal cancer have better survival when treated with a combination of radiation therapy, chemotherapy and surgery when compared to surgical treatment alone. In one study that included patients with stomach cancer and cancer of the gastro-esophageal junction, survival was better in patients who received chemotherapy and radiation therapy after surgery, when compared to those treated with surgery alone. Other studies have shown improved survival with a combination of chemotherapy and radiation therapy given before surgery. All of the studies that strongly support adjuvant radiation therapy and chemotherapy for esophageal cancer have been

of RT for cancer treatment may be offset by cardiopulmonary toxicity, but the researchers noted that it was much more likely that patients died from the esophageal cancer than from cardiopulmonary disease (3,124 vs. 405 deaths). No significant difference in cardiopulmonary mortality was found between patients who did not undergo any RT and those who did (7% vs. 5%, respectively, at five years, and 10% vs. 8%, respectively, at 10 years). The authors concluded that preoperative RT provides superior survival compared with postoperative RT, and that RT treatment should not be withheld out of concern for toxicity to the patient’s heart or lungs.

The finding that adjuvant treatment did not appear to increase mortality from heart or lung problems provides some reassurance regarding long-term effects of adjuvant therapy.

EXPERT INSIGHT

study; median survival was 28 months. There was an approximately 2:1 ratio of patients who received preoperative (1,881) or postoperative (901) RT, and there were 2,730 patients who did not receive any RT. Over the treatment period, there was an increase in preoperative versus postoperative RT. Patients who underwent preoperative RT had a better five-year OS than those who received postoperative RT (33% vs. 23%; P<0.0001). The OS rates at 10 years favored preoperative RT (22% vs. 15%). Patients receiving preoperative RT also had a better five-year CSS (41%) than those receiving postoperative treatment (41% vs. 31%; P<0.0001). It was hypothesized that the benefits

randomized clinical trials. Because randomized trials are the gold standard for medical evidence, adjuvant radiation and chemotherapy for carefully selected patients, either before or after surgery, has become widely accepted among oncologists who treat esophageal cancer. The current collaborative study analyzed outcomes in patients with esophageal cancer who received a course of radiation therapy either before or after surgical removal of their cancer. The study used the National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) database. They found that patients treated with preoperative radiation therapy had better survival than those treated with postoperative radiation therapy: 33% vs. 23% at five years. They also analyzed

the risk of death from heart and lung problems following treatment. They did not find a statistically significant difference, either when comparing patients treated with radiation versus no radiation or when patients in the preoperative radiation therapy group were compared to those in the postoperative radiation therapy group. The SEER study provides useful information. In particular, the finding that adjuvant treatment did not appear to increase mortality from heart or lung problems provides some reassurance regarding long-term effects of adjuvant therapy. However, the study must be interpreted with caution for several reasons. Unlike the gold-standard randomized studies that provide strong evidence for adjuvant treatment for esophageal cancer, the SEER study was not a controlled study. No information regarding the details of the radiation therapy was available from the

SEER study. Also, information about chemotherapy, a critical aspect of adjuvant treatment in esophageal cancer, was not available in the SEER study. Patients who died within 90 days of surgery were excluded from the survival analysis. As a result, if the negative side effects of preoperative radiation therapy contributed to a patient’s death within 90 days of surgery, this was not accounted for in the SEER study. Because of the uncontrolled nature of the SEER study, the results cannot be considered definitive. Additional studies will be needed to further improve treatment for esophageal cancer. The findings of the SEER study should be carefully considered by investigators working to improve care for patients with cancer of the esophagus. Dr. Martenson reported no relevant conflicts of interest.

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REVIEWS & COMMENTARIES

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.NEWS

Positive Bias Plentiful in Phase III Breast Cancer Trials From Annals of Oncology

ias in reporting results from Phase III randomized clinical trials (RCTs) is common—at least in breast cancer research, a review has found. From an initial pool of 568 possible RCTs found on MEDLINE that were published between January 1995 and August 2011, the authors, headed by F. E. Vera-Badillo, MSc, of the University of Toronto, Canada, excluded all papers that had less than 200 enrollees, were in abstract form only, or concerned malignancies other than breast cancer. They identified 164 articles that met the review criteria. Results were

reported recently in Annals of Oncology (2013 Jan 9. [Epub ahead of print], PMID: 23303339). The authors noted that clinicians often scan journals and only read the abstracts. By omitting critical results, or by emphasizing insignificant findings, abstracts can lead to inaccurate interpretation. Positive studies with a significant P value were seen as unbiased (n=72; 43.9%). Studies in which a nonsignificant P value was reported as favoring the experimental arm, or studies in which the primary end point was restated, were viewed as biased (n=92; 56.1%). Results were reported as positive in 54 RCTs (32.9%), despite being based on a non-primary

Tufia Haddad, MD Medical Oncologist and Assistant Professor of Oncology, Mayo Clinic

Mayo Clinic

ith escalating clinical burdens and time constraints, practicing oncologists frequently rely on study abstracts for key trial data to help guide clinical decisions and to counsel patients on the risks and benefits of therapy. Likewise, fellows in training also rely on these abstracts to build their knowledge base. Therefore, the accuracy and integrity of data reported in trial abstracts are paramount. The review by Vera-Badillo et al is a comprehensive analysis of the reporting of primary efficacy end points and toxicity in randomized clinical trials (RCTs) for breast cancer. The study demonstrated that one-third of published trials showed bias in how the primary end point was reported in the abstract conclusion. In addition, two-thirds of trials reported bias in toxicity reporting, as defined by not providing grade 3 or

reporting by failing to mention serious adverse events in either the discussion section or the abstract’s conclusion. The use of overall survival as the primary end point was significantly associated with bias in the reporting of toxicity. Interestingly, the authors did not find that the source of funding (industry vs. academic or governmental grants) affected the frequency of bias in reporting results. They did recommend increased scrutiny of clinical trial results by editors and reviewers. The adoption of guidelines for reporting RCT results ultimately would assist clinicians in making informed treatment choices.

This article is … a call to action for the scientific community to continue to raise the bar for peer review and publication standards.

EXPERT INSIGHT

end point and not finding a statistically significant difference in the primary end point between the study arms. The authors also reviewed the presentation of adverse events in these reports. They looked for reports of grade 3 or 4 toxicities that were published in the results table and also mentioned in the discussion as well as highlighted in the abstract. The least biased reporting would require that the adverse events be reported in the paper’s results table, be raised in the discussion section, be contained within the abstract and be mentioned in the abstract’s concluding statement. The authors found that 110 (67.1%) met the definition of biased

4 toxicities in a results table or within the abstract, with worst offenders being those trials with a positive efficacy end point. Industry sponsorship of a trial was not associated with biased efficacy or toxicity reporting. With the extraordinary resources utilized to conduct Phase III RCTs— multi-institution collaboration for trial design and execution, significant financial costs, large research-specific and patient care personnel, and the precious lives of the hundreds to thousands of patients who willingly enroll in each trial—it is no wonder that clinical investigators, deeply invested from the moment of study conception to the time of final data analysis and manuscript preparation, will highlight the positive findings and minimize the negative results. Reporting as such reflects our human nature and not necessarily a

malicious motive to deceive. The major strength of this study is that in its final analysis, it was a comprehensive evaluation of the data reporting of 164 RCTs. Trials were selected based on pre-specified criteria that each was a large (>200 subjects), contemporary (1995-2011), potentially practice-changing, Phase III RCT in breast cancer. There are some issues with the study methodology, however, a few of which the authors acknowledge. For example, the algorithms used to define bias in the reporting of both efficacy end points and toxicity were created by the study investigators and have not been validated. Some of the outcomes measured were subjective. Notably, the efficacy and toxicity reporting data extraction from the 164 RCTs was conducted by two of the study authors, but not reviewed and confirmed by a single (unbiased) investigator independent of the study team. There was also no mention of the percentage agreement between the two investigators’ data sets or the method

used to resolve disagreements. Despite these flaws, their efforts are commendable because they address the extremely important issue of data quality and reporting integrity in published RCTs. They remind us that we must take pause and read critically, discern facts from interpretation, recognize relevant missing data, and ultimately draw our own conclusions about efficacy and toxicity for a given therapy. This article is also a call to action for the scientific community to continue to raise the bar for peer review and publication standards. The trial reporting guidelines set forth in the Consolidated Standards of Reporting Trials (CONSORT) statement1 and mandatory trial registry on clinicaltrials.gov are steps in the right direction.

Reference 1. www.consort-statement.org.

Dr. Haddad reported no relevant conflicts of interest.

Send us your news Clinical Oncology News appreciates news tips and suggestions for coverage from readers. All submissions will be considered for publication.

Write to managing editor Gabriel Miller at gmiller@mcmahonmed.com

CURRENT PRACTICE

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Palliative Care Misunderstandings ‘Astonishingly High’ Majority of patients do not understand purpose of palliative treatments

wo recent studies have revealed that between 60% and 80% of patients receiving palliative therapy with radiation or chemotherapy for incurable cancer do not understand that the intent of the treatment is palliative, not cure. The studies highlight a communication chasm between doctors and patients, but oncologists say it is unclear who is to blame. The gap surprised some clinicians.

