The October 2012 Digital Edition of Clinical Oncology News by McMahon Group

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Independent News on Advances in Hematology/Oncology CLINICALONCOLOGY.COM • October 2012 • Vol. 7, No. 10

SOLID TUMORS Blocking angiogenesis throughout cancer treatments . . . . . . . . . . . . . . .......... 16 Olanzapine’s role in breakthrough nausea debated . . . . . . . . . . . . . . . . . ........... 17 New ablative technologies for risky and untreatable tumors . . . . . . . . . . . . . . . . . . . ........... 18 The future of breast cancer therapy: Neoadjuvant dual HER2-targeted therapy . . . . . . . . . . . . . . . . . . . ......... 30

Cancer Drug Costs Under Scrutiny

Drug Trials: Often Long On Hype, Short on Gains

Some newer agents provide only marginal gains

The delusion of ‘significance’ in drug trials

n recent years, the FDA has approved a number of cancer drugs based on small improvements in survival. An increasing number of health care economists and physicians are raising the alarm that these treatments are not cost-effective. “When we go out and buy a new car, if we are buying a Ford, we don’t expect to pay for a Ferrari. That is what we are doing at the moment see DRUG COSTS, S page 20

HEMATOLOGIC DISEASE New multidrug combo for elderly with Hodgkin lymphoma . . . . . . . . . . . . . . . .......... 12 Improving mantle cell lymphoma response in the elderly . . . . . . . . . . . . . . . . . . . . ........... 15 Case Report: Vemurafenib treats hairy cell leukemia patient . . . . . . . . . . . . . . . . . . . . .......... 16 Limited radiotherapy for pediatric Hodgkin lymphoma . . . . . . . . . . . . . . . .......... 23 CURRENT PRACTICE Maurie Markman, MD: Using large databases rationally . . . . . . . . . . . . . . . ............ 4 New column: Case Reports in Hematology/Oncology ...... 8

Vogl, NY...

t the annual meeting of the American S i for Society f Clinical Cli i l Oncology O l in i June, J the results of three potentially practice-altering Phase III trials in metastatic colorectal

Probability

INSIDE

see SIGNIFICANCE, E page 5

Weekly Pac-Bev Should Not Be Abandoned

P Value

Observed size of effect

CALGB confirms long breast cancer remissions

t ASCO 2012, Hope Rugo, MD, professor of medicine at the University of California in San Francisco, presented the results of a randomized study comparing Steven Vogl, MD two new drugs, ixabepilone and nanoparticle albumin-bound (nab)paclitaxel, with weekly paclitaxel for first-line chemotherapy of metastatic breast cancer.1 Each was combined with bevacizumab. The results were disappointing, since the best arm was the “old” chemotherapy of weekly paclitaxel plus see VOGL, page 10

cancer were presented: bevacizumab b beyond d progression i (TML Study), S d ) afliberflib cept (VEGF-Trap) added to second-line FOLFIRI (the VELOUR study), and regorafenib after progression following standard therapies (the CORRECT study). “Significant benefits in overall survival [OS] and progression-free survival [PFS]” declared the conclusions for all three trials. And that was certainly true.

A P value is the probability of an observed result arising by chance; the P value does not indicate the size or importance of the observed effect.

By the NUMBERS: ‘Upcoding’ $11 billion

-25

Amount Medicare has been overbilled by physicians in the past decade.

Billing code modifier targeted by the U.S. Justice Department in its ‘yearly work plans.’

$4.1 million

15 Number of states that can expect a surge in Medicare audits.

Amount that Georgia Cancer Specialists, an Atlanta oncology practice, recently agreed to pay for violating the False Claims Act.

$12.8 billion

Percent of consultations billed at the highest level that are miscoded.

Total amount the U.S. Justice Department has recovered under the act since January 2009.

Sources: The Center for Public Integrity, the American Academy of Family Physicians, the Department of Health and Human Services Office of Inspector General, United States Attorney’s Office Northern District of Georgia.

EXPERT COMMENTARIES FROM SITEMAN CANCER CENTER

Vitamin D levels in early, primary breast cancer . . . . . . . . . . . . . . . . .. 14 Antonella Rastelli, MD

Bortezomib induction plus post-transplant maintenance examined .............. 25 Keith StockeriGoldstein, MD

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

EDITORIAL BOARD

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

Breast Cancer

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

Hematologic Malignancies

Andrew Seidman, MD

Jennifer R. Brown, MD, PhD

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

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

Maura N. Dickler, MD

Harry Erba, MD, PhD

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

University of Michigan Ann Arbor, MI

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

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

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

Gastrointestinal Cancer and Sarcoma

Sara S. Kim, PharmD

University of California, San Diego, CA

The Mount Sinai Medical Center New York, NY

Infection Control

Bioethics

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

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

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

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

Shaji Kumar, MD Mayo Clinic Rochester, MN

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

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

Pharmacy Cindy O’Bryant, PharmD Richard Stone, MD

University of Colorado Cancer Center Denver, CO

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

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

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

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

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

Charles F. von Gunten, MD

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

Mission Statement

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

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

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

Steven Vogl, MD Medical Oncologist New York, NY

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

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

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

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

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

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

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

CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS •OCTOBER 2012

A Rational Use of National Databases The real-world impact of new therapeutic strategies

ver the past decade, there has been a proliferation of peer-reviewed medical publications that use information available in large public databases such as the Surveillance, Epidemiology, and End Results (SEER)-Medicare database.1 These papers have focused on a variety of outcomes, including the quality and cost of medical care, adherence to guideline-based management, and geographic and other disparities in the provision of various medical services. Although the objectivity and relevance of certain reports using these databases may sometimes be questioned, such as in a study that attempted to suggest that one group of medical professionals appeared to provide a superior level of care compared with another among a specific patient population,2 it is clear that appropriate examination of these large data sets has the potential to address important clinical and societal issues. One interesting example of the strategic approach to employing national databases is their use to explore the realworld impact of a new oncologic therapeutic paradigm that has been introduced into clinical practice. It is well recognized that the so-called evidencebased clinical trials usually required and cited for regulatory approval rarely accurately reflect the quite heterogeneous population encountered in typical clinical practice. For example, the elderly are almost always profoundly underrepresented in such trials, and patients with very common and clinically

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

gmiller@mcmahonmed.com

McMahon Publishing is a 40-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© 2012 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

relevant comorbidities, such as medication-dependent diabetes, hypertension and heart disease, are frequently excluded from study entry. Therefore, the overall clinical relevance (both efficacy and toxicity) of even the most “positive” evidence-based studies to the community of patients actually encountered in the real world of oncology practice—for example, elderly patients

would be that some or many clinical trials are specifically designed (manipulated?) to maximize the opportunity for a “statistically significant” favorable outcome, while minimizing the chances that serious risks will be observed. An interesting use of this real-world process is provided by a recent report of an analysis of the use of bevacizumab combined with chemotherapy in the pri-

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

Fundamentally, what is being measured here is the true heterogeneity and complexity of the real world of cancer care and not the highly artificial environment … that characterizes many patient populations entered into controlled clinical trials. with pre-existing comorbid medical conditions—may be questionable. The examination of national databases may provide valuable insight into these clinically important issues. For example, just how effective (overall survival) and toxic (required hospitalizations) is regimen A in patients over the age of 70? It is quite interesting to note that one of the common criticisms of these databases in any published analysis is the absence of investigator control of disease management (e.g., number of administered treatment cycles, initial dose and subsequent dose modifications) as well as the relatively poorly characterized clinical features of the patient population (e.g., severity of comorbid conditions), since in such reports it is actually a specific strength of the process. Fundamentally, what is being measured here is the true heterogeneity and complexity of the real world of cancer care and not the highly artificial environment of the severely eligibility-restricted, carefully selected and homogeneous grouping that characterizes many, if not most, patient populations entered into controlled clinical trials. Of course, an alternative and admittedly more cynical view of the situation

mary management of metastatic colorectal cancer.3 Employing linked data from SEER and Medicare databases, the investigators identified more than 2,500 patients with stage IV disease receiving first-line fluoropyrimidine-based combination (with either irinotecan or oxaliplatin) antineoplastic drug management. Bevacizumab (Avastin, Genentech) was administered to 36% of the patients in this group. Compared with treatment without the anti-angiogenic agent, the addition of bevacizumab improved overall survival (hazard ratio, 0.85), with an apparent increased benefit when this drug was combined with irinotecan (compared with oxaliplatin [Eloxatin, Sanofi-aventis]). Patients who received bevacizumab experienced a greater risk for gastrointestinal perforation (2.3% vs. 1.0%; P<0.01) and stroke (4.9% vs. 2.5%; P<0.01). There was no increase in either venous thrombosis or cardiac toxicity when bevacizumab was added to the chemotherapy regimens. A reasonable argument can be advanced that this current analysis and similar reports examining the use of novel management strategies outside the confines of clinical trials provide a far more

meaningful assessment of both the potential benefits and risks associated with using such therapies. Furthermore, this examination focused on the Medicare patient population, a group likely to represent a substantial proportion of individuals with colorectal cancer being considered for systemic antineoplastic therapy. Finally, one can argue that when discussing particular therapeutic options with patients, the data in this type of report are as relevant as, if not more relevant than, those relied upon by any regulatory agency to formally approve the agent for use in routine clinical care.

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References 1. Chagpar R, Xing YH, Chiang Y-U, et al. Adherence to stage-specific treatment guidelines for patients with colon cancer. J Clin Oncol. 2012;30:972-979, PMID: 22355049. 2. Silber JH, Rosenbaum PR, Polsky D. Does ovarian cancer treatment and survival differ by the specialty providing chemotherapy? J Clin Oncol. 2007;25:1169-1175, PMID: 17401005. 3. Meyerhardt JA, Li Ling, Sanoff HK, et al. Effectiveness of bevacizumab with first-line combination chemotherapy for Medicare patients with stage IV colorectal cancer. J Clin Oncol. 2012;30:608-615, PMID: 22253466.