IV lung cancer who had received palliative radiation therapy. Aileen Chen, MD, MPP, a radiation oncologist at Brigham and Women’s Hospital and Dana-Farber Cancer Institute in Boston, who presented the study, pointed out that stage IIIB with malignant effusion is now considered stage IV by the American Joint Committee on Cancer. Researchers analyzed answers to the same question used in the

‘The rates, to me, were astonishingly high. I didn’t expect it to be zero, but based on prior, smaller studies, I expected it to be more like one-third of the patients.’ —Jane Weeks, MD “The rates, to me, were astonishingly high. I didn’t expect it to be zero, but based on prior, smaller studies, I expected it to be more like one-third of the patients,” said Jane Weeks, MD, an oncologist at Dana-Farber Cancer Institute in Boston, who was involved with both investigations. Both studies relied on data gathered between 2003 and 2005 from CanCORS (Cancer Care Outcomes Research and Surveillance Consortium), a multicenter prospective cohort study of patients with lung or colorectal cancers (CRC). The Consortium includes 15 Veterans Affairs facilities and five large health maintenance organizations in five geographic regions of the United States—northern California, Los Angeles County, North Carolina, Iowa and Alabama. In the study led by Dr. Weeks, reported in The New England Journal of Medicine (NEJM 2012;367:1616-1625, PMID: 23094723), researchers analyzed survey data from 1,193 patients in CanCORS who received chemotherapy for newly diagnosed metastatic lung cancer or CRC. Responses were evaluated based on the following three-part question: After talking with your doctors about chemotherapy, how likely did you think it was that chemotherapy would (a) help you live longer, (b) help you with problems you were having from cancer or (c) cure your cancer? Respondents could answer one of five ways: very likely, somewhat likely, a little likely, not at all likely, or don’t know/ refuse to answer. Overall, 69% of patients with lung cancer and 81% of patients with CRC said they did not understand that chemotherapy was not at all likely to cure their cancer. In a second study, reported at the 2012 annual meeting of the American Society for Radiation Oncology (ASTRO; abstract 4), investigators analyzed survey data from 384 patients diagnosed with stage IIIB with malignant effusion or stage

NEJM study, but with the word radiation substituted for chemotherapy. The researchers found that 64% of patients did not understand that radiation was not at all likely to cure their disease. Nonwhites were more likely to believe that radiation might be curative (blacks, odds ratio [OR], 1.5; other nonwhites, OR, 3.3). Of the 384 patients, 70% were white and 14% were black. Additionally, older patients were more likely to have inaccurate beliefs, and patients whose surveys were completed by surrogates were less likely to have inaccurate beliefs. The communication disconnect can cause several problems. “Patients with unrealistic expectations are less able to make informed decisions about end-oflife care and may therefore pursue more intensive therapies,” said Dr. Chen. Dr. Weeks pointed out that studies show that when end-of-life discussions happen early, patients have a better quality of life, are less likely to receive futile medical care and are more likely to die at home, if that is their desire. Patients who don’t understand their true prognosis also may delay getting their affairs in order. The researchers admitted that the studies were limited because they did not ascertain the underlying reasons for patients’ expectations. According to

Robert Arnold, MD, the chief of Palliative Care and Medical Ethics at the University of Pittsburgh School of Medicine, the problem with these types of studies is that they “often don’t distinguish between what people think and how they came to that thinking. “Is the problem that the patient didn’t hear what the doctor said, the doctor didn’t say it, or is the problem that the doctor said it and the patient heard it, but they don’t sort of believe it. I may have heard the doctor say ‘this is what happens to most people,’ but I don’t think I’m most people. I am way better than most people,’” said Dr. Arnold. “I think we need to try to be clear about

and they don’t come back to it later in time,” she said. “They don’t reinforce that message, and they allow the patient to slip into thinking that chemotherapy might be curative.” She said another problem could be the use of ambiguous language. “The physician will talk about having a wonderful response to chemotherapy and that is actually quite a technical term that means tumor shrinkage. It doesn’t mean cure,” explained Dr. Weeks. “But somebody who isn’t trained in medical oncology would hear that and say ‘I’m being cured.’ If a physician doesn’t make a point of being clearer and reinforcing what is really happening, it is not hard to understand how the misunderstanding develops.” David Hui, MD, an assistant professor in the Department of Palliative Care and Rehabilitation Medicine at the University of Texas MD Anderson Cancer Center in Houston, believes the two CanCORS studies are more representative of what is going on in the community setting than other smaller studies that have shown the communication regarding palliative therapy is not that bad. He pointed out that given the high prevalence of gaps in communication, oncologists should routinely assess patients’ understanding. “A good way to start is to ask patients,

Studies show that when end-of-life discussions happen early, patients have a better quality of life, are less likely to receive futile medical care and are more likely to die at home, if that is their desire. where the communication breaks down, and the problem is we don’t know.” If an oncologist discovers that a patient doesn’t agree with what he or she said, action should be taken. “In that case, we can say, ‘I see you are really hoping it gets better, and I wonder if you are willing to think about if it doesn’t get better,’” suggested Dr. Arnold. He said studies have shown that when doctors present things in a positive framework, patients are less likely to hear bad news. If a doctor says, “I can’t cure it, but there is a lot we can do,” then patients spend time focusing on the “lot we can do” and are less likely to hear the bad news. Dr. Weeks thinks a major factor contributing to the communication gap is that doctors are stating the facts, but not reinforcing them. “My strong hunch is that the oncologist tells the patient at the time they are initially discussing chemotherapy that it is not going to be curative, but that they don’t dwell on it

‘What is your understanding of your illness? Based on what we discussed earlier, what do you think we can achieve with this treatment?’” said Dr. Hui. “Understanding whether the treatment is of a curative nature or not is important because patients make decisions based on the perceived benefit.” Dr. Arnold said that researchers should launch studies to identify the root of the problem. “The problem with both of those studies is that they tell you what the patient heard. They don’t tell you what was said or what did the doctor think they were saying,” he said. “Part of what you have to do is triangulate all three pieces of information. These studies tell us there is a problem. What the solution is to the problem, how to fix that problem … [we] don’t know that. If you don’t know what happened in the black box, you don’t know what to change.” —Kate O’Rourke

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Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Beta-Blockers Improve Survival in Patients with NSCLC From Annals of Oncology

ncidental use of beta-blockers in patients with non-small cell lung cancer (NSCLC) improved distant metastasis–free survival (DMFS), disease-free survival (DFS) and overall survival (OS). Inoperable NSCLC is treated currently with a regimen of chemotherapy or radiation therapy (RT), but the prognosis remains poor, with a five-year OS of about 15%. H.M. Wang, MD, PhD, and colleagues analyzed the records of patients with NSCLC who were treated with definitive RT with or without

concurrent chemotherapy at MD Anderson Cancer Center between 1998 and 2010; results were reported in Annals of Oncology (2013 Jan 8. [Epub ahead of print], PMID: 23300016). Records from 722 patients were analyzed. All patients received an RT dose of at least 60 Gy, had no history of other cancers and had not been enrolled in study protocols. Patients with incomplete medication records were excluded. The final study population included 155 patients who had incidental use of beta-blockers, primarily for hypertension (n=105; 68%) or non-hypertensive

EXPERT INSIGHT Steven E. Schild, MD Chair, Department of Radiation Oncology, Mayo Clinic Arizona

his retrospective study explored the association between the use of beta-blockers and the outcome of patients treated with definitive radiotherapy for NSCLC. The data for this analysis was prospectively gathered at MD Anderson in their clinical database. The outcomes were evaluated using both univariate and multivariate methodologies. The authors found that three end points (DMFS, DFS and

OS) were significantly associated with the use of beta-blockers. These findings are important for a multitude of reasons, but mainly because the survival of these patients is generally poor and beta-blockers appear to potentially improve patient outcome. Additionally, beta-blockers are not particularly expensive or toxic. Thus, the costs of integrating these findings into current practice would

disorders such as coronary heart disease (n=50; 32%); the remaining 567 patients did not use beta-blockers. Other studies have shown a positive correlation between use of betablockers and anti-tumor activity and extended survival time. Researchers have hypothesized that beta-blockers reduced the rate of disease progression by blocking the growth and preventing the development of micrometastases. After adjusting for several variables, including age, clinical factors, disease stage, treatment profile and aspirin use, the use of beta-blockers was associated

with better DMFS, DFS and OS. Use of beta-blockers did not show any improvement in locoregional progression-free survival (LRPFS). The authors suggested that beta-blockers may be affecting the tumor metastatic cascade rather than the primary tumor, which may explain their results. Information about the duration and timing of beta-blocker use was not studied. Nevertheless, the promising results from this retrospective study of a large cohort of patients with NSCLC provide further evidence for the possible treatment benefit of beta-blocker medications.

Beta-blockers are not particularly expensive or toxic. Thus, the costs of integrating these findings into current practice would be quite modest compared to other new therapeutic options. be quite modest compared to other new therapeutic options. The authors did not go one step further and search for associations between toxicity and beta-blocker use. This potential analysis would have broadened the findings to possibly reveal an improvement in overall therapeutic index associated with this therapy. The analysis does have drawbacks, as do all retrospective studies. There may have been uncontrolled biases included. One drawback, which was

pointed out by the authors, included the statistically significant association between lower stage and beta-blocker use. However, multivariate methodology can help adjust for this in assessing the relationships. The authors point out that prospective trials are needed to prove that beta-blockers can actually enhance the outcome of patients irradiated for NSCLC.

Dr. Schild reported no relevant conflicts of interest.

by the

numbers The Costs of Febrile Neutropenia

eutropenia ranks among the most common and potentially severe side effects of cancer treatment. A recent study has provided estimates for the costs of febrile neutropenia–related hospitalizations in cancer patients. The data was derived from a retrospective cohort study using 2007-2010 hospital discharge data from the Premier healthcare alliance database, one of the largest hospital databases in the United States. The study population included adult patients with febrile neutropenia and either female breast cancer, lung cancer, colorectal cancer, ovarian cancer, non-Hodgkin lymphoma or Hodgkin lymphoma. The study was presented at the 2012 annual meeting of the American Society of Hematology (abstract 239).