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CLINICAL ONCOLOGY NEWS • OCTOBER 2012

SIGNIFICANCE continued from page 1

All three studies had OS and PFS P values well below 0.05. But whether they continued a patient on bevacizumab (Avastin, Genentech) beyond progression, added aflibercept (Zaltrap, Sanofi and Regeneron) to FOLFIRI after progression on oxaliplatin (Eloxatin, Sanofi-aventis) or prescribed regorafenib (Bayer HealthCare) after failure on other standard therapies, each of these trials bought their patients exactly the same amount of additional time, on average: 1.4 months. • Regorafenib: from 5 to 6.4 months. • Aflibercept: from 12.1 to 13.5 months. • Bevacizumab beyond progression: from 9.8 to 11.2 months. In the audience, and disappointed, was Leonard Saltz, MD, chief of the Gastrointestinal Oncology Service at Memorial Sloan-Kettering Cancer Center (MSKCC) in New York City. “Is this the kind of goal we should be aiming for? If you tell patients that there are significant survival benefits to a drug, and you stop there, I assure you that they are not thinking that they will get an average of six weeks more to live,” Dr. Saltz said. Of course, the term significant should always be modified by the all-important adverb statistically when reported at meetings like American Society of Clinical Oncology (although that’s not always the case), but when results like these get translated to headlines that patients (and even community oncologists) read, that modifier often disappears. Instead, you’ll read “aflibercept significantly improved survival in metastatic colorectal cancer” in publications like Medical News Today, and it is easy to misinterpret “significantly improved” as “substantially improved.” Dr. Saltz believes that oncology has become addicted to what he calls “P-value trials.” “I’d like to see us get away from the selfserving term of significant benefit, and stress much more clearly when we are talking about statistical significance—and explain to the public what that means. We should also move toward taking a harder look at what constitutes a clinicallyy significant benefit to the patient. And I would like to see us call our shots better in advance,” he says. “If we told the average observer—patients, regulators, the general public—that we’re planning a study that will cost tens to hundreds of millions of dollars to see if an agent improves survival by less than a couple of months, they’d be very disappointed. But that’s become our game plan. We power these trials with thousands of patients so as to be able to pick up those small differences.” Many oncology trials today are overpowered, agreed Donald Berry, PhD,

professor of biostatistics at the University of Texas MD Anderson Cancer Center, in Houston, who founded MD Anderson’s Division of Quantitative Sciences. “I’ve heard statisticians say that trials can never be too big, but I think they are. We close our eyes while running trials for five years, and then open them and see a 1.4-month advantage. You can’t get a 1.4-month advantage from a smaller trial; it’s only big trials that get P value significance from modest amounts. If you ran a 100,000-patient trial, you could see P value significance in a three-day benefit, but what would that mean to the patient?”

A classic example is the study presented at ASCO in 2005 that led to the approval of erlotinib to treat advanced pancreatic cancer. In combination with gemcitabine, it was found to increase OS from 5.99 to 6.37 months—in other words, about two weeks. But in the 569-patient study, those 14 extra days of OS added up to a P value of 0.025—statistically significant. Part of the problem, said Alex Adjei, PhD, the senior vice president of clinical research and professor and chair of the Department of Medicine at Roswell Park Cancer Institute in Buffalo, N.Y., is that oncology has lost focus on what exactly

a P value means. “A P value of less than 0.05 simply means that there is less than a 5% chance that the difference between two medications—whatever it is—is not real, that it’s just chance. If there’s a fourweek overall survival difference between two drugs and my P value is less than 0.05, it’s statistically significant, but that just means that the number in the study is large enough to tell me that the difference I’m seeing is not by chance. It doesn’t tell me if those additional four weeks are clinically significant.” “ values are even more complicated “P see SIGNIFICANCE, E page 6

The Greenspan Meeting XXX

November 7-10, 2012, New York City

CHEMOTHERAPY FOUNDATION SYMPOSIUM INNOVATIVE CANCER THERAPY FOR TOMORROW ® Practical Applications for the Practicing Oncologist New Agents, Clinical Trials, Emerging Developments Wednesday, November 7 Pediatric Oncology Therapeutic Advances in Cancers of Childhood

Saturday, November 10 Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Therapeutic Advances, Treatment Related Complications, Supportive Care, Symptom Management, Targeted Therapies Schedule Nov. 7 Hematology, GI, Pediatric Oncology Nov. 8 GYN, Head and Neck, Breast Nov. 9 GU, Lung, Melanoma, OncoTechnology Nov. 10 New Perspectives in Oncology Practice Pediatric Oncology November 7 in separate room

Conference Highlights Wednesday, November 7 Keynote Speaker Norman Wolmark, MD Thursday, November 8 Ezra M. Greenspan Memorial Lecture José Baselga, MD

Complimentary Breakfasts, Lunches, Dinners

A CME Oncology Conference Presented by The Chemotherapy Foundation in collaboration with the Tisch Cancer Institute of the Mount Sinai School of Medicine

CURRENT PRACTICE

SIGNIFICANCE continued from page 5

than that,” said Dr. Berry. “No one understands P values, because they are fundamentally non-understandable.” (He elaborates on this problem in “Multiplicities in Cancer Research: Unique and Necessary Evils,” a commentary in August in the Journal of the National Cancer Institute [2012;104:1125-1133].) Of course, if you could offer any patient with any form of metastatic cancer an additional 1.4 months—or four weeks, or four days—of life with no downside,

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

8%. “If you have 10 days spent being very uncomfortable, or worse, because of toxicities, should we subtract that from the drug’s overall survival?” asked Dr. Bach. “There’s a whole field being built around this—quality-adjusted life-years, or QALYs—but for trials right now, we don’t do that at all. We just count survival days without considering how many of those days are worse days than they would have been otherwise. For the FDA’s purposes, effectiveness is the only end point right now, but for purposes of our discussions with patients, it would be better if we could incorporate these quality adjustments more clearly.”

they’re not dramatic, but if you put them together they do make a difference.” But even when this is not the case, the temptation can become very high for oncologists—who of course want to do their best to keep every one of their patients alive—to offer hope without much supporting evidence. “I’m already seeing practitioners telling their patients who have exhausted standard therapy with bevacizumab, ‘Well, aflibercept will be coming along soon and we can try that.’ But we don’t have a shred of evidence that aflibercept will do anything whatsoever in patients whose tumors have progressed through all other standard therapies, and

‘A physician getting $1,000 to serve on the advisory board for a drug company is not nearly as much of a conflict of interest as is the whole way we advance academically. No one will publish a negative study, so you have to have positive studies to get promoted. And we in oncology want to show that we’re making progress—“winning the war on cancer”—so we talk it up.’ —Alex Adjei, PhD it would be a no-brainer. “If I could prescribe wearing green socks and it would give my patients an additional four weeks of life, of course they would all do it,” says Deborah Schrag, MD, MPH, a gastrointestinal cancer specialist at the Dana-Farber Cancer Institute in Boston. “But the challenge is that there are toxicities associated with any treatment, and the hard question to ask is how to weigh the risks and benefits and decide ‘Is this treatment worth it?’” Also, average benefits don’t tell the whole story. Each patient receiving a drug with a median OS benefit of 1.4 months doesn’t get six weeks pasted magically onto his or her life span. “Some patients won’t respond to an intervention at all and achieve no benefit, whereas others may achieve substantial benefit,” Dr. Schrag said. “The trick is that we don’t know how to figure out who is who ahead of time and we need to get a whole lot more strategic about distinguishing between studies with a lot of benefit for a few, and studies with a little benefit for many.” “What patients count on is improved experience with illness—hopefully prolonged survival with enhanced quality of life,” said Peter B. Bach, MD, attending physician and director of the Center for Health Policy and Outcomes at MSKCC. “The problem with trial design is that we don’t subtract away the things we could subtract away. Even treatments with no toxicities have inconveniences, and most cancer treatments have much more than that. If we ‘netted out’ the downsides, that might help patients better understand the true clinical significance of a study result.” For example, regorafenib was associated with hand–foot–skin reactions in 17% of patients, fatigue in 15% and diarrhea in

Of course, some trials presented at ASCO had more clearly impressive results. In the GRID (GIST–Regorafenib in Progressive Disease) trial, patients with gastrointestinal stromal tumors who were given regorafenib after failure of imatinib and sunitinib, experienced a median PFS of 4.8 months compared with less than one month in the placebo arm. The median OS end point had not yet been reached, but a four-month boost in PFS looks a lot more promising than the 0.2-month PFS improvement for regorafenib in metastatic colorectal cancers that the CORRECT (Colorectal Cancer Treated With Regorafenib or Placebo After Failure of Standard Therapy) trial found. Still, in many cases, what gets presented at these meetings, and trumpeted to the world, are incremental improvements. “We tend to accept these incremental improvements and say, well, it’s the best we’ve got and we owe people that,” says Dr. Saltz. “But it’s created the business model for biotech and pharma. It’s a much lower risk strategy to spend money on a big trial, get a statistically significant P-value, and make money, than to try an innovative idea and see if you can really move the bar. I fear we’re disincentivizing ourselves to push for the big wins because we’re touting small victories as more than they are.” Incremental benefits do sometimes add up to meaningful change, however, with breast cancer a key example. “Breast cancer hasn’t had that many home runs— maybe tamoxifen, which is arguably the drug that has saved more lives than any other single cancer drug,” said Dr. Berry. “But most of the advances in breast cancer have been incremental. But if you ‘daisy-chain’ those advances, put together they have decreased mortality risk and recurrence risk by over 50%. Individually,

there’s no good reason to believe it will— yet it will likely become a standard practice,” Dr. Saltz said. “That’s not really the advance we want. It’s what we’re paying for in the absence of what we want, and ultimately we’re creating an unsustainably expensive system that is using hundreds of thousands of dollars’ worth of drugs per patient for not much benefit.” It’s human nature for patients to

to get them on the market. Investigators have a vested interest too: If they have a positive study that they can publish and present at ASCO, that’s their career. A physician getting $1,000 to serve on the advisory board for a drug company is not nearly as much of a conflict of interest as is the whole way we advance academically. No one will publish a negative study, so you have to have positive studies to get promoted. And we in oncology want to show that we’re making progress, ‘winning the war on cancer,’ so we talk it up.” There are no easy solutions to any of this, but it’s a conversation that oncology must have. “For starters, it would be good if we, as a community, could agree on what is a clinically significant finding,” said Dr. Saltz. “If I said that I could reliably improve median survival by one month at $1 billion per patient with serious side effects, you’d say ‘No way.’ If I said I could do it for $10 per patient with no side effects, you’d say, ‘Sure.’ But where, in the vast gap between those two scenarios, is the cutoff?” (That’s what the whole QALY concept tries to tease out.) Dr. Saltz believes that oncology in the United States will ultimately have to turn to something like what the United Kingdom has put in place, with its National Institute for Health and Clinical Excellence. “We need a consensus panel, with some teeth in it, that will set goals and standards for trial outcomes and drug approvals.”

‘It’s a much lower risk strategy to spend money on a big trial, get a statistically significant P value, and make money, than to try an innovative idea and see if you can really move the bar.’ —Leonard Saltz, MD believe that they will be the one person in 100 who gets the survival benefit on the far end of the bell curve, with few side effects. “Expectations are so high. I see patients all the time who want to know what’s the next trial they can go on that will guarantee another year or two of life now that they’ve exhausted standard therapy, and they’re shocked and angry to hear that I don’t think there is such a trial right now,” Dr. Saltz said. And there’s little incentive in the oncology world to change those expectations. Patients want hope and their doctors, with all good intentions, want to give them that hope. That hope is currency, and it’s an undeniable fact that oncology has become big business. “Oncology now is commercially driven,” says Dr. Adjei. “You have companies who have shareholders, who have board members, and they want to sell their drug and have their share price go up. The whole goal is to get regulatory approval. You go to our meetings now, and it’s all about the drugs and trying

And clinical researchers may need to start changing how they talk about trial results. “Everybody got up at ASCO and said, ‘This drug provides a significant survival benefit.’ We know that’s going to be misinterpreted. The public is reading our literature now, the Internet has put everything in everyone’s lap, and they’re not understanding it,” said Dr. Saltz. “We’re obfuscating the limits of what we’ve accomplished.” —Gina Shaw

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on this column? Please send comments to gmiller@mcmahonmed.com

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Effective Hand–Foot Syndrome Treatment Identified Phase II, randomized trial has some clinicians changing practice Chicago—Urea-based skin creams can reduce the incidence of hand–foot skin reactions (HFSR) in patients treated with sorafenib (Nexavar, Bayer), according to results from a large Phase II, open-label, randomized study. An example of this skin cream is Eucerin (Beiersdorf, Inc), a commonly available product. The finding, reported at the annual meeting of the American Society of Clinical Oncology (abstract 4008), has already spurred practitioners to make changes. “I would definitely recommend Eucerin cream in patients who are on sorafenib,” said Ed Chu, MD, chief of Hematology/

function. Grade 3 HFSR is ulcerative dermatitis or skin changes with pain that interferes with function. The researchers also found that the median time to the first HFSR event was 2.5-fold longer in patients who received the skin cream than in those who did not receive it (84 vs. 34 days; P<0.0001). “This is important because sorafenib is the most effective agent in hepatocellular

cancer, but it is a marginally effective agent,” said Colin Weekes, MD, PhD, an assistant professor of Medical Oncology at the University of Colorado School of Medicine in Denver. “When we look at an agent that may not benefit everybody, it is nice when we might be able to delay the toxicity for those patients who aren’t going to turn out to have a benefit.” Sheng-Long Ye, MD, of the Zhongshan

Hospital, Fudan University, in Shanghai, China, who presented the research at the meeting, said the study was limited in that it did not document the extent to which the patients used the moisturizing skin cream. —Kate O’Rourke Dr. Chu, Weekes and Ye reported no relevant disclosures.

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advisor

Examples of hand-foot syndrome.

Oncology and deputy director of the University of Pittsburgh Cancer Institute, who was not involved with the study. “It might also be interesting to use Eucerin cream with other drugs that are associated with hand–foot syndrome, such as the oral fluoropyrimidine Xeloda [Roche], and I’ve already discussed this with my nurse and mid-level provider,” he said. Hand–foot skin reactions occur in 21% of patients who are treated with sorafenib for unresectable hepatocellular carcinoma and 30% of patients who receive this drug for advanced renal cell carcinoma. Investigators of the new study, which was conducted at 64 centers in China, enrolled patients with advanced hepatocellular carcinoma who were sorafenibnaive. Approximately 900 patients were given sorafenib and randomized to concomitant best supportive care (BSC) or BSC plus urea-based skin cream. The treatment arms were well balanced in terms of baseline patient characteristics. Patients who were treated with the skin cream had a significantly lower incidence of all-grade HFSR within 12 weeks (56.0% vs. 73.6%; P<0.0001), as well as grade 2/3 HFSR (20.7% vs. 29.2%; P=0.004). The prophylactic use of urea-based cream improved health-related quality of life, reducing symptom burden and the effect of symptoms on daily activities. Grade 2 HFSR is characterized by skin changes, such as peeling, blisters, bleeding, edema or pain that does not interfere with

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Mentor Memos

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Top-Tier Centerss Share Tips

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

Top-Tier page 5

Master Work–Life Balance

raining to be an oncologist can be rough. In the face of long hours, sleep deprivation, and patient suffering, young oncologists may sacrifice hobbies, interests, and even relationships. Many fellows find comfort in reminding themselves that better days are ahead but experts say that they may be setting themselves up for disappointment. Oncologists who cope by looking to the future may miss opportunities in the present to shape their career to meet their needs.1 “Putting aside one’s personal needs or personal wellness can eventually come back in a negative

or unhealthy way that can lead to burnout,” said Charles M. Balch, MD, FACS, professor of surgery in the Division of Surgical Oncology at University of Texas Southwestern Medical School in Dallas, Texas. “A successful medical career at the expense of personal wellbeing is not at all successful.” One in 3 oncologists will experience significant career burnout— described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leads to decreased effectiveness at work.2 Some of its more tragic consequences see, Work–Life page 2

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

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CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Case Reports: Hematuria With Lymph Node Activity and Pulmonary Nodules T

his is the first in a quarterly column focusing on interesting case reports from Cancer Treatment Centers of America (CTCA). CTCA is a national network of cancer care hospitals specializing in treating patients who have complex or advanced-stage cancer. CTCA combines medical expertise and state-of-the-art technology with nutritional counseling, naturopathic medicine, mind–body therapy and spiritual support. Clinical Oncology News is pleased to introduce this new column and we look forward to providing readers with interesting and engaging case reports. Have a comment on this case or on our new series? Clinical Oncology News encourages reader feedback. Please email managing editor Gabriel Miller at gmiller@mcmahonmed.com.

CTCA att Eastern E t Regional R i l Medical M di l Center. C t

Case Background On June 5, 2011, William D., a 57-yearold man, presented to the local emergency room with a sudden onset of hematuria. He was otherwise in good health. Unable to void urine, he did, however, pass a large blood clot and a computed tomography (CT) scan of the abdomen and pelvis performed that day revealed nonspecific and large lymph node activity in the retroperitoneum, the largest of which was in the periaortic area measuring 1.4 cm. A 1.9-cm mass-like area was seen involving the left posterior bladder. Attending physicians believed that the patient had metastatic cancer. The following day, a CT scan of the chest was performed, which confirmed multiple pulmonary nodules of the left lung base that measured 3.1, 2.0, 1.6 and 0.8 cm. There were additional subcentimeter pulmonary nodules. On June 7, the doctors performed a transurethral resection of the bladder tumor with evacuation of many clots. A solid-appearing lesion, located at a slightly elevated, 1-cm area lateral to the left urethral orifice, was resected at its base and fulgurated. There was no evidence of bladder perforation. Pathology was consistent with sarcomatoid carcinoma and a microscopic exam showed the presence of multiple malignant spindle-shaped cells with inflammatory changes. Immunohistochemical stains were performed. The slides were sent for review to nearby Johns Hopkins Medical Center in Baltimore—where there are experts in bladder cancer—and bladder cancer was confirmed. On June 9, four days after his arrival at the hospital, William D. underwent a CT-guided biopsy of the left pulmonary nodule. The pathology was nondiagnostic. However, given the confirmed bladder carcinoma and the presence of pulmonary nodularity, the doctors

Axillary (underarm) lymph nodes.

recommended a chemotherapy regimen for metastatic bladder cancer. William D. was given a projected oneyear survival. He was released from the hospital and returned home to consider his options.

Initial Intake On June 27, 2011, William D. arrived at Cancer Treatment Centers of America (CTCA) at Eastern Regional Medical Center (Eastern) in Philadelphia seeking a second opinion. Confused by the inconclusive results that had led to his diagnosis, he told the intake team at CTCA: “I need to know what to do, and what I have.” An thony Perre, M D, medical director of New Patient Intake, CTCA at Eastern Regional Medical Center:

“When William D. was initially diagnosed, the local doctors did a CT scan and saw lymph node enlargement in the abdomen, as well as pulmonary nodularity in the left lower lobe and the right lower lobe. We took this information into consideration, but began by performing a medical history from the beginning,

and doing a fresh work-up.” Next Steps: A positron emission tomographic (PET) scan revealed the widespread enlargement of lymph nodes in the chest, abdomen, pelvic area, spine and lung. A magnetic resonance imaging scan of the brain did not reveal any presence of tumors. The team also completed a full patient history from which they learned—for the first time—that William D. had experienced left-sided cervical and supraclavicular lymphadenopathy for the previous 18 years. The patient recalled that it had been biopsied many years ago and was found to be benign. The patient was referred to medical oncologist and hematologist/oncologist Sramila Aithal, MD.

Diagnosis Instead of further investigating the lungs, Dr. Aithal requested a needle biopsy of the axillary node. Interventional radiology performed the biopsy, but the results did not confirm a presence of cancer, mirroring the inconclusive results from the emergency room biopsy of the lung tissue. Dr. Aithal then ordered an excisional biopsy of the left axillary node that was performed on July 7. The cells were CD30-positive and the surgery confirmed Hodgkin lymphoma. S ra mila Aith al , MD, medical oncologist and hematologist/oncologist, CTCA Eastern:

“One could have proceeded thinking two attempts have been made and assumed there was no presence of cancer. I was so insistent because carcinosarcoma is so rare. And the lymph node activity that was ongoing for 18 years gave me a suspicion that something else was going on. I wanted

the confirmed diagnosis. “At first, the surgeon did not understand why I wanted this procedure because we already had confirmed bladder cancer. However, once I explained my perspective—that carcinosarcoma is so rare and the ongoing lymph node activity caused concern— he realized the importance and most readily agreed with it. “Everyone was surprised. We also were very happy. Hodgkin lymphoma carries a much better prognosis than metastatic bladder cancer. The choice of chemotherapy for Hodgkin lymphoma is completely different from that which is used for bladder cancer and the chemotherapy for bladder cancer is much harsher. The patient’s earlystage bladder cancer did not require any chemotherapy.” Dr. Perre: “Often for people with Hodgkin lymphoma, a core biopsy is not enough. Dr. Aithal recommended an excisional biopsy of the lymph node and this step really made the difference, because pathology indicated Hodgkin lymphoma. We took things a step further. Dr. Aithal knew that carcinosarcoma is rare; additionally, the pathology demonstrated that the carcinosarcoma was not muscle-invasive, and metastatic disease in this circumstance would have been exceedingly unusual. When we noted the lymph nodes in the left axilla, it gave us another place to investigate, and Dr. Aithal knew that an excisional biopsy could give us a better chance at making a definitive diagnosis. The excisional biopsy is what resulted in the Hodgkin lymphoma diagnosis.” Had the Hodgkin lymphoma not been detected, William D. would not only have received treatment for the wrong diagnosis, but also unnecessarily suffered the harsh side effects of advanced bladder cancer treatment.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ OCTOBER 2012

Recommended Treatment Next Steps: It was clear that William D. had two cancersâ&#x20AC;&#x201D;early-stage bladder cancer as well as advanced Hodgkin lymphoma. Urology confirmed that his bladder was stable and he began chemotherapy for Hodgkin lymphomaâ&#x20AC;&#x201D;four cycles of ABVD (adriamycin-bleomycin-vinblastine-dacarbazine) as firstline treatment for Hodgkin lymphoma. Dr. Perre: â&#x20AC;&#x153;The new diagnosis and subsequent treatment plan was formulated quickly. William D. went from thinking he would die to understanding he could live.â&#x20AC;?