Tumor Type

Average Length of Hospital Stay in days (95% CI)

All tumor types

16,273

8.6 (8.5–8.8)

$18,880 ($18,479–$19,281)

Female breast cancer

3,279

5.9 (5.7–6.1)

$11,132 ($10,649–$11,615)

Lung cancer

4,792

8.4 (8.2–8.7)

$17,689 ($17,129–$18,249)

Ovarian cancer

754

9.0 (8.2–9.7)

$18,958 ($17,000–$20,917)

Colorectal cancer

1,542

9.6 (9.0–10.1)

$19,667 ($18,365–$20,969)

Hodgkin lymphoma

469

8.6 (7.6–9.6)

$20,622 ($17,746–$23,498)

Non-Hodgkin lymphoma

5,437

10.1 (9.8–10.4)

$24,219 ($23,328–$25,109)

Average Hospitalization Cost in 2010 Dollars (95% CI)

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Clinical Oncology News â&#x20AC;˘ April 2013 â&#x20AC;˘ CLINICALONCOLOGY.COM

Curing Follicular Lymphoma with Stem Cell Transplantation From Annals of Oncology

ong-term follow-up of patients with disseminated follicular lymphoma (FL) can be difficult, which has led to uncertainty as to what extent high-dose therapy (HDT) with autologous stem cell transplantation (ASCT) is curative. A recent part-prospective, part-retrospective study has concluded that longterm clinical and molecular remissions are achievable using ASCT in patients with FL. Bernd Metzner, MD, and colleagues from Klinikum Oldenburg in Oldenburg,

Germany, collected data from 60 consecutive patients with advanced-stage FL who were treated between 1995 and 2012. Patients were grouped into one of three categories: ASCT with total body irradiation and cyclophosphamide given as first-line treatment (n=18); second-line ASCT with high-dose BEAM (i.e., BCNU [carmustine], etoposide, cytarabine and melphalan) chemotherapy (n=34); and third-line or greater ASCT with BEAM (n=8) chemotherapy. Results were published in Annals of Oncology (2013 Feb 7 [Epub ahead of print], PMID 23393125).

EXPERT INSIGHT Stephen Ansell, MD, PhD Hematologist, Mayo Clinic

L is an indolent B-cell malignancy that commonly responds to treatment and may be associated with a prolonged disease course. Responses to treatment often are quite durable; however, the disease, unfortunately, is not curable for most patients when standard chemotherapy is used. Although allogeneic stem cell transplantation provides a potential curative option for some patients with FL, it may not be feasible for all patients due to potential toxicities and lack of an appropriate donor. For most patients, therapies that potentially result in a long disease-free interval are attractive, provided the toxicities are manageable. In this regard, high-dose chemotherapy followed by ASCT is an appropriate therapeutic approach for FL, with very durable long-term remissions seen in a subset of patients. A recent article by Metzner et al describes the long-term clinical and molecular remissions seen in patients with FL treated with HDT and ASCT. The authors specifically highlight the durable remissions seen particularly in second-line patients who received BEAM conditioning therapy, and note that in a cohort of 60 patients analyzed at their institution, no relapses occurred

after six years following ASCT. They further note that a favorable outcome after stem cell transplant was seen in patients with low FL International Prognostic Index (FLIPI) scores; patients who had the stem cell transplant early in their disease course; and patients who had no residual disease post-transplant as determined by molecular methods. This study confirmed previous findings from both single-center studies and registry data that show that patients with a favorable prognostic profile, as well as patients who receive a chemotherapy-only conditioning regimen, have a better long-term outcome after ASCT. These previous studies also highlighted the importance of the patientâ&#x20AC;&#x2122;s age, with younger patients doing significantly better than older patients in terms of PFS and OS. In the study by Metzner et al, predominantly younger patients were analyzed and this may account in part for the favorable results. The median age of patients in the study was 48 years when patients had ASCT in first line, and 52 and 56 years, respectively, when they had an ASCT in second or third line. The inclusion of younger patients who were in good health and able to proceed to an aggressive treatment approach may have resulted in

This study is valuable because it includes long-range follow-up of patients treated at a single institution, although some patients were included in clinical trials with slightly different treatment regimens. Blood tests were performed in those patients achieving remission greater than six years (n=17) to assess for the presence of residual disease at a molecular level. Sustained clinical and molecular remissions were demonstrated in 16 patients for periods up to 17.5 years. There are 41 surviving patients in this study: Twenty-nine relapses occurred in the 60 patients. Long-term survival has

been best among those who were treated with first-line ASCT (n=9; median 9.1 years, range 5.6-15.5 years) or secondline ASCT (n=7; median 9.6 years, range 6.0-17.3 years). One patient treated with ASCT as fourth-line therapy is at followup, totaling 11.0 years. The 10-year overall survival (OS), progression-free survival (PFS) and freedom from progression for the first-line group were 79%, 57% and 64%, respectively; for the second line group, these were 41%, 35% and 42%, respectively. There was no treatment-related mortality of the ASCT in this group.

Although it is tempting to consider an aggressive approach for patients who have high-risk disease, the longer-term data suggest that these patients are at significant risk for disease relapse and may not have a favorable outcome even when treated aggressively. a degree of patient selection in which only patients with a favorable prognosis underwent this therapy and hence had a good outcome. This study also highlights the challenges in managing patients with FL, particularly when aggressive approaches such as HDT and ASCT are considered. Many patients eligible for this more aggressive approach are younger and hence are expected to have a better outcome with most therapies. The average age, however, for patients with FL commonly is far older than that of the patients in this study and many patients are not considered or eligible for ASCT. Also, as outlined in the study, patients with a favorable FLIPI score typically do well with many therapies including ASCT. These low-risk patients may do equally well when treated with lessintensive therapy. Furthermore, patients commonly have the greatest and most durable benefit from the earliest lines of therapy. As shown in this study, patients who received ASCT as part of front-line therapy had the best outcome. Again, the favorable outcome may be similar to that seen with any initial therapy, as the frontline randomized controlled trial comparing chemotherapy to ASCT (which included some of the

patients reported in this study) did not show a benefit for ASCT as part of initial treatment. In contrast, there is a survival benefit for patients treated with an ASCT as second-line therapy based on the results of a randomized trial showing that patients receiving an ASCT had a superior outcome when compared with those receiving chemotherapy. The greatest challenges in FL management, however, are the patients who seem to have a poor outcome despite the choice of therapy, including aggressive approaches such as an ASCT. These include patients with poor-risk disease as defined by high FLIPI scores, those who have chemo-resistant disease or patients who are old and frail. Although it is tempting to consider an aggressive approach for patients who have high-risk disease, the longer-term data suggest that these patients are at significant risk for disease relapse and may not have a favorable outcome even when treated aggressively. To attain durable, long-term clinical and molecular remissions in these patients, alternative approaches will need to be explored. Dr. Ansell reported no relevant conflicts of interest.

SOLID TUMORS

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Study Sets Stage for Standard-of-Care Change For breast cancer, 50 Gy course difficult to justify in light of new data San Antonio—A British trial has concluded that the standard of care for women requiring adjuvant radiotherapy for early breast cancer should be 40 Gy in 15 fractions for three weeks instead of 50 Gy in 25 fractions for five weeks, which is the regimen most oncologists use in the United States. This news comes from results of the United Kingdom START trials (Standardization of Breast Radiotherapy Trials) reported at the 2012 San Antonio Breast Cancer Symposium (SABCS; S4-1). “A lower total dose delivered in fewer visits to the hospital over a shorter time can be gentler on the normal tissues and noninferior in terms of local tumor control,” said John Yarnold, MBBS, a professor of clinical oncology at the Institute of Cancer Research in London, who presented the study. START, which consisted of two trials, included women with completely excised invasive, T1-3, N0-1, nonmetastatic breast cancer. START trial A was an “explanatory design” that allowed for an “unconfounded direct estimate of the sensitivity of both normal tissues and the breast cancer to the size of the fractions.” Trial B was pragmatic. Trial A randomized 2,236 patients to receive five weeks of treatment with either 50 Gy in 25 fractions (2.0 Gy), 39.0 Gy in 13 fractions (3.0 Gy), or 41.6 Gy in 13 fractions (3.2 Gy). At 10 years, the 41.6- and 50-Gy arms were comparable in terms of locoregional tumor relapse and late-occurring adverse events (AEs). AEs were lowest in patients receiving 39 Gy. Dr. Yarnold pointed out, however,

that a five-week regimen is not convenient for patients, and thus the pragmatic START trial B is of greater interest to practicing clinicians. START trial B randomized 2,215 patients to 50 Gy in 25 fractions (2.0 Gy) for five weeks or 40 Gy in 15 fractions (2.67 Gy) for three weeks. The majority of patients had small tumors (Table). At 10 years, the 40-Gy group was noninferior in terms of rate of locoregional tumor relapse and was superior in terms of percentage of patients free of AEs (hazard ratio, 0.77; 95% confidence interval, 0.66-0.89).

Kimmel Comprehensive Cancer Center at Johns Hopkins University in Baltimore, said Hopkins started using the Canadian radiation regimen roughly four years ago when the data was presented at the 2007 SABCS. According to Dr. Zellars, there is “no real meaningful difference” between the START trial B and Canadian regimens, and although some academic centers have switched over to the Canadian regimen, most community oncologists have continued to use 50 Gy for a number of reasons. First, change is difficult. Second, an exploratory, sub-

‘A lower total dose delivered in fewer visits to the hospital over a shorter time can be gentler on the normal tissues and noninferior in terms of local tumor control.’

—John Yarnold, MBBS

Dr. Yarnold said that 40 Gy in 15 fractions for three weeks has been the standard in the United Kingdom for all patients with invasive breast cancer since 2009. He suggested U.S. clinicians might want to consider adopting the regimen. Some academic oncologists actually started using a shorter regimen of 42.5 Gy in 16 fractions over a period of 22 days, after a Canadian study showed this was comparable (N Engl J Med 2010;362:513-520, PMID: 20147717). Richard Zellars, MD, an associate professor of radiation oncology and molecular radiation sciences at the Sidney

set analysis of the Canadian study suggested that women with high-grade disease do better with longer rather than shorter radiation courses. Third, radiation oncologists are reluctant to use large fraction sizes because of fear of late complications, particularly cardiac complications in women with leftsided breast cancer. Additionally, studies that have shown a benefit of using a boost have been conducted using the 50-Gy regimen, and thus oncologists are in the dark about whether to recommend a boost if they use the shorter regimen. Finally, there is a financial reason: Oncologists make more money

Artificial Intelligence Comes to Cancer Care IBM’s Watson advises clinicians on treatment decisions

wo years after beating human champions on “Jeopardy!,” the cognitive computing system IBM Watson is ready for a new challenge: advising clinicians on the treatment of cancer. Announced on Feb. 8 by partners IBM, WellPoint, Inc., and Memorial SloanKettering Cancer Center, the new venture is one of the first commercially developed Watson-based products. Also announced at the same time is a set of utilization management tools to streamline the review process between patients’ physicians and health plans. Using advances in natural language processing and analytics, Watson is able to process information in a way similar to how people think, according to a press release from the partners. Since

its appearance on “Jeopardy!,” Watson has improved by 240% in system performance. The Watson product in oncology, called Interactive Care Insights for Oncology, provides a Watsonbased advisor, accessible through the cloud, that is intended to help identify individualized treatment options for patients with cancer, starting with lung cancer, according to the press release. In principle, oncologists anywhere will be able to access detailed treatment options to help them decide how best to care for a patient. To prepare for its work in oncology, Watson has taken in more than 600,000 pieces of medical evidence, and 2 million pages of text from 42 medical

journals and clinical trials, the press release states. Watson is able to search through 1.5 million patient records and provide physicians with evidence-based treatment options in seconds. In less than a year, Memorial SloanKettering in New York City has immersed Watson in the complexities of cancer and genetic research. Starting with 1,500 lung cancer cases, the medical center’s clinicians and analysts are training Watson to extract and interpret physician notes, lab results and clinical research, while sharing their expertise and experiences in treating patients with cancer. “It can take years for the latest developments in oncology to reach all practice settings. The combination of

Table. Patient Characteristics in START Trial B Patients, % BCS

Tumor size <2 cm 2-3 cm 3+ cm

64 26 10

Grade 3

Node positive

Breast boost (BCS patients)

Lymphatic radiation

Chemotherapy

Tamoxifen

BCS, breast-conserving surgery

giving 25 fractions instead of 15. START discounts two of these reasons. The trial did not find any difference in outcome by tumor grade or any increase in cardiac events in patients with left-sided breast cancer. “The community physicians have hung onto the 50-Gy course, but I think it will be difficult to justify that now for the majority of patients,” said Dr. Zellars. —Kate O’Rourke Drs. Yarnold and Zellars had no relevant disclosures.

transformational technologies found in Watson with our cancer analytics and decision-making process has the potential to revolutionize the accessibility of information for the treatment of cancer in communities across the country and around the world,” Craig B. Thompson, MD, the president and CEO of Memorial Sloan-Kettering Cancer Center, said in a statement. “Ultimately, we expect this comprehensive, evidence-based approach will profoundly enhance cancer care by accelerating the dissemination of practice-changing research at an unprecedented pace.” The Maine Center for Cancer Medicine, with headquarters in Scarborough, and WESTMED Medical Group in Purchase, N.Y., are the first two adopters of an application based on Watson’s cognitive computing used to help diagnose lung cancer and recommend treatment. —George Ochoa

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Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Adding Chemotherapy After Breast Cancer Recurrence CALOR provides support for controversial, common treatment San Antonio—In patients with completely resected locoregional recurrent breast cancer, adjuvant chemotherapy reduced the risk for disease-free survival events by 41%, according to results from the CALOR (Chemotherapy as Adjuvant Therapy for Locally or Recurrent Breast Cancer) trial. The study, reported at the recent San Antonio Breast Cancer Symposium (abstract S3-2), also found that adjuvant chemotherapy reduced the risk for death by 59%. “Adjuvant chemotherapy should be recommended for patients with completely resected, isolated local or regional recurrence of breast cancer,” said Stefan Aebi, MD, head of the Division of Medical Oncology at Luzerner Kantonsspital in Luzern, Switzerland, who presented the study. “The evidence is strongest for ER [estrogen receptor]negative recurrences.” Because women with isolated local and/or regional recurrence of their breast cancers are at high risk for developing metastases after complete resection, some clinicians offer chemotherapy after surgery. The effectiveness of this tactic, however, has been controversial because there has been no evidence to support the practice until now. CALOR was an international collaboration of the Breast International Group, the National Surgical Adjuvant Breast and Bowel Project and the International Breast Cancer Study Group. The trial included patients with first ipsilateral local and/or regional recurrence, complete gross excision of recurrence, no evidence of supraclavicular lymph nodes and no evidence of metastasis. The investigators had originally hoped to enroll

977 women, but because of difficulties in accruing patients, the trial was amended, and the final sample size was 85 patients who received chemotherapy and 77 who did not. Patients could receive other standard therapies, such as endocrine therapy and HER2-directed therapy. Radiation was recommended for all patients and mandatory for those with microscopically involved margins. The chemotherapy regimen was left to the investigators’ discretion with a recommendation to provide at least two drugs for three to six months of therapy.

OS (94% vs. 80%; P=0.87). Breast cancer clinicians say the study is important. “I have previously offered chemotherapy in the adjuvant setting to patients who have a locoregional recurrence, and will continue to do so with more confidence that these patients, particularly in the triple-negative subgroup, derive benefit,” said Maura Dickler, MD, an associate attending physician in the Breast Cancer Medicine Service at Memorial Sloan-Kettering Cancer Center in New York City, who was not involved with the study. “As this was a subset anal-

‘I have previously offered chemotherapy in the adjuvant setting to patients who have a locoregional recurrence, and will continue to do so with more confidence that these patients, particularly in the triple-negative subgroup, derive benefit.’

—Maura Dickler, MD

At five years, the disease-free survival (DFS) rate was higher in patients receiving chemotherapy (69% vs. 57%; hazard ratio [HR], 0.59; P=0.045) and this pattern also was true for overall survival (OS; 88% vs. 76%; HR, 0.41; P=0.02). A subset analysis showed that at five years, the DFS rate in patients with ER-negative breast cancer was 67% in those who received chemotherapy compared with 35% in those who did not (P=0.007). In this subset of women, OS rates also were higher in patients who received chemotherapy (79% vs. 69%; P=0.12). In the ERpositive subset of women, those receiving chemotherapy also had improved rates of DFS (70% vs. 69%; P=0.87) and

ysis in a trial that did not meet its accrual goals, I will not use receptor status as the deciding factor to guide adjuvant therapy in these patients.” Robin Zon, MD, the principal investigator of the Northern Indiana Cancer Research Consortium Community Clinical Oncology Program (NICRC-CCOP) and vice president at Michiana Hematology-Oncology, in South Bend, Ind., said the standard in the community has been to provide some form of systemic therapy option when local recurrences occur; and based on the characteristics of the tumor, therapies are preferentially hormonal agents and, especially for hormone-negative tumors, chemotherapy.

A graphic representation of breast cancer, with a malignant tumor in red.

However, she said, clinicians have been aware of the limited data supporting the use of chemotherapy and have disclosed this to patients. “This information now allows us to share with patients research-based evidence for our recommendations,” said Dr. Zon. “I agree with the conclusion citing the appropriateness of chemotherapy in hormone-insensitive tumors. This study allows the clinician to be able to refer to data supporting this recommendation to patients as a way to improve outcomes beyond removal of the isolated recurrence. This will be especially helpful for patients who would ordinarily shy away from systemic therapy. This is also particularly important as cost issues arise, including coverage determinations by payers. The results of this study should be accepted by payers supporting coverage for treatment.” —Kate O’Rourke Drs. Aebi and Zon have no relevant disclosures. Dr. Dickler has served as a consultant for Genentech.

by the

numbers Leukemia Risk After Breast Cancer

or years, researchers have known that topoisomerase-targeting agents and DNA-damaging alkylating agents can cause myelodysplastic syndrome (MDS) and acute myelogenous leukemia (AML). Now a new study has quantified the risk for breast cancer patients developing leukemia, including MDS, after treatment. The study was reported at the San Antonio Breast Cancer Symposium by Antonio Wolff, MD, an oncologist at Johns Hopkins Kimmel Cancer Center in Baltimore (abstract S3-5). The researchers analyzed data collected between July 1997 and December 2008 from the National Comprehensive Cancer Network Breast Cancer Database. In a population of 20,533 breast cancer patients without prior cancer, overall, there was a 0.25% incidence of leukemia five years after a breast cancer diagnosis and a 0.46% incidence of leukemia at 10 years out (Table). “About half of the events occurred beyond five years,” said Dr. Wolff, who pointed out that the incidence is higher than previously reported. “Radiation alone appears to be a risk factor, but may not add much to patients already treated with chemotherapy.”