Managing Side Effects William D. also received naturopathic recommendations to help manage the side effects of his prescribed chemotherapy regimen, as well as to monitor supplement and vitamin intake and prevent drugâ&#x20AC;&#x201C;herb and drugâ&#x20AC;&#x201C;nutrient interactions. Renee Lang, ND, a naturopathic oncology provider:

â&#x20AC;&#x153;Specifically, we focused on managing leg cramping, fatigue and mouth sores, as well as the reduction and prevention of neuropathy.â&#x20AC;? Next Steps: In addition to some general immune support, Edward was prescribed coenzyme Q10 as an antioxidant to decrease fatigue and as a protectant against potential cardiotoxicity that can arise from the use of adriamycin.

Coping With Cancer During his treatment, CTCA clinicians noted that William D. experienced mood disturbance and heightened anxiety. To address those challenges, the patient met with a member of the CTCA mindâ&#x20AC;&#x201C; body medicine team, a group of licensed mental health professionals who help support and maintain patientsâ&#x20AC;&#x2122; psychological well-being. The team uses evidence-based therapies such as cognitivebehavior therapy (CBT), sleep hygiene and relaxation training, which can help with physical symptoms such as dyssomnia, pain and nausea, as well as motivational interviewing, which can help to optimize adherence to treatment recommendations. Carol Roth, LCSW, a mindâ&#x20AC;&#x201C;body medicine clinician at CTCA:

â&#x20AC;&#x153;Getting a cancer diagnosis can be very traumatic and very shocking. People have a lot of other complex things going on, just by the nature of life itself, such as complex family and social relationships or demanding work and professional

relationships. And in the midst of that, a cancer diagnosis can upend a personâ&#x20AC;&#x2122;s life. As a result, there can be quite a bit of change in a personâ&#x20AC;&#x2122;s affect and their mood, and that can manifest in a variety of ways. â&#x20AC;&#x153;People can cope with stress in positive or negative ways. We help patients examine their individual coping style, identify their own strengths and build successful coping strategies to help them with the way they are feeling. We donâ&#x20AC;&#x2122;t change the facts of what is going on, but we can help patients with how they are coping, and help them build more positive ways of coping. For some people, cancer-related anxiety is transient and for others it is long-term. Some people are more open to it than others, but those who do use the services benefit a great deal.â&#x20AC;?

Outcome Three months into treatment, a PET/ CT scan demonstrated favorable response to therapy. Today, William D. is in remission and under surveillance, with cystoscopies performed every three months. Dr. Perre: â&#x20AC;&#x153;A diagnosis can cause a patient to become distraught and anxious. For William D., being told he would be dead in a year, and now in complete remission â&#x20AC;Ś he has a new lease on life. Part of what we do here is help comfort patients and provide tools to face challenges, because part of the battle is spiritual and emotional.â&#x20AC;? This is the first in a new series featuring case reports and highlighting multidisciplinary approaches to patient management. Clinical Oncology News welcomes your feedback on this new column. Please email managing editor Gabriel Miller at gmiller@mcmahonmed.com.

What are your thoughts?

FDA Drug Approvals

egorafenib (Stivarga, Bayer HealthCare Pharmaceuticals) was approved by the FDA for the treatment of metastatic colorectal cancer following previous treated with fluoropyrimidine-, oxaliplatin- and irinotecan-based chemotherapy, an anti-VEGF therapy, and, if KRAS wild type, an anti-EGFR therapy. In a trial of 760 previously treated patients, regorafenib improved median survival time by 1.4 months compared with placebo. The FDA approved bosutinib (Bosulif, Pfizer) for the treatment of chronic, accelerated or blast phase Philadelphia chromosome positive (Ph+) chronic myelogenous leukemia (CML) in adult patients with resistance or intolerance to prior therapy. Approval was based on a trial with 546 patients who were all resistant or intolerant to imatinib. Among patients with chronic phase CML who had been treated with imatinib alone, 53.4% achieved a major cytogenetic response at some point during the trial and of those patients, 52.8% had a major cytogenetic response lasting at least 18 months. For the 32.4% of patients with chronic phase CML previously treated with imatinib and at least one additional tyrosine kinase inhibitor who achieved a major cytogenetic response, 51.4% had a major cytogenetic response lasting at least 9 months. Enzalutamide (XTANDI Capsules, Medivation and Astellas Pharma) was approved by the FDA for patients with metastatic castration-resistant prostate cancer who have previously received docetaxel. In a randomized, placebo-controlled trial of 1199 patients who had received prior docetaxel, an interim analysis after 520 events demonstrated a statistically significant improvement in overall survival in the enzalutamide arm (hazard ratio, 0.63 [95% confidence interval: 0.53, 0.75], P<0.0001). The FDA also granted accelerated approval for everolimus tablets for oral suspension (Afinitor Disperz, Novartis Pharmaceuticals) for pediatric and adult patients with tuberous sclerosis complex who have unresectable subependymal giant cell astrocytoma (SEGA). The new dosage form expands the approved indication to include children less than 3 years of age. The application also provides a higher starting dose, revisions to dose modifications, and additional safety and efficacy data in the SEGA population. â&#x20AC;&#x201D;from FDA press releases

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

Letters to the Editor Readers respond to â&#x20AC;&#x153;Vogl, NYâ&#x20AC;? column on the EMILIA trial To the Editor:

Clinical Oncology News welcomes letters to the editor. Please send comments to

gmiller@mcmahonmed.com.

udos to Steve Vogl, MD, for once again rendering his thoughtful and straightforward opinion, in this instance regarding the EMILIA trial results and industryâ&#x20AC;&#x2122;s and governmentâ&#x20AC;&#x2122;s roles in making it more difficult than it needs to be to advance toward more cost effective delivery of quality medical care. And kudos to Clinical Oncology News for publishing Dr. Voglâ&#x20AC;&#x2122;s always interesting, thought provoking and frequently iconoclastic musings. Marc Slatkoff, MD Medical Oncologist Piedmont Hematology-Oncology Associates Winston-Salem, NC

To the Editor:

hank you for your thoughtful and timely editorial in Clinical Oncology News. There is a lot of nonsense being circulated out there and it was great to read a lucid article that has not forgotten the lessons of the past when treating patients with chemotherapy. Gary H. Lyman, MD, MPH Professor of Medicine Director, Comparative Effectiveness and Outcomes Researchâ&#x20AC;&#x201C;Oncology Duke University School of Medicine and the Duke Cancer Institute

CURRENT PRACTICE

VOGL continued from page 1

bevacizumab (“pac-bev”). Response and progression-free survival (PFS) were significantly inferior for the ixabepilone arm, and slightly but not significantly worse for the nab-paclitaxel arm (Table 1). Unfortunately, toxicity was excessive with the dose of abraxane chosen (150 mg/m2 three of four weeks, Table 2), resulting in dose reductions, dose delays, dose interruptions and an early time-totreatment failure (cessation of chemotherapy) a median of four months before disease progression. However, the most important observation from this study was not mentioned until the question-and-answer period: that the “control” group duplicated the extraordinarily long PFS of 11.5 months for weekly pac-bev originally reported by Kathy Miller, MD, in ECOG 2100 (Table 1).2 Genentech/Roche clearly erred in the development of bevacizumab for metastatic breast cancer. Rather than fund a convincing study to duplicate the results of ECOG 2100, Genentech decided to fund a series of first- and second-line chemotherapy studies of bevacizumab with different partner chemotherapy drugs called AVADO, RIBBON-1 and RIBBON-2. The results were much less impressive, with improvements in PFS of only two to three months and again no prolongation of survival, leading the FDA to withdraw its approval for the use of bevacizumab for metastatic breast cancer.

How To Interpret the Extraordinarily Long PFS of Paclitaxel-Bevacizumab The near doubling of median time to progression from six to 11.5 months without prolongation of median- or long-term survival is an incremental benefit. The assumption, which still needs to be validated prospectively, is that delaying disease progression prevents worsening of symptoms and improves quality of life,

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Instead of developing nab-paclitaxel as an easier to administer, less toxic, yet still effective formulation of an effective drug, Abraxis chose to push for higher doses, ignoring CALGB data that higher doses of paclitaxel are not more effective in treating metastatic breast cancer, but are still more toxic. even if it does not prolong life. Among women with symptomatic metastatic breast cancer who improve or resolve their symptoms on paclitaxel plus bevacizumab, delaying disease progression by 5.5 months must be a substantial benefit provided disease progression is accompanied by worsening of symptoms. As a compassionate physician, my goal in treating metastatic breast cancer is control of symptoms and prolongation of high-quality life, not prolongation of life by a few miserable months when death is near and impairment is major.

How Big of an Advance Is Paclitaxel Plus Bevacizumab? The addition of bevacizumab to weekly paclitaxel is not a “home run.” A “home run” would be a therapy that produced either some cures, a lot of long complete remissions—especially if they are unmaintained or maintained with minimal toxicity—or completely controlled symptoms for long periods with minimal levels of toxicity. Nonetheless, in 2012, I know of no other chemotherapy for HER2-negative breast

as first-line chemotherapy for metastatic disease, assuming I can induce their insurance companies to pay the very high price Roche seems to be able to charge for bevacizumab.