Table. Cumulative Incidence of Leukemia in Breast Cancer Patients Treatment

5-Year Incidence, %

10-Year Incidence, %

All

0.25

0.46

Surgery

0.05

0.2

Radiation

0.19

0.44

Chemotherapy

0.30

0.52

Chemotherapy/Radiation

0.32

0.51

SOLID TUMORS

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FACE OFF continued from page 1 

General Hospital in Boston, at the San Antonio Breast Cancer Symposium (abstract S1-9). The ATAC trial 10-year follow-up data demonstrated that late disease recurrence is a hallmark of estrogen receptor (ER)-positive breast cancer, with greater than 50% of recurrences occurring after five years of adjuvant tamoxifen or anastrozole therapy. TransATAC collected tumor blocks for biomarker assessment. Previous analyses have shown that RS and IHC4 (ER, progesterone receptor, HER2 and Ki67) predict overall recurrence risk in the TransATAC cohort, beyond the Clinical Treatment Score (CTS), an algorithm consisting of nodal status, tumor size and grade, age and treatment. In the new TransATAC study, researchers evaluated whether BCI adds prognostic information to clinical variables in predicting distant recurrence in ER-positive, lymph node–negative patients with primary breast cancer. The test stratifies patients into three risk groups and combines two independently developed biomarkers: HOXB13:IL17BR gene expression ratio, which is both prognostic and predictive for extended adjuvant hormone therapy, and the molecular grade index, a set of cell cycle–related genes

that predicts distant recurrence beyond tumor grade. The study cohort included 665 primary tumor samples. At 10 years of follow-up, BCI distinguished three risk groups with a 10-year rate of distant recurrence of 4.2% in the low-risk group, 18.3% in intermediate-risk patients and 30% in the highrisk group. “In analyzing the comparative prognostic performance over the same time frame [0 to 10 years], one sees that BCI, IHC4 and the recurrence score demonstrate highly significant prognostic performance,” said Dr. Sgroi. “BCI and IHC4 provided equivalent prognostic information and both biomarkers provide greater prognostic information than the recurrence score.” Dr. Sgroi said recurrence information is valuable in two time frames. The early recurrence time frame is at diagnosis, when one is considering using adjuvant hormone therapy alone or in combination with other systemic therapy. The late recurrence time frame is at five years postdiagnosis, when one is considering extending adjuvant therapy for patients who are disease-free after five years of hormonal therapy. BCI identified two early recurrence risk groups. The first group, 83% of the cohort, consisted of BCI low- and intermediate-risk patients who had an average five-year rate of distant recurrence of less than 4%. The second group consisted

Table 1. Multivariate Analysis of Comparative Prognostic Performance: Early Recurrence (Years 0-5) Likelihood Ratio Statistic

P Value

Breast Cancer Index

15.4

<0.0001

IHC4

28.8

<0.0001

Recurrence Score

18.2

<0.0001

Table 2. Multivariate Analysis of Comparative Prognostic Performance: Late Recurrence (Years 5-10) Likelihood Ratio Statistic

P Value

Breast Cancer Index

0.0005

IHC4

1.6

0.2

Recurrence Score

0.5

of BCI high-risk patients with a five-year rate of distant recurrence of 18.1%. BCI identified two late recurrence risk groups. The first, 61% of the cohort, consisted of BCI low-risk patients who had a five-year rate of distant recurrence of 3.5%. The second group consisted of intermediate-/high-risk patients who had an average rate of distant recurrence of 13.5%. BCI was a significant prognostic factor beyond CTS for prediction of late distant recurrences (Tables 1 and 2).

‘In the early recurrence time frame, all three biomarkers demonstrate highly significant prognostic performance in a multivariate analysis adjusted for the Clinical Treatment Score. However, when we compared the performance in the late recurrence time frame … BCI demonstrates sustained prognostic performance in a multivariate analysis, whereas IHC4 and the RS lose their prognostic ability.’ —Dennis Sgroi, MD

“In the early recurrence time frame, all three biomarkers demonstrate highly significant prognostic performance in a multivariate analysis adjusted for the Clinical Treatment Score,” said Dr. Sgroi. “However, when we compared the performance in the late recurrence time frame. … BCI demonstrates sustained prognostic performance in a multivariate analysis, whereas IHC4 and the RS lose their prognostic ability.” A patient with an intermediate BCI score will do well in the first five years with adjuvant hormone therapy, Dr. Sgroi said, but should be considered for extended adjuvant therapy at that point. Mathew Goetz, MD, a medical oncologist and an associate professor of oncology and pharmacology at Mayo Clinic in Rochester, Minn., said the three tests provide different information, with BCI providing “better information in years 5 through 10.” He said the test has been validated in multiple data sets, including the MA.17 trial. From a clinician standpoint, he continued, the lymph node– negative, ER-positive patients are the ones in whom clinicians are least likely to use extended adjuvant hormone therapy, and identifying a high-risk subset in this group in years five through 10 is novel. “I would consider using this test in lymph node–negative, ER-positive patients that have completed five years of tamoxifen,” said Dr. Goetz. He pointed out, however, that many community oncologists are using aromatase inhibitors earlier on, and studies have not defined the benefit of extending aromatase inhibitor therapy in this group. “If we have additional data demonstrating that 10 versus five years of aromatase inhibitors is beneficial, this will really extend the potential ability of this test at that point,” he said. —Kate O’Rourke Drs. Sgroi and Goetz have no relevant disclosures.

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With Changing Treatments, New Liability Risks Oral chemo agents demand a new approach to working with specialty pharmacies

s a physician, Lori Meyerhoffer, MD, JD, knows the problems that can arise when a patient takes oral treatment at home and there is a split in responsibilities between the pharmacist and the prescribing physician. “Every time you put things outside the physician’s office and the physician’s control, even in the hands of trained health care professionals who are not physicians, I think you increase the risk for not knowing an adverse outcome earlier,” she said. And as an attorney at the firm Yates, McLamb and Weyher in Raleigh, N.C., who specializes in malpractice claims, Dr. Meyerhoffer knows that these problems often end in lawsuits. “The further removed the physician is from that tangible interaction, the more likely that something will go wrong, and I don’t think the physician can escape potential liability,” she said.

Pressures from payers and manufacturers force oncologists into an arranged, and not always happy, marriage with specialty pharmacies. Until recently, oncologists avoided such problems because the patient went to the oncology office for most facets of care. “Oncology has always been set up as having a very robust infrastructure with these checks and balances. We have all this certain stuff in place because with IV chemo they get it here, they are able to talk with the nurses, communicate about adverse effects,” said Anthony Jarkowski, PharmD, a clinical pharmacy specialist in hematology/oncology in Buffalo, N.Y. This clinic-centered model naturally controls liability risks. “The more times physicians can see a patient during active treatment, [the more] they can potentially lower their liability, just because they have more opportunity to have those discussions about adverse events with patients,” Dr. Meyerhoffer said. But changes in oncology practice are eroding the clinic-centered system. In the past decade, self-administered oral chemotherapy has become increasingly common, leaving doctors with fewer opportunities to counsel and monitor patients. “Now you are telling the patient to go home, so you are putting more of the onus on them. There are fewer of these controls and these checks and

balances in place,” Dr. Jarkowski said. These risks grow as a result of the increasingly fragmented system used to administer oral chemotherapy. Payers often will not cover oral chemotherapy unless physicians prescribe it through off-site specialty pharmacies that provide additional patient instruction and monitoring. It becomes more difficult to coordinate the care when treatment responsibilities splinter between the specialty pharmacy and the oncology office, said Dawn Holcombe, MBA, an oncology consultant who specializes in physician–payer negotiations. “If you just look at the treatment, there is a natural conflict between the two” because “they both are instructing patients,” Ms. Holcombe said. If something goes wrong, patients may sue. “I think liability would increase because we normally think of the hierarchy of the physicians at the top and everything flows beneath them,” said Dr. Meyerhoffer.

Financial Forces Push Oncologists and Specialty Pharmacies Together Oncologists have little choice but to work within this fragmented system. Because of distribution agreements with specialty pharmacies, payers will not cover drug costs unless oncologists prescribe them through designated specialty pharmacies. “The payer usually puts the caveat on it that in addition to getting this prior authorization, you must only buy it from this particular situation,” said Bonnie Kirschenbaum, MS, a health care consultant in Breckenridge, Colo., who specializes in pharmacy reimbursement issues. Because oral chemotherapy may cost hundreds of dollars per pill, most patients cannot afford treatment without prior authorization. “When drugs are expensive, as in $100,000 courses of therapy, you can bankrupt the patient’s family,” Ms. Kirschenbaum said. Payers use specialty pharmacies in part because they offer additional patient instruction and monitoring. “It’s hard for doctors. It’s a lot of resources to have a nurse, a pharmacist on staff who calls and reaches out to patients,” said Kim Farina, a pharmaceutical industry analyst in Houston. Specialty pharmacies can improve adherence rates. “I think one of the ‘pros’ of specialty pharmacy is that they really jump in there and offer patient education and adherence promotion programs,” said Ms. Farina. Additional monitoring can be especially valuable to small oncology clinics. “The community oncology office might derive the most benefit from the specialty pharmacy working

with them,” Dr. Jarkowski said. But payers also contract with specialty pharmacies to control costs. “First and foremost they can lower their cost site,” Dr. Jarkowski said. By distributing through specialty pharmacies, payers can contract lower prices and “reduce expenditures,” he said. When payers go through specialty pharmacies, they prevent physicians from charging administration fees. “It’s less expensive because there’s no visit to the infusion clinic, there’s no sitting in the infusion chair, there’s no payment for all the infusion drug administration fees,” Ms. Kirschenbaum said. Prior authorizations for oral chemotherapy give payers additional control over treatment and costs. Payers tell physicians “unless you’ve followed all the steps down this clinical pathway, I don’t think this is a good choice for this patient,” Ms. Kirschenbaum said. “Of course, what that payer is trying to do is to control spending on a very expensive drug.” Drug manufacturers also push oncologists to work with specialty pharmacies. Manufacturers sometimes distribute drugs through a closed network, which forces doctors to work with certain spe-

account with someone who they do 95% of their business with, and then they have to have another account open for the rare occasions where they need something that’s in these closed-distribution models.” Pressure from payers and manufacturers force oncologists into an arranged, and not always happy, marriage with specialty pharmacies. “From my experiences, they give you a limited choice,” Dr. Jarkowski said. “They say ‘we contracted with the employer of the patient’s insurance and they have to get all their specialty drugs at x, y or z.’” Oncologists often have to work within this strained partnership and confront its treatment challenges and heightened liability risks.

Problems Caused by Poor Communication and Care Coordination Working with off-site specialty pharmacies poses two basic challenges to oncologists: communication of patient information and coordination of treatment. Communication problems occur

‘I don’t know that the physician always is responsible for the patient, but I know that the plaintiff will always try to attach that liability to the physician because [the physician has] the deepest pockets, and they are the highest person on that totem pole.’

—Lori Meyerhoffer, MD, JD

cialty pharmacies or distribution networks. “If there’s a closed-distribution model, [the physician] has some wholesaler telling him he has to establish a new account before they let him get the drug,” Ms. Kirschenbaum said. She noted that this might force oncologists to work with unfamiliar specialty pharmacies. “They [oncologists] may have a regular

in both relaying patient information from the oncologist to the pharmacist, and then back to the physician. Because specialty pharmacies often do not have access to the patient’s full medical records, they must rely on oncologists to share information, a process that often is drawn out through a protracted see LIABILITY, page 28 

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Perspectives in Non-Hodgkin’s Lymphoma: Evolving Treatment Paradigms MM111 Release Date: August 22, 2012 Expiration Date: August 22, 2013 The goal of this activity is to provide hematologists-oncologists, medical oncologists, specialty nurses, and other relevant health care professionals with up-to-date, clinically useful information on the management of non-Hodgkin’s lymphoma. FACULTY • Julie M. Vose, MD, MBA, Nebraska Medical Center • John P. Leonard, MD, Weill Medical College of Cornell University • Jonathan W. Friedberg, MD, University of Rochester Medical Center

Perspectives on Breast and Ovarian Cancers: Integrating Data, Improving Outcomes

Cases and Conversations: Individualizing Therapy in Metastatic Breast Cancer MM112 Release Date: October 22, 2012 Expiration Date: October 22, 2013 The goal of this activity is to educate community oncologists on recent evidence in the individualized management of metastatic breast cancer. FACULTY • Linda T. Vahdat, MD, Weill Cornell Medical Center • Adam Brufsky, MD, PhD, University of Pittsburgh Cancer Institute • William J. Gradishar, MD, Northwestern University

MN122 Release Date: October 31, 2012 Expiration Date: October 31, 2013 The goal of this activity is to provide general oncologists with a concise summary of the most clinically important findings in breast and ovarian cancer research in the previous year. FACULTY • • • •

Stefan Glück, MD, PhD, FRCPS, University of Miami Ruth O’Regan, MD, Emory University Robert A. Burger, MD, Fox Chase Cancer Center Samer I. Schuman, MD, FACS, FACOG, University of Miami

CURRENT PRACTICE

LIABILITY continued from page 26 

series of phone calls or faxes. Some oncologists also feel reluctant to share patient information. “The most they will do is … give the bare information necessary to get the [prescription] filled,” Ms. Holcombe said. “A physician office will not give detailed clinical information about a patient or the patient’s treatment to the pharmacist because the pharmacist, in the eyes of the physician office, is merely an agent in impacting the shipping of the drug.” However, by withholding information from a pharmacist, the oncologist ultimately may be causing a negative effect on the patient. “We are seeing drug interactions that we are catching later because they [pharmacists] don’t have access to that information or they don’t know what the impact of the care is on that other medication,” Dr. Jarkowski said. Patient information does not always flow smoothly from pharmacists to oncologists either. Patients may make disclosures to the pharmacist, assuming that the pharmacist and oncologist are part of an integrated care team. If a patient discloses a side effect solely “to a nurse in a specialty pharmacy, who’s only trying to see that you take this pill or not, then you can see there is a potential for a severe disconnect related to the actual care of the patient,” Ms. Holcombe said. Coordination problems between the specialty pharmacy and the oncology office create further risks for error, including providing inconsistent advice that may lead to confusion for the patient. Treatment gaps may occur when an oncologist incorrectly assumes that a specialty pharmacy will provide a certain level of monitoring. “There are really good specialty programs out there, I don’t want to discount that,” Dr. Jarkowski said. “But then there are some that aren’t as good and that don’t provide the same level of care. So although you assume they are providing that same level of care, sometimes they’re not, and you don’t know it.” Reduced physician–patient contact exacerbates these risks by making it more difficult for physicians to recognize when a problem arises. “That’s why losing that face-to-face between MD and patient is so critical, because the pharmacist either isn’t seeing the patient or isn’t going to know,” Dr. Meyerhoffer said. As the oncologist loses control, bad outcomes and litigation become more likely.

Liability Risks to Oncologists Because these issues have not been heavily litigated yet, the precise legal duties of oncologists and specialty pharmacists remain uncertain. Timothy Hall, JD, a professor of law at the University of Louisville in Kentucky, said that

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

physicians have a legal duty to provide the care that an ordinary, competent professional having the same training and experience would provide under the circumstances. To establish liability, the plaintiff must show that the physician breached a duty of care, and that this breach caused the plaintiff’s injury. Additionally, if an undisclosed risk injures the patient, and the patient proves he or she would not have gone through with the procedure had the risk been disclosed during the informed consent process, the physician would be liable, Mr. Hall said. Dr. Meyerhoffer believes that litigation arising from the division of care between oncologists and specialty pharmacies often will concern less common side effects. “It’s when you get into the notso-frequently observed but known [side effects], that you can expect the litigation because the physician doesn’t share it with the patient and the pharmacist may or may not be familiar with it,” she said. “It’s going to be the unusual or less wellknown side effects and [it will be] infrequent, so it’s even going to be harder to capture those through patient education.” The physician also could be liable for failing to monitor patients and for “not making disclosures that the patient has consented to,” Mr. Hall said. Patients could further assert that the physician was negligent in selecting the specialty pharmacy used to distribute the drugs. “It will all be analogous to the negligent hiring argument, where they say, ‘But doctor, the patient came to see you and you recommended this person and you didn’t know them, or you didn’t educate them enough so they knew what to look for,’” Dr. Meyerhoffer said. Specialty pharmacies also could face liability if something goes wrong during treatment. “The pharmacists could be responsible for undertaking a duty and then failing to satisfy it, failing to act competently when the pharmacist could have remained silent or could have just said ‘you need to ask your physician about that,’” Mr. Hall said. But a fault on the part of a pharmacist will not necessarily insulate physicians. “You could certainly have multiple actors all partially responsible for an injury,” Mr. Hall said. The patient often will sue all the parties involved in treatment to increase the chance of recovery. “I think the idea that a plaintiff would ever just sue the pharmacy is far-fetched,” Dr. Meyerhoffer said. “If I was a plaintiff’s counsel, I would cast a wide net too, because you don’t want to have an empty chair.” And even if the specialty pharmacy is primarily responsible, the physician still may need to deal with a lawsuit. “I don’t know that the physician always is responsible for the patient, but I know that the plaintiff will always try to attach that liability to the physician because [the physician has] the deepest pockets,

Close relationships between oncologists and specialty pharmacists may be difficult to form because different payers or manufacturers force physicians to work with multiple specialty pharmacies. and they are the highest person on that totem pole,” Dr. Meyerhoffer said. “I can’t imagine the doctor not being in the complaint originally. Everything is so gray, and the doctor is the one who steered that ship.” Although the physician may ultimately prevail, defending a lawsuit leaves professional damage. “It’s the process that hurts so much, and all of the reporting that follows,” she said. “Financially it doesn’t usually impact us, but everything else is touched.”

Ways To Reduce Liability Exposure Oncologists and specialty pharmacists can employ several strategies to improve care coordination and bolster patient instruction and monitoring. Integrated electronic medical records that are accessible by both the off-site specialty pharmacy and the physician promise to improve communication and reduce fragmentation of care. “Hopefully down the road, if there’s more integration of care, the doctors would be able to see those records and see those refill records,” Ms. Farina said. In-house specialty pharmacy programs also could reduce risk for litigation. After John Grubbs, MS, MBA, RPh, the director of pharmacy at the University of California, Davis, developed an in-house specialty pharmacy program at his institution, he saw significant benefits from having the specialty pharmacy and oncologists operating under the same umbrella. “Having direct communication with all the members of the care team allows us to do a better job on care coordination,” he said. He has found that greater access to patient information and closer relationships between the physician and the pharmacist produces more efficient care. “If we do these in-house, we have electronic medical records, so we have immediate access to information on the patient,” Mr. Grubbs said. “We know the providers typically. We already have a relationship established with them so there’s not going to be any concerns in terms of sharing information with an outside entity.” Although in-house pharmacies are not realistic options for small community clinics, community oncologists can reduce communication problems by building closer relationships with specialty pharmacies, with a clear division of responsibilities. “There are some very good relationships. But they are very focused and scripted,” Ms. Holcombe said. “A physician practice is more likely

to turn to a number of payers in its market and say ‘this is the specialty pharmacy I’ve chosen to work with; don’t bring me the other ones.’” But these relationships are difficult to form because different payers or manufacturers force physicians to work with multiple specialty pharmacies. “The problem occurs when you have a patient and five different pharmacies that you have to work with,” Dr. Jarkowski said. “You need to know who knows what, who you are really talking to and develop new relationships.” Despite these challenges, oncologists must strive for close communication with specialty pharmacies. Dr. Meyerhoffer said that “very, very good communication with your pharmacist” reduces liability risk. When first working with a specialty pharmacist, she said that oncologists should ask, “Did you send out this package insert? In your literature, do you talk about this?” Improved patient instruction and monitoring could further reduce the chance of a lawsuit. New video communication technology also may help to reduce miscommunication and thus the potential for a lawsuit by replicating “face time” between a physician and patient. An oncologist, or the oncologist’s staff, may be able to monitor that the “administration of the $500-a-day chemotherapy took place exactly the way it was supposed to,” Ms. Kirschenbaum said. As more oral chemotherapy agents are developed, documenting informed consent remains critical. “The bottom line is it’s impossible to anticipate every scenario. But try to document what you do, prevent what you can, and that way someone looking at it will have an easier time saying, ‘you know, I think that doctor met the standard of care,’” Dr. Meyerhoffer said. With oral chemotherapy on the rise, the relationship between specialty pharmacies and oncologists will only become more important. “Twenty-five percent of antineoplastic drugs in the research pipeline are oral chemo drugs or oral drugs targeted at different things,” Dr. Jarkowski said. “I think it is only going to get bigger as time goes on.” Increasing numbers of treatments are going to occur outside the oncologist’s office. “The typical kind of ‘buy and bill’ that has been in place for multiple years for the oncology physician in private practice is on its way out pretty quickly,” Ms. Kirschenbaum said. —Michael McLaughlin