Is Nab-Paclitaxel Just a More Toxic, Less Effective Formulation? It is unclear whether this is the case. In a metastatic disease population of 454 women (60% with prior chemotherapy for metastatic disease, 78% recruited from Russia or Ukraine), William Gradishar, MD, a professor of hematology and medical oncology at Northwestern University in Chicago, reported in 2005 that nab-paclitaxel is more active and less toxic than paclitaxel dissolved in Cremophor EL (polyethoxylated castor oil) when each is given every three weeks, although the differences in response rate (33% vs. 19%) and median time to tumor progression (37 vs. 23 weeks) were modest.3 A subsequent four-arm Phase II study, also largely recruited in the former Soviet Union, made “Phase III-type” comparisons with only 75 patients in each of the

As a compassionate physician, my goal in treating metastatic breast cancer is control of symptoms and prolongation of high-quality life, not prolongation of life by a few miserable months when death is near and impairment is major. cancer that produces such long remissions, and, until something better comes along, I intend to offer it to my patients

four arms. Every-three-week nab-paclitaxel seemed neither more nor less effective than every-three-week docetaxel,

Table 1. Two Randomized Trials of Paclitaxel Plus Bevacizumab ECOG E2100

CALGB 40502

Paclitaxel (n=326)

Paclitaxel + Bevacizumab (n=347)

Paclitaxel + Bevacizumab (n=283)

Nab-Paclitaxel + Bevacizumab (n=271)

Median PFS, mo

5.9

11.8

10.6

9.2

Median TTF, mo

5.1

7.1

5.4

Median OS, mo

25.2

26.7

25%

49%

ORR

49%

Dose reduction by cycle 3

15%

45%

Treatment discontinuation by cycle 5

28%

47%

ECOG, Eastern Cooperative Oncology Group; CALGB, Cancer and Leukemia Group B; ORR, overall response rate; PFS, progression-free survival; TTF, time-to-treatment failure (cessation of chemotherapy portion); OS, overall survival from entry a

Among measurable disease patients only.

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

but weekly nab-paclitaxel at 100 or 150 mg/m2 seemed more effective, with overall response rates of 63% and 74% versus 39% with docetaxel, and longer median PFS (7.5 and 14.6 vs. 7.8 months for docetaxel). The confidence intervals for these figures were broad and these results were not exactly reproduced by independent radiologic review. Grade 3/4 neutropenia went from 25% at 100 mg/m2 weekly to 46% at 150 mg/m2 nab-paclitaxel weekly to 94% with every-threeweek docetaxel.4 I suspect it was the very long PFS on the high-dose weekly arm in this small study that led Abraxis to convince the Cancer and Leukemia Group B (CALGB) to use this dose in study 40502.

Was Positive Interaction of Nab-Paclitaxel With Bevacizumab Lost Because Doses Were Missed? In CALGB 40502, there was much more hematologic and neurologic toxicity with nab-paclitaxel than with solventbased paclitaxel, leading to many more dose reductions—and presumably, interruptions—as well as early discontinuation of therapy (Table 1). Because there appears to be a special interaction of bevacizumab with weekly paclitaxel, if toxicity led to a significant number of missed doses of weekly nab-paclitaxel, the special interaction may have been lost as an unexpected result of the loss of weekly scheduling. In addition, no favorable interaction in terms of duration of disease control can be expected if chemotherapy has been discontinued for toxicity. Unfortunately, we may never know whether a lower planned weekly nab-paclitaxel dose produces longer remissions, since it seems unlikely that this study will be repeated at a lower nab-paclitaxel dose. According to Dr. Rugo, the pharmaceutical company, Abraxis/Celgene,

What are your thoughts? Clinical Oncology News welcomes letters to the editor. Do you have thoughts on Dr. Vogl’s commentary? Please send comments to gmiller@mcmahonmed.com

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

chose the dose of nab-paclitaxel. Instead of developing nab-paclitaxel as an easier to administer, less toxic, yet still effective formulation of an effective drug, Abraxis chose to push for higher doses, ignoring earlier CALGB data that higher doses of paclitaxel are nott more effective in treating metastatic breast cancer, but are still more toxic.5 Perhaps Abraxis did not yet know the results of a large randomized Phase II study the company supported in the United States that looked at bevacizumab with three schedules of high-dose nab-paclitaxel.6,7 In this study, 37% of the 209 enrolled patients had their therapy stopped because of toxicity. One arm— 260 mg/m2 nab-paclitaxel given every 14 days—was closed to accrual early due to excessive toxicity after only 54 patients had been entered. Table 3 focuses on the 79 patients in this study assigned to weekly nab-paclitaxel plus bevacizumab at 130 mg/m2 per week without planned interruption. Although objective response was a respectable 45%, median duration of treatment was only 4.1 months (six three-week cycles), much shorter than the median time to disease progression of nine months. Hematologic and neurologic toxicity were at levels I consider excessive for the palliative treatment of incurable cancer (Table 3). By pushing to such high doses and high levels of toxicity, the duration of paclitaxel therapy was shortened and the favorable interaction with bevacizumab was probably impaired. Doses that were skipped for toxicity or not given because chemotherapy was stopped could not possibly interact favorably with bevacizumab.

Where Do We Go From Here? It would be reassuring to have studies to demonstrate that adding bevacizumab improves patients’ time with a high quality of life. I frankly doubt it is worth committing large numbers of patients and years of effort to prove this. A more reasonable and hopeful plan would probably be to use pac-bev as a control arm with which to compare promising therapies in the future, measuring symptoms and quality of life both on study and after the study period. If pac-bev prolongs time to progression, then patients will be “on study” longer, and we will need to compare their symptoms and quality of life both early and late in their pac-bev therapy to the quality of life of the patients on comparator therapies over the same

Table 2. Toxicity in CALGB 40502 Paclitaxel + Bevacizumab (n=262)

Nab-Paclitaxel + Bevacizumab (n=258)

Any grade toxicity >3

55%

79%

Hematologic toxicity grade >3

21%

51%

Nonhematologic toxicity grade >3

44%

60%

Sensory neuropathy grade >3

16%

25%

Motor neuropathy grade >3

10%

Neutropenia grade >3

18%

47%

CALGB, Cancer and Leukemia Group B Schedule: Paclitaxel given at 90 mg/m2 on days 1, 8 and 15 every 28 d; nab-paclitaxel given at 150 mg/m2 on days 1, 8 and 15 every 28 d.

In 2012, we need to encourage our patients to enjoy the extra 5.5 months of disease control that bevacizumab adds to initial chemotherapy for metastatic breast cancer with weekly paclitaxel. Table 3. Celgene’s Phase II Trial of Nab-Paclitaxel At 130 mg/m2 Weekly1 Efficacy ORR

44%

Median time to tumor progression, mo

9.0

Median OS, mo

23.7

Treatment delivery >1 dose delay

86% (56% of these for neurotoxicity)

>1 dose reduction

67% (43% of these for grade 3/4 neurotoxicity)

Median duration of treatment, mo

4.1 (6 cycles of 21 d each)

Toxicity Neurotoxicity grade >3, %

Sensory neuropathy grade >2, %

Neutropenia grade >3, %

ORR, overall response rate; OS, overall survival 1. Seidman AD, Conlin AK, Bach A, et al. Randomized Phase II trial of weekly vs. q 2-weekly vs. q 3-weekly nanoparticle albumin-bound paclitaxel with bevacizumab as first-line therapy for metastatic breast cancer. Presented at the San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. Abstract P1 P1-14-01. 14 01.

time period. These comparator patients may already have switched to secondor even third-line therapies while the weekly pac-bev patients continue in their first remissions! Although we have never conducted chemotherapy studies in this way in the past, it makes sense to do this when quality of life is the major

end point, and prolongation of life is not attainable. Once quality of life integrated over time becomes the major end point, then minimization of subjective toxicities assumes great importance in trial design and dose selection—a good thing, I would argue.

gmiller@mcmahonmed.com

It may be that pac-bev will prove a spine on which to add other therapies either at the start of therapy, at the time that neuropathy forces cessation of the paclitaxel component, or at some time point after stable partial remission. It seems more likely that the modest achievement of prolonging remission for a few months by pac-bev will prove a “dead end” and that further advances will depend on new drugs with different mechanisms of action. Nonetheless, in 2012, we need to encourage our patients to enjoy the extra 5.5 months of disease control that bevacizumab adds to initial chemotherapy for metastatic breast cancer with weekly paclitaxel.

References 1. Rugo HS, Barry WT, Moreno-Aspitia A, et al. CALGB 40502/NCCTG N063H: randomized phase III trial of weekly paclitaxel (P) compared to weekly nanoparticle albumin bound nab-paclitaxel (NP) or ixabepilone (Ix) with or without bevacizumab (B) as first-line therapy for locally recurrent or metastatic breast cancer (MBC). Presented at the Annual Meeting of the American Society of Clinical Oncology; June 1-5, 2012; Chicago, IL. Abstract CRA1002. 2. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357:2666-2676, PMID: 18160686. 3. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794-7803, PMID: 16172456. 4. Gradishar WJ, Krasnojon D, Cheporov S, et al. Significantly longer progression-free survival with nab-paclitaxel compared with docetaxel as first-line therapy for metastatic breast cancer. J Clin Oncol. 2009;27:36113619, PMID: 19470941. 5. Winer EP, Berry DA, Woolf S, et al. Failure of higher-dose paclitaxel to improve outcome in patients with metastatic breast cancer: cancer and leukemia group B trial 9342. J Clin Oncol. 2004;22:2061-2068, PMID: 15169793. 6. Conlin AK, Hudis CA, Bach A, et al. Randomized phase II trial of nanoparticle albumin-bound paclitaxel in three dosing schedules with bevacizumab as first-line therapy for HER2-negative metastatic breast cancer (MBC). Presented at the Annual Meeting of the American Society of Clinical Oncology; May 29-June 2, 2009; Orlando, FL. Abstract 1006. 7. Seidman AD, Conlin AK, Bach A, et al. Randomized Phase II trial of weekly vs. q 2-weekly vs. q 3-weekly nanoparticle albumin-bound paclitaxel with bevacizumab as first-line therapy for metastatic breast cancer. Presented at the San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. Abstract P1-14-01.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Regimen Shows Promise in Older Patients With Hodgkin Lymphoma From Blood

multi-drug chemotherapeutic regimen containing vinblastine, cyclophosphamide, prednisolone, procarbazine (Matulane, Sigma Tau), etoposide, mitoxantrone and bleomycin has been shown to be effective in older adults with Hodgkin lymphoma (with the exception of procarbazine, all are available in generic form in the United States). The U.K.-based Phase II clinical trial, part of the SHIELD (Study of Hodgkin In the Elderly/Lymphoma Database) study, was designed to expand on the findings of the Italian Lymphoma Group, which first developed

and studied the regimen in elderly patients with the disease in the early 2000s ((Ann Oncol 2004;15:123-128; PMID: 14679131). The results of the present study on the regimen, known collectively as VEPEMB, were published in the June 21 issue of the journal Blood d (2012;119:6005-6015; PMID: 22577177). In the SHIELD study, 103 patients (median age, 73) with Hodgkin lymphoma were treated with VEPEMB and another 54 were registered (offstudy) prospectively and treated with ABVD (doxorubicin, bleomycin, vinblastine and dacarbazine)—a regimen that is considered the gold standard for treatment of younger patients with Hodgkin lymphoma—or CLVPP

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

ge is an independent, poor prognostic feature in Hodgkin lymphoma.1 The ABVD regimen may be excessively toxic in older adults; in one retrospective cohort study, the treatment-related mortality rate was 20%, whereas only 20% of patients over the age of 60 years achieved a CR.2 Thus, efforts have been made to seek new treatment options. In a study from the German Hodgkin Study Group, 75 patients aged 66 to 75 were randomized to BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) or COPP-ABVD (cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine).3 The CR rates were 76% and 77% in the BEACOPP and COPP-ABVD arms, respectively, but the toxic death rates were 21% and 8%, respectively. Thus, BEACOPP is too toxic for older adults. The SHIELD study sought to prospectively enroll older patients with Hodgkin lymphoma and assess the

efficacy and safety of the VEPEMB regimen. Patients underwent a prospective evaluation of their comorbid medical conditions. In this study, 175 patients over the age of 60 years with Hodgkin lymphoma were enrolled. Of these, 103 were treated with VEPEMB, whereas the remainder, who were deemed too frail for the experimental regimen, were treated at physician discretion. In the patients treated with VEPEMB, the overall CR rate was 65.3%. Patients who failed to complete a course of chemotherapy and who required dose reduction were less likely to achieve CR. The treatment-related septic death rate was 3%. In an evaluation of the entire cohort (including those treated with other regimens), factors predictive of achieving CR included hemoglobin, comorbidities, dependence on instrumental activities of daily living, Eastern Cooperative Oncology Group performance status and albumin. There is growing evidence of the importance of incorporating principles of geriatric assessment into the

(chlorambucil, vinblastine, procarbazine hydrochloride and prednisolone). Additionally, 18 patients also were registered (off-study) prospectively and administered alternative treatments, such as radiotherapy, surgery or CHOP (cyclophosphamide, doxorubicin, vincristine and prednisolone). Among the patients in the VEPEMB arm, 31 had early-stage disease (stages 1A or 2A); these patients received three cycles of VEPEMB followed by radiotherapy. After a median followup of 36 months, 74% of these patients achieved complete remission (CR), and three-year overall survival (OS) and progression-free survival (PFS) were 81% and 74%, respectively. The remaining 72 patients in the VEPEMB

arm had advanced disease (stages 1B, 2B, 3 or 4) and received six cycles of VEPEMB followed by radiotherapy. In this group, 61% achieved CR, and three-year OS and PFS were 66% and 58%, respectively. Patients in the other treatment arms did not fare as well. In the CLVPP arm, for example, only 62% of those with early-stage disease achieved CR. Among those with advanced disease in this arm, only 46% achieved CR. The data were similar for the ABVD arm. The most common adverse events associated with VEPEMB in the trial included neutropenic sepsis and pyrexia. The ABVD regimen “demonstrated substantial toxicity,” the authors noted.

oncologic assessment of older adults.4 Geriatric assessments include evaluation of comorbidities, functional status, cognition, depression, nutritional status, falls and social support. Geriatric assessment is predictive of grade III/IV toxicity of chemotherapy in older adults with cancer.5,6 In a prospective cohort of older patients with diffuse large B-cell lymphoma, geriatric assessment was superior to clinical judgment in distinguishing which patients were fit for standard therapy; patients who were frail by geriatric assessment who received anthracycline-based therapy had no better outcomes than frail patients who received palliative treatment.7 In summary, with the aging of the population, an increase in the number of elderly with most malignancies is anticipated.8 New treatment approaches should incorporate geriatric principles, as was done in this study, both for selecting therapy for subgroups of older adults, but also subsequently as predictors of toxicity and outcomes to facilitate decision making for clinicians, patients and their caregivers.

Hodgkin’s lymphoma patients older than 45 years. Pathol Oncol Res. 2012;18(3):675680, PMID: 22234624.

References 1. Hasenclever D, Diehl V. A prognostic score for advanced Hodgkin’s disease. International Prognostic Factors Project on Advanced Hodgkin’s Disease. N Engl J Med. 1998;339(21):1506-1514, PMID: 9819449. 2. Andjelic BM, Mihaljevic BS, Jakovic LR. ABVD as the treatment option in advanced

3. Ballova V, Rüffer JU, Haverkamp H, et al. A prospectively randomized trial carried out by the German Hodgkin Study Group (GHSG) for elderly patients with advanced Hodgkin’s disease comparing BEACOPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005;16(1):124131, PMID: 15598949. 4. Dale W, Mohile SG, Eldadah BA, et al. Biological, clinical, and psychosocial correlates at the interface of cancer and aging research. J Natl Cancer Inst. 2012;104(8):581-589, PMID: 22457474. 5. Hurria A, Togawa K, Mohile SG, et al. Predicting chemotherapy toxicity in older adults with cancer: a prospective multicenter study. J Clin Oncol. 2011;29(25):3457-3465, PMID: 21810685. 6. Extermann M, Boler I, Reich RR, et al. Predicting the risk of chemotherapy toxicity in older patients: The Chemotherapy Risk Assessment Scale for HighAge Patients (CRASH) score. Cancer. 2012;118(13):3377-3386, PMID: 22072065. 7. Tucci A, Ferrari S, Bottelli C, Borlenghi E, Drera M, Rossi G. A comprehensive geriatric assessment is more effective than clinical judgment to identify elderly diffuse large cell lymphoma patients who benefit from aggressive therapy. Cancer. 2009;115(19):4547-4553, PMID: 19562776. 8. Smith BD, Smith GL, Hurria A, Hortobagyi GN, Buchholz TA. Future of cancer incidence in the United States: burdens upon an aging, changing nation. J Clin Oncol. 2009;27(17):2758-2765, PMID: 19403886.

Dr. Wildes reported no financial disclosures relevant to this study.

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CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Vitamin D Linked to Breast Cancer Survival, Tumor Size Lower vitamin D levels at time of diagnosis did not significantly correlate with lymph node invasion, receptor status or tumor grade. This finding suggests a possible mechanism of action: “Our own observations, indicating that low 25(OH) D levels correlate with larger breast tumors, clearly point toward a role of vitamin D in breast tumor biology. In particular, vitamin D could be involved in local growth-inhibitory effects in the microenvironment of the breast tumor,” the investigators wrote. All women were diagnosed with primary, non-metastatic breast cancer at University Hospitals Leuven in Belgium between June 2003 and February 2010. In terms of survival, a serum vitamin D level greater than 30 ng/mL

From Carcinogenesis

itality and vitamin D very likely could be linked for women diagnosed with early, primary breast cancer, according to a study. Higher serum 25-hydroxyvitamin D3 (25[OH]D) levels among 1,800 women significantly correlated with improved survival and lower relapse rates, particularly among postmenopausal patients. One tumor characteristic also emerged as significantly associated with vitamin D level. “Our most remarkable finding was that reduced 25(OH) D levels correlate with increased tumor size. This observation is intriguing and has not previously been reported,” the authors wrote in Carcinogenesis (2012;33:1319-1326, PMID: 22623648).

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

his study adds to the growing literature on the association of vitamin D and cancer, and reminds us that the vitamin D signaling pathway remains an elusive system. The investigators looked prospectively at SNPs of several genes related to vitamin D metabolism in 1,800 newly diagnosed patients with early breast cancer and performed linear regression analysis to determine whether the association

between 25(OH)D serum levels and tumor characteristics was maintained at the gene level. An inverse relationship between tumor size and 25(OH) D level in postmenopausal women was indeed noted; however, no correlation between SNP genotypes and tumor characteristics could be found. This negative result is not entirely surprising considering the extraordinarily complex signaling pathway of

conferred a significant benefit for overall survival (OS; P=0.0101) and significant disease-specific survival (DSS; P=0.0192). In a stratified analysis, postmenopausal (but not premenopausal) women exhibited a significant advantage in DSS, disease-free interval and distant disease-free interval. Specifically, during a median follow-up of 4.7 years, the observed relapse rate among women with 25(OH)D levels below or equal to 30 ng/mL was 7.8% versus 5.6% for the group with serum 25(OH)D levels greater than 30 ng/mL. Because previous researchers demonstrated certain genetic variants are significantly associated with vitamin D status, the investigators also assessed eight potentially relevant single nucleotide polymorphisms (SNPs) in a subset of

1,338 patients with available data. However, they found no significant association between these genetic factors and tumor characteristics or survival. Although the association between lower vitamin D levels and greater tumor size was significant, it was “rather modest,” representing a potential limitation of the study, the researchers noted. Analysis of breast cancer–specific survival and a documented cause of death in 87% of participants who died were strengths of the study. Future study to resolve the unanswered question about whether vitamin D supplementation should be administered to women to prevent breast cancer is warranted. These future findings could dictate inclusion of such recommendations in standard treatment regimens.

vitamin D which, besides regulating the homeostasis of calcium and phosphorus, exerts a paracrine effect on almost every cell in the body, including breast cells. Breast cells in fact possess the enzyme that converts the precursor of 25(OH)D into its active form 1,25-dihydroxyvitamin D, which in turn regulates a cascade of other pathways. Unfortunately, it is still unclear whether there is a causal effect of vitamin D on cancer, and if anything, this study advises caution before encouraging vitamin D supplementation to further the goal of preventing cancer. There is an abundance of studies showing that all-cause mortality is increased with lower vitamin D levels; however, we still do not know what is the safe upper limit of normal. For instance, the National Health and Nutrition

Examination Survey III study suggests that 25(OH)D levels above 50 ng/mL may be associated with an increased all-cause mortality in women,1 and that lung cancer and other digestive system cancers may also be higher in men with high levels of 25(OH)D.2

References 1. Melamed ML, Michos ED, Post W, et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168:1629-1637; PMID: 18695076. 2. Freedman DM, Looker AC, Abnet CC, et al. Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (19882006). Cancer Res. 2010;70:8587-8597; PMID: 20847342.

Dr. Rastelli reported no relevant financial disclosures.