HEMATOLOGIC DISEASE

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

Mutations Linked to Relapse in Pediatric ALL 20 mutations emerge between diagnosis and relapse

utations in the gene NT5C2 have been linked to relapse in pediatric acute lymphoblastic leukemia (ALL), according to a study published in Nature Genetics (2013;45:290-294, PMID: 23377183). “Although the outlook for children with ALL has improved dramatically, up to one in five will suffer a relapse,” said lead investigator William L. Carroll, MD, the director of the NYU Cancer Institute in New York City. “This study provides an explanation to understanding why these patients relapse.” Using transcriptome sequencing, the researchers studied bone marrow specimens from 10 patients with pediatric B-lymphoblastic leukemia (B-ALL), the most common subtype of ALL. They found 20 novel mutations that were present at relapse but absent at diagnosis and remission. Two patients had relapse-specific mutations in the same gene, NT5C2, which encodes the protein cN-II, a 5’-nucleotidase enzyme active in cell cytoplasm. The researchers performed full-exon sequencing of NT5C2 in 61 additional relapse specimens, and identified mutations in five more cases. The occurrence rate was seven out of 71, or 10%. “We discovered a mutation that surfaces at relapse, in an enzyme, called NT5C2,” said Dr. Carroll. “In some cases, we found that it is contained in a small clone at diagnosis below the limits of usual detection. It survives chemotherapy and becomes dominant. It’s like evolution in nature: The [fittest] survives and outgrows everything. Fifteen percent of early relapse patients have this mutation.” Dr. Carroll added, “The mutation prevents the active compounds of drugs used commonly in the treatment of leukemia, 6-mercaptopurine [known as 6-MP] and 6-thioguanine [known as 6-TG], from accumulating in a leukemia cell.” Patrick Zweidler-McKay, MD, PhD, the section chief for pediatric leukemia and lymphoma at MD Anderson Cancer Center in Houston, who was not affiliated with the study, said, “The reason for the interest from Nature Genetics is this is a new targetable genetic lesion for a disease where there are relatively few effective therapies after relapse.” He continued, “Unlike a lot of biomarkers, this mutated gene is linked to a mechanism, so we can target it with a drug. The drug doesn’t exist clinically now, but preclinical compounds do exist.” Dr. Carroll said this was the first time relapsed ALL had been linked to specific mutations in B-ALL. He noted

that a second group of investigators had simultaneously published similar findings on the less common T-cell ALL (Nat Med 2013;19:368-371, PMID: 23377281). The major strength of the study is that “the discovery was unexpected and unbiased,” said Dr. Zweidler-McKay. However, a major limitation, he said, is that only one in 10 relapsed samples

have mutations in the gene. The research has clinical applications. “An application would be in the treatment of leukemia, by developing an inhibitor of this mutation. Also, if we could detect the mutation at a low level on maintenance, we might be able to switch the patient to alternate therapy,” Dr. Carroll said. Dr. Zweidler-McKay said, “We’re

DECEMBER 1014, 2013

not too far off from testing this in patients. Once it is shown that inhibitors of this gene sensitize leukemia cells to chemotherapy, then a clinically viable drug must be identified. Although patients with relapsed ALL may be the most obvious [group] to benefit from this type of drug, perhaps many patients would ultimately benefit as well.” —George Ochoa Drs. Carroll and Zweidler-McKay reported no relevant financial conflicts of interest.

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Clinical Conundrums

Prepared by

Syed A. Abutalib, MD

Clinical Hematology Review: Highlights from ASH 2012 and NEJM, Blood and JCO QUESTIONS

University Hospital in Aarhus, Denmark, provides the most convincing evidence yet that positron emission tomography (PET)/ computed tomography (CT)–assessed stage I and II patients with classical Hodgkin lymphoma (cHL) can be spared the pain and expense of bone marrow biopsy (BMB).

1. True or False. In a

study published in The New England Journal of Medicine (NEJM), older adults with mantle cell lymphoma (MCL) had longer life expectancy when treated with rituximab than with interferon alfa maintenance therapy.

True or False. In a study published in NEJM, Primum non nocere. True or False. In Michael W. Climo, MD, of (First, do no harm.) a collaboration between Hunter Holmes McGuire Veterans Affairs Medical Center in Rich- the British Columbia Cancer Agency mond, Va., and his colleagues showed and four North American cooperative that patients bathing with 2% chlorhex- groups, a gene expression–based preidine gluconate (2% Chlorhexidine Glu- dictor, applicable to routinely availconate Cloth Patient Preoperative Skin able formalin-fixed paraffin-embedPreparation, Sage Products) had reduced ded tissue (FFPET) biopsies, identirates of hospital-acquired bloodstream fies patients with advanced-stage cHL infections (BSIs) and colonization with at increased risk for death when treated with standard-intensity up-front multidrug-resistant organisms. regimens. True or False. The International Kidney and Monoclonal GammopaAt the 2012 annual meeting of the thy Research Group has proposed a new American Society of Hematology, David term, “monoclonal gammopathy of renal Porter, MD, and his colleagues at the significance” (MGRS), which includes University of Pennsylvania in Philadelpatients with multiple myeloma (MM) phia, presented longer follow-up data and isolated renal damage. of nine patients treated with chimeric antigen receptor T cells directed against True or False. The retrospective CD19, which had induced responses in analysis by Tarec Christoffer El-Gala- relapsed, refractory chronic lymphocytly, MD, and his colleagues from Aarhus ic leukemia (CLL) patients.

ANSWERS

True. Therapy with maintenance rituximab was continued until progression in patients who responded to the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone) regimen. Rituximab was continued at a dose of 375 mg/m2 every two months. In this prospective study, “older adults” were defined as being aged 66 years or older or aged 60 to 65 years if they were ineligible for highdose treatment. The authors concluded that it might be attractive to combine the rituximab-based maintenance regimen with other drugs that have been shown to be active against MCL. However, physicians need to be aware of the potential interactions between the initial and maintenance therapies, as well as potential combination toxicities in this frail group. Kluin-Nelemans HC, Hoster E, Hermine O,

et al. Treatment of older patients with mantlecell lymphoma. N Engl J Med. 2012;367:520-531, PMID: 22873532.

2. True. Patients in nine intensive

care and bone marrow transplant units in six hospitals were randomly assigned to either non-antimicrobial washcloths (Comfort Bath, Sage Products) or washcloths impregnated with 2% chlorhexidine gluconate during the initial sixmonth study period, followed by daily bathing with the alternate product during the second six-month period. Daily bathing with chlorhexidine-impregnated washcloths is a relatively straightforward strategy to implement and sustain because it does not require a substantial change from routine patientbathing practices. The study concluded that this intervention was associated with reductions in the rates of methicillin-resistant Staphylococcus aureus and vancomycin-resistant Enterococci colonization and hospital-acquired BSIs.

All of the following statements about this ongoing, genetically engineered trial for CLL are correct except: a. Patients with rapidly progressive disease are the best candidates for this trial. b. Patients failing two previous therapies are suitable candidates for this trial. c. Patients with relapsed disease who have refused available alternative established options such as allogeneic hematopoietic transplantation are suitable candidates for this trial. d. Infused autologous T cells can undergo robust in vivo expansion, persist for up to two years and can be associated with a significant cytokine release syndrome (CRS) that responds to anti-cytokine therapy.

John C. Riches, MD, and his colleagues from Barts Cancer Institute at Queen Mary University in London, speculate that a “pseudo-exhausted” state of CLL T cells results in decreased proliferation and the ability to kill target cells ex vivo. The study was able to add to the existing literature on T-cell defects in CLL by showing increased expression of all of the following “exhaustion” markers except: a. PD1 b. CD244 c. CD160 d. CTLA-4

Climo MW, Yokoe DS, Warren DK, et al. Effect of daily chlorhexidine bathing on hospitalacquired infection. N Engl J Med. 2013;368:533542, PMID: 23388005.