Regorafenib Offers New Option for Refractory GIST Double-blind study of 199 patients Chicago—A Phase III trial has shown that regorafenib (Bayer) is a new potential therapeutic option for patients with advanced gastrointestinal stromal tumor (GIST) resistant to tyrosine kinase inhibitors (TKIs). In late August, Bayer submitted a New Drug Application for regorafenib in GIST. “Regorafenib has the potential to fulfill an unmet need for patients with advanced GIST progressing after imatinib and sunitinib and potentially represents a new standard of care for this patient population,” said George Demetri, MD, director of the Center for Sarcoma and Bone Oncology at Dana-Farber

Cancer Institute and Harvard Medical School in Boston. He presented the study at the recent annual meeting of the American Society of Clinical Oncology (abstract LBA1008). Imatinib (Gleevec, Novartis) and sunitinib (Sutent, Pfizer) are the only two FDA-approved drugs for advanced GIST. Although these two TKIs have revolutionized the care of this disease, drug resistance remains a challenge. Regorafenib is a structurally distinct oral inhibitor of multiple kinases including KIT, VEGFR-1/2, PDGFR, RET, BRAF and FGR1. The GRID (GIST-Regorafenib in

Progressive Disease) trial enrolled patients with metastatic/unresectable GIST who were progressing despite prior treatment with imatinib and sunitinib. The double-blind trial involving 17 countries across Europe, North America and Asia-Pacific, randomized 199 patients in a 2:1 ratio to regorafenib or placebo, each with best supportive care. Patients were followed until disease progression, at which point patients were unblinded and allowed to cross over to receive regorafenib. The median progression-free survival was 4.8 months in patients receiving regorafenib compared with 0.9 months in

GIST cells under a microscope.

patients receiving placebo (hazard ratio [HR], 0.27; P<0.0001). Similar activity was seen in patients whether they were treated in third-, fourth- or later-line therapy, as well as whether the primary KIT T mutation was in KIT T exon 11 or exon 9.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Rituximab Maintenance for Elderly With Mantle Cell Lymphoma From The New England Journal of Medicine

one–two punch against mantle cell lymphoma (MCL) in older patients has demonstrated the potential to improve an otherwise dismal prognosis. Researchers from the European Mantle Cell Lymphoma Network assessed 485 patients newly diagnosed with stage II to IV cancer. Median age was 70 years. Beginning in 2004, they searched for an optimal chemotherapy strategy since currently only a minority of patients achieves complete remission (CR). Relapse or progression typically occurs within two to three years of diagnosis, spurring an overall survival (OS) rate that is less than five years. This study, published in August in The New England Journal of Medicine

(2012;367:520-531, PMID: 22873532), was a double-randomized trial that had two goals: first, compare the induction regimens R-FC (rituximab, fludarabine and cyclophosphamide) with R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone); and second, in patients who responded at induction, compare maintenance therapy using rituximab or interferon-alfa (IFN-α). α The percentage of patients who achieved CR following induction did not differ significantly between the R-CHOP group (34%; 81 of 239 patients) and the RF-C group (40%; 98 of 246 patients). However, fewer patients in the R-CHOP arm experienced progressive disease (5%) compared with the RF-C group (14%). Patients who responded to induction were re-randomized to maintenance therapy with either rituximab or IFN-α.

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

atients aged 65 years and over represent a majority of new MCL diagnoses, limiting use of aggressive treatment strategies that have improved outcomes in younger patients. The results of this study will help inform, but not define, therapy for older patients with MCL. The good news was that maintenance rituximab enhanced remission duration compared with IFN-α. Because the efficacy of IFN-α maintenance in MCL has been demonstrated previously, a comparison between maintenance

Median overall survival had not yet been reached, but was trending in favor of regorafenib (HR, 0.77; P=0.199). Dr. Demetri pointed out that because of the crossover design, a statistically significant difference was not expected. “Eighty-five percent of patients on the placebo arm crossed over to regorafenib,” said Dr. Demetri. Most grade 3 treatment-emergent adverse events were similar in the two arms, but patients receiving regorafenib had a greater incidence of hand–foot– skin reaction (19.7% vs. 1.5%), hypertension (22.7% vs. 3%), and diarrhea (5.3% vs. 0%). However, patients were able to

rituximab and no maintenance likely would have demonstrated an even greater benefit. It is important to highlight that the maintenance rituximab regimen used here was continued every two months until disease progression instead of stopping after two years, as is standard in follicular lymphoma. The bad news was the poorer OS seen in the R-FC arm. This was due to increased deaths from relapse, infection, secondary malignancy and other causes, many of which were seen while patients were in remission. Although

Those who received rituximab experienced a longer duration of remission during a median 36-month follow-up. Hematologic toxic effects were more frequent in the R-FC group compared with the R-CHOP group, including grade 3 or 4 anemia, leukocytopenia, lymphocytopenia, neutropenia and thrombocytopenia. In contrast, grade 1 or 2 constipation and neuropathy were more frequent in the R-CHOP group. “Our results show that the fludarabine-containing induction regimen was not more effective but was more toxic than R-CHOP,” the authors wrote. “Maintenance therapy with rituximab almost doubled the duration of remission in patients who had a response to induction therapy and significantly improved overall survival among patients who had a response to R-CHOP.” Thus, the researchers demonstrated

some synergy in OS between induction and maintenance. Looking at only the maintenance period, overall survival (OS) at four years did not differ significantly between 79% with rituximab and 67% with IFN-α. However, a significant survival gain at four years emerged for patients treated with R-CHOP followed by rituximab maintenance (87%) versus those treated with R-CHOP followed by IFN-α maintenance (63%; P=0.005). Rituximab was associated with a 45% reduction in risk for progression or death compared with IFN-α. “The excellent results with rituximab administered as maintenance therapy are important. Maintenance therapy with rituximab showed not only a progression-free survival benefit but also a significant survival advantage among patients who were successfully pretreated with R-CHOP,” the authors noted.

we cannot be certain of a direct relationship, the profound and sometimes prolonged suppression of the lymphoid and myeloid cell lines associated with fludarabine is highly suspect. Fludarabine-induced immune suppression could directly increase the risk for relapse, infection and secondary malignancy, and it also may limit the ability to administer effective treatment at the time of relapse. Overall, fludarabine-based therapy should probably be avoided in this population under most circumstances. The difficult (i.e., ugly) news arises when we try to interpret these results in the context of the modern clinical landscape. One drawback of large studies of rare diseases is the delay between study inception and conclusion. Such studies often answer questions that are less clinically relevant by the time they are published. Perhaps due to extrapolation

from studies of elderly chronic lymphocytic leukemia patients, most clinicians would already avoid fludarabine in elderly patients with MCL, decreasing the relevance of this finding. Furthermore, bendamustine plus rituximab improves progression-free survival and has less toxicity in comparison to R-CHOP in patients with MCL, a finding that has already affected clinical practice. Whether maintenance rituximab will have a similar impact after bendamustine induction therapy is unknown. However, given the relatively short median survival seen in elderly patients with MCL and the manageable side-effect profile associated with maintenance rituximab, I would advocate for rituximab maintenance therapy in patients who respond to first-line therapy.

‘Clearly this is a positive study and there is no doubt that regorafenib is a viable third-line option for our patients.’ —Grant McArthur, MBBS, PhD continue successfully on regorafenib with study-defined dose modifications, and the rate of toxicity-related treatment discontinuation was actually slightly higher in patients receiving placebo than those on regorafenib (7.6% vs. 6.1%). “Clearly this is a positive study and there is no doubt that regorafenib is a viable third-line option for our patients,”

said Grant McArthur, MBBS, PhD, a GIST expert at the Peter MacCallum Cancer Center in Melbourne, Victoria, Australia. Dr. McArthur pointed out, however, that not all clinicians treating refractory GIST offer only best supportive care. Some clinicians might choose to continue a previous TKI therapy following progression of disease or try a different,

Dr. Carson reported no relevant financial disclosures.

unapproved TKI. It is unclear how regorafenib would stack up against either of these two treatment choices, he said. —Kate O’Rourke Dr. Demetri disclosed a consultant or advisory role with Deciphera, GlaxoSmithKline, Infinity, Novartis, Pfizer, Roche/Genentech, and research support from the latter four. Dr. McArthur disclosed an uncompensated consultant or advisory role with Bristol-Myers Squibb, GlaxoSmithKline, Millennium, Novartis and Roche/Genentech, as well as research funding from Millennium, Novartis and Pfizer.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Blocking Angiogenesis Throughout Cancer Treatments In metastatic colorectal cancer, continuing bevacizumab benefits survival Chicago—Continuing bevacizumab during a second-line chemotherapy regimen slows the growth of metastatic colorectal cancers (mCRC), according to results of a multicenter Phase III trial. In patients who received bevacizumab (Avastin, Genentech) in first-line treatment and were then randomized to receive either bevacizumab or no antiangiogenesis agent during a second-line course of different chemotherapy, the addition of bevacizumab significantly improved survival (ASCO meeting; abstract CRA3503). “This study confirms that continuing bevacizumab after first progression while altering chemotherapy is beneficial,” Dirk Arnold, MD, PhD, the medical

director of the Hubertus Wald Tumor Center at University Cancer Center in Hamburg, Germany, said. Dr. Arnold suggested a new model for mCRC treatment in which angiogenesis inhibition is maintained through multiple lines of chemotherapy. In the trial, 820 patients with unresectable mCRC who had progressed within three months of discontinuing a first-line oxaliplatin (Eloxatin, Sanofi-aventis)- or irinotecan-based chemotherapy were randomized to receive second-line chemotherapy with or without bevacizumab. In the second-line regimen, which was anchored with an agent not used previously, bevacizumab was administered at a dose of 2.6 mg/kg per week. The primary end point was overall survival (OS). Secondary end points

AT A GLANCE Angiogenesis inhibitors in advanced cancers Continuing bevacizumab through second-line chemotherapy improved OS by six weeks There were no additional adverse events Bevacizumab binds to vascular endothelial growth factor (VEGF) extracellularly to prevent interaction with cell surface receptors, blocking angiogenesis via the VEGF pathway.

‘I expect that there will be a label change for bevacizumab which will be bevacizumab beyond progression.’