3. False. A growing number of renal

diseases associated with monoclonal gammopathies are being recognized. The hematologic disorder in these patients is more consistent with monoclonal gammopathy of undetermined significance (MGUS) than with MM. Unfortunately, due to limitations of the current diagnostic schema, they are frequently diagnosed as MGUS. Because treatment is not recommended for MGUS, appropriate therapy is commonly withheld. In addition to end-stage renal disease, the persistence of the monoclonal gammopathy is associated with high rates of recurrence after kidney transplantation. Preservation and restoration of kidney function is possible with successful treatment targeting the responsible clone. Achievement

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

True or False. In a multicenter, randomized, prospective trial published in the Journal of Clinical Oncology, administration of triptorelin, a gonadotropin-releasing hormone agonist, was associated with a significant decreased risk for primary ovarian failure (POF) in young patients treated for lymphoma.

True or False. A Phase I study showed that intraventricular rituximab plus methotrexate is feasible and highly active in the treatment of refractory central nervous system (CNS) lymphoma.

10.

True or False. During the 2012 annual meeting of the American Society of Hematology, Edward A. Copelan, MD, of the Levine Cancer Institute, on behalf of the Center for International Blood and Marrow Transplant Research, reported that in patients with acute myeloid leukemia (AML) in first complete remission (CR1), the myeloablative regimen of cyclophosphamide (Cy) with busulfan (Bu) is associated with a significantly lower treatmentrelated mortality with superior survival compared with Cy and total body irradiation (TBI) in combination.

of hematologic CR has been shown to prevent recurrence after kidney transplantation. The term “MGRS” is most helpful to indicate a causal relationship between the monoclonal gammopathy and the renal damage and because the significance of the monoclonal gammopathy is no longer undetermined. Of note, the presence of MGUS is not in itself an indication for renal biopsy and the introduction of this terminology does not change the indications for renal biopsy. Leung N, Bridoux F, Hutchison CA, et al. Monoclonal gammopathy of renal significance: when MGUS is no longer undetermined or insignificant. Blood. 2012;120:4292-4295, PMID: 23047823.

True. A consistent finding of this study was the absence of positive BMBs in PET/CT-assessed stage I to II disease. An elegant editorial accompanying the study written by Bruce Cheson, MD, of Georgetown University Hospital

CURRENT PRACTICE

Clinical Oncology News • April 2013 • CLINICALONCOLOGY.COM

and the Lombardi Comprehensive Cancer Center in Washington, D.C., noted that “many current studies (and all future studies) will no longer need to include either a routine chest radiograph or a bone marrow biopsy, and these changes in practice will be codified in the upcoming modification of the staging and response criteria that is expected to be presented at the 17th International Conference on Malignant Lymphoma in Lugano, Switzerland, in June 2013. We have succeeded in curing the vast majority of patients with HL [Hodgkin lymphoma]. The next goal is to minimize the torture while rescuing those in distress.” El-Galaly TC, d’Amore F, Mylam KJ, et al. Routine bone marrow biopsy has little or no therapeutic consequence for positron emission tomography/computed tomography–staged treatment-naive patients with Hodgkin lymphoma. J Clin Oncol. 2012;30:4508-4514, PMID: 23150698. Cheson BD. Hodgkin lymphoma: protecting the victims of our success. J Clin Oncol. 2012:44564457, PMID: 23150696.

5. True. The aim of this retrospec-

tive study was to reliably identify patients with advanced-stage cHL at increased risk for death by developing a robust predictor of overall survival (OS) using gene expression measured in routinely available FFPET. Pretreatment FFPET biopsies from 290 patients enrolled in the E2496 Intergroup trial comparing ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine) and Stanford V regimens in locally extensive and advancedstage cHL were analyzed. The model was tested in an independent cohort of 78 patients enriched for treatment failure but otherwise similar to patients in a population-based registry of patients treated with ABVD. There was a 29% absolute difference in five-year OS between the high- and low-risk groups (63% vs. 92%, respectively; P<0.001; hazard ratio, 6.7; 95% confidence interval [CI], 2.6-17.4). The predictor was superior to the International Prognostic Score and CD68 immunohistochemistry in multivariate analyses.

Scott DW, Chan FC, Hong F, et al. Gene expression-based model using formalin-fixed paraffinembedded biopsies predicts overall survival in advanced-stage classical Hodgkin lymphoma. J Clin Oncol. 2013;31:692-700, PMID: 23182984.

6. A. The therapy consists of repro-

gramming the patient’s (autologous) T cells (ex vivo) to target tumor cells— specificity for the B-cell antigen CD19, coupled with CD137, a co-stimulatory receptor in T cells—through a gene modification technique using a HIVderived lentivirus vector. This process usually requires six weeks of waiting. Thus, CLL patients with rapidly progressive disease are not the ideal candidates. Moreover, in order to proceed, the T cells should grow in culture to levels suitable for infusion to cause potential therapeutic response. Reportedly, the toxic side effect of CRS is manageable, albeit a few concerns remain, including the following: diminishing the strength of anti-leukemia therapy by counteracting this side effect with the administration of steroids, antiinterleukin (IL)-6 antibody, etanercept and tocilizumab; and application of the therapy in the more prevalent, frail and elderly population with this disease. Porter DL, Grupp SA, Kalos M. et al. Chimeric antigen receptor T cells directed against CD19 induce durable responses and transient cytokine release syndrome in relapsed, refractory CLL and ALL. ASH Annual Meeting Abstracts. Blood. 2012;120:642. Porter DL, Levine BL, Kalos M, et al. Chimeric antigen receptor-modified T cells in chronic lymphoid leukemia. N Engl J Med. 2011;365:725-733, PMID: 21830940.

7. D. The CTLA-4, TIM3 and LAG3

exhaustion markers were not increased. T-cell exhaustion, originally described in chronic viral infections, was recently reported in solid and hematologic cancers. The authors investigated the phenotype and function of T cells from CLL patients and age-matched controls. CD8+ and CD4+ T cells from CLL patients had increased expression of exhaustion markers CD244, CD160 and PD1 with expansion of a PD1+ BLIMP1HI subset. CLL CD8+ T

cells showed functional defects in proliferation and cytotoxicity, with the cytolytic defect caused by impaired granzyme packaging into vesicles and nonpolarized degranulation. In contrast to virally induced exhaustion, CLL T cells showed increased production of interferon-γ and tumor necrosis factor-α and increased expression of TBET, and normal IL-2 production. Therefore, although CLL CD8+ T cells exhibit features of T-cell exhaustion, they retain the ability to produce cytokines. This work also opens up potential routes to exploit “exhaustion” or “pseudo-exhaustion” therapeutically by pharmacologic targeting of inhibitory receptors such as via PD1. Riches JC, Davies JK, McClanahan F, et al. T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood. 2013;121:1612-1621, PMID: 23247726.

8. False. The study was done to

assess the efficacy of gonadotropinreleasing hormone agonist (GnRHa) in preventing chemotherapy-induced ovarian failure in patients treated for Hodgkin or non-Hodgkin lymphoma (NHL) within the setting of a multicenter, randomized, prospective trial. The primary end point was POF rate (follicle-stimulating hormone [FSH] ≥40 IU/L) after one year of follow-up. More than 50% of patients in each group completely restored their ovarian function (FSH <10 IU/L). The occurrence of adverse events was similar in both groups with the exception of metrorrhagia, which was more frequently observed in the control group than in the GnRHa group (38.4% vs. 15.6%, respectively; P=0.024). Approximately 20% of patients in both groups exhibited POF after one year of followup. Triptorelin was not associated with a significant decreased risk for POF in young patients treated for lymphoma but may provide protection of the ovarian reserve. Demeestere I, Brice P, Peccatori FA, et al. Gonadotropin-releasing hormone agonist for

the prevention of chemotherapy-induced ovarian failure in patients with lymphoma: 1-year follow-up of a prospective randomized trial. J Clin Oncol. 2013;31:903-909, PMID: 23129737.

9. True. Fourteen patients received

10 or 25 mg intraventricular rituximab twice weekly for four weeks, with rituximab administered as monotherapy during the first treatment each week and rituximab administered in combination with methotrexate (MTX) during the second treatment each week. In a population with high-refractory CNS NHL, 75% of patients achieved complete cytologic responses and 43% achieved an overall CR in cerebrospinal fluid protein and/or brain parenchyma. Two patients achieved a CR1 of CNS NHL with intraventricular rituximab/ MTX, including one with CNS lymphoma refractory to high-dose systemic and intrathecal MTX plus IV rituximab.

Rubenstein JL, Li J, Chen L, et al. Multicenter phase I trial of intraventricular immunochemotherapy in recurrent CNS lymphoma. Blood. 2013;121:745-751, PMID: 23197589.

10.

True. The most widely used myeloablative preparative regimens for allogeneic hematopoietic cell transplantation (alloHCT) in myeloid malignancies is Cy/TBI or BuCy. The relative advantages and shortcomings of these regimens have been debated for more than 25 years. Despite the inherent limitations of a retrospective study, it does have important clinical implications favoring the combination of BuCy in patients with AML in CR1 with either match-related or -unrelated source. It is important to note that the median age of patients was 35 years (aged 2-64 years) and Bu combination was superior in both oral and IV formulations compared with Cy/TBI. Copelan EA, Hamilton BK, Ahnet KW, et al. Lower transplant-related mortality and improved survival for patients with AML in first CR receiving BuCy compared to Cy/TBI as myeloablative preparation for allogeneic transplantation: a report from the Center for International Blood and Marrow Transplant Research (CIBMTR). ASH Annual Meeting Abstracts. Blood. 2012;120:217.

LOOK AHEAD Next month’s issue of Clinical Oncology News will feature in-depth coverage of the economic forces changing oncology practices today And coverage of the 17th International Congress on Hematologic Malignancies: Focus on Leukemias, Lymphomas and Myeloma

—————————— New Column —————————— Upcoming issues of Clinical Oncology News will be featuring The Tumor Board, a new column edited by Conrad Simpfendorfer, MD, of Cleveland Clinic, that focuses on challenging cases and alternative treatment options in oncology.

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