—Alan P. Venook, MD

included progression-free survival (PFS) and safety. Most of the 220 participating treatment centers were in Europe. Continuing bevacizumab produced an absolute benefit in OS of about six weeks (9.8 vs. 11.2 months), which translated into a 19% reduction in the hazard ratio (HR, 0.81; 95% confidence interval [CI] 0.69-0.94; P=0.0062). On the basis of PFS, a secondary end point, the relative advantage (5.7 vs. 4.1 months) was even greater (HR, 0.67; 95% CI, 0.58–0.78; P<0.0001). Adverse events were mild and

comparable to those observed in firstline therapy for mCRC. Slightly more patients in the bevacizumab arm had grade 3 or higher adverse events, but the rate of serious adverse events was slightly lower (32% vs. 34%). Based on these results, “I expect that there will be a label change for bevacizumab which will be bevacizumab beyond progression,” said Alan P. Venook, MD, a professor of hematology and oncology at the University of California, San Francisco. Dr. Venook suggested that the benefits are relatively modest

The high cost of antiangiogenic agents is a serious hurdle

with these therapies, however the costs remain high. He suggested that in the future hard choices will have to be made in valuing these therapies and suggested research that improves the cost-benefit ratio, particularly the development of biomarkers that will identify those most likely to respond. —Ted Bosworth Dr. Arnold has served as a consultant and received honoraria from Amgen, Merck Serono and Roche, as well as received research funding from Roche. Dr. Venook has served as a consultant for Abbott Laboratories, Bristol-Myers Squibb and Chugai Pharma and received research funding from Bayer and Onyx.

HEMATOLOGIC DISEASE

Vemurafenib Induces Remission in Patient With Hairy Cell Leukemia Clinical trial to test therapy in relapsed HCL patients Chicago—A single case study has shown that vemurafenib (Zelboraf, Genentech) may be effective in treating patients with hairy cell leukemia (HCL). The drug jettisoned a chemotherapy-refractory patient with HCL into remission, according to researchers who reported the success story at the annual meeting of the American Society of Clinical Oncology (abstract 6519). Vemurafenib is currently approved for BRAF V600E metastatic melanoma. BRAF V600E is found in virtually all cases of HCL, suggesting disease-specific oncogene dependence. For this reason, German researchers led by Sascha Dietrich, MD, from the University Hospital Heidelberg, decided to try vemurafenib in a

‘One single patient with one and a half feet in the grave … was brought back to life with this drug, and the remission is continuing.’ —Kanti Rai, MD

Hairy cell leukemia.

chemotherapy-refractory HCL patient with a confirmed BRAF V600E mutation. The patient had subtotal bone marrow infiltration and massive splenomegaly (24.8 × 8.3 cm) leading to severe

cytopenia (leukocytes 680/mcL; hemoglobin 10 g/dL; platelets 36,000/mcL). After a single loading dose of vemurafenib 960 mg, clinicians started the patient on a dose of 240 mg twice daily, slowly escalating to 1,920 mg per day. The patient quickly responded, with a complete clearance of hairy cells on day 36 and a complete remission on day 43. Clinicians discontinued treatment after 56 days, and at three months, remission persisted. The case study was also

reported in the New England Journal of Medicine (2012;366:2038-2040, PMID: 22621641). “Mutation of BRAF V600E is virtually pathognomonic of hairy cell leukemia. Therefore, it is eminently sensible to start to mount therapies in hairy cell leukemia using this newly available drug,” said Kanti Rai, MD, the chief of CLL Research and Treatment Programs at North Shore-Long Island Jewish Medical Center in New Hyde Park, N.Y.

CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Olanzapine Beats Metoclopramide for Breakthrough Nausea But other agents still may be first-line therapy

he antipsychotic drug olanzapine is superior to metoclopramide for breakthrough chemotherapy-induced nausea and vomiting (CINV), according to a Phase III trial. Lead investigator Rudolph M. Navari, MD, PhD, the clinical director of the Harper Cancer Institute at Indiana University School of Medicine-South Bend, said the study is the first time that breakthrough CINV has been studied in a systematic way. American Society of Clinical Oncology (ASCO) president Sandra Swain, MD, said the drug provides oncologists with a new tool to help patients who experience breakthrough CINV. “I would definitely consider using olanzapine in a patient who had already had optimal first-line treatment with multiple drugs, which include a 5-HT3 antagonist to prevent nausea and vomiting. Relatively speaking, it is very inexpensive,” she wrote in an email to Clinical Oncology News. Some community oncologists, however, say the study won’t change their practice. “I don’t think metoclopramide is used much in the breakthrough CINV setting—that agent is more useful for chronic nausea in cancer patients,” said Michael Fisch, MD, MPH, an associate professor of general oncology at the University of Texas MD Anderson Cancer Center in Houston.

Table. NCCN Recommended Agents for Breakthrough Chemotherapy-Induced Nausea and Vomiting Benzodiazepine Lorazepam

“More commonly used agents for breakthrough CINV are prochlorperazine or 5-HT3 antagonists,” Dr. Fisch said. “These agents are familiar, similarly effective, and prochlorperazine is much cheaper than olanzapine. Thus, I don’t see the Navari trial changing practice much, other than further reducing the already infrequent use of metoclopramide in this particular setting.”

chemotherapy (cisplatin, cyclophosphamide and doxorubicin) who were receiving guideline-directed prophylactic antiemetics. Roughly 80 patients were randomized to receive either olanzapine (10 mg per day for three days) or metoclopramide (10 mg three times per day for three days). At the annual ASCO meeting, Dr. Navari reported that during a 72-hour

Cannabinoids Dronabinol Nabilone Phenothiazines

‘I don’t see the Navari trial changing practice much, other than further reducing the already infrequent use of metoclopramide in this particular setting.’

Prochlorperazine

—Michael Fisch, MD, MPH

Promethazine 5-HT3 Antagonists Dolasetron Granisetron Ondansetron Corticosteroid Dexamethasone Others Haloperidol Metoclopramide Olanzapine Scopolamine

Olanzapine costs around 45 cents per dose, whereas prochlorperazine is less than 10 cents per dose. The National Comprehensive Cancer Network guidelines currently recommend a number of drugs for treating breakthrough CINV (Table) and suggest adding an agent that has not already been used in a patient. Investigators tested olanzapine for breakthrough CINV because when the drug was used as an antipsychotic in mental patients, it appeared to prevent nausea and vomiting caused by other drugs. The study included chemotherapy-naive patients with a variety of cancers who received highly emetogenic

period, 71% of patients taking olanzapine reported no emesis compared with 32% of patients on metoclopramide ( <0.01; abstract 9064). The percent(P age of patients reporting no nausea was also greater in the olanzapine arm (67% vs. 24%; P<0.01). While olanzapine is known to cause a variety of side effects when taken daily for six months or longer, the short-term use in this study did not lead to any significant toxicities.

Sloan-Kettering Cancer Center in New York City and North Shore-Long Island Jewish Medical Center are in the process of launching a clinical trial to test vemurafenib in HCL patients who have relapsed. Dr. Rai estimates that there are only roughly 200 of these patients in the United States each year, because the disease is so rare. He hopes that clinicians who learn about the soon-tobe launched trial will refer patients to the two centers and that the trial will

expand to additional sites. Dr. Rai also pointed out that the International HCL Research Consortium has launched a clinical trial to test the Bruton’s tyrosine kinase inhibitor ibrutinib (Pharmacyclics) in relapsed HCL.

—Kate O’Rourke Drs. Navari, Swain and Fisch have no relevant disclosures.

HEMATOLOGIC DISEASE

“This is a fascinating poster,” Dr. Rai said. “One single patient with one and a half feet in the grave—multiply treated, huge splenomegaly, wall-to-wall hairy cells, performance status poor— was brought back to life with this drug, and the remission is continuing. It is a dramatic drug that we should expect to hear more about.” Richard Stone, MD, the program director of the Adult Leukemia Program at Dana-Farber Cancer Institute in Boston, also has high hopes for

the drug. “We need to do a formal trial to prove the value of vemurafenib in HCL, but I do expect it to work,” he said. He doesn’t expect much off-label use of the drug because of reimbursement issues and because other good options for HCL, such as cladribine, exist. But he thinks that some clinicians will use the drug in patients who are refractory to available treatments. A concrete answer on the value of the drug may not be too far away. Memorial

—Kate O’Rourke

Dr. Rai disclosed a consultant or advisory role with Genentech. Dr. Stone and Dr. Dietrich had no relevant disclosures.

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

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Ablative Technologies Promising for Risky Tumors Field awaits long-term data on efficacy and safety of two modalities Chicago—Two emerging ablative technologies hold promise for treating tumors that are too risky to ablate with existing technologies, experts told attendees of the 2012 World Conference on Interventional Oncology (WCIO). These new technologies—irreversible electroporation (IRE) and image-guided high-intensity focused ultrasound (HIFU)—were discussed as potential options for ablating tumors located in close proximity to critical structures and blood vessels, but experts noted that their exact place in the treatment armamentarium remains unknown because of a paucity of data. “These are very interesting technologies that may have applications in selected patients,” said Eileen O’Reilly, MD, a gastrointestinal oncologist at Memorial Sloan-Kettering Cancer Center and associate professor of medicine at Weill Cornell Medical College, both in New York City. Dr. O’Reilly said IRE has been used at her institution to ablate tumors close to blood vessels and the biliary tract in selected patients and it has proven safe. However, outcomes data for both IRE and HIFU, the latter of which has not received FDA approval for use, are lacking. “Given that the field of ablative technologies is crowded and reported experience with these two technologies is relatively limited, further prospective study is needed to determine where they might fit in,” she said. According to Govindarajan Narayanan, MD, the chief of vascular and interventional radiology at the University of Miami’s Miller School of Medicine, the strength of IRE is that, unlike radiofrequency ablation (RFA), microwave ablation (MWA) and cryoablation, it is a non-thermal technology. Instead, it uses high-level electrical pulses to damage cell membranes and induce apoptosis. “Since it does not emit heat, IRE is safer than thermal ablation when used in close proximity to critical structures like bile ducts and blood vessels,” Dr. Narayanan said.

IRE treatment led to few bile duct complications, including a 5% incidence of mild biliary dilatation but no instances of strictures, stenoses, leaks or fistulas, in a retrospective review of 76 patients with 114 primary and metastatic liver tumors (WCIO paper 35).

Similarly low rates of complications were reported by Riccardo Lencioni, MD, a professor and the director of diagnostic imaging and intervention at Pisa University School of Medicine in Pisa, Italy, y and colleagues at several Europe-

an centers.

In 26 patients with 29 early-stage, unresectable hepatocellular carcinomas, major complications with IRE included one punctured intercostal artery and one case of transient hepatic decompensation that resolved without treatment (WCIO paper 9). Complete response occurred in 77% of patients and 79% of tumors. “IRE appears to be safe and effective and could potentially be a very promising new tool for image-guided ablation of solid tumors,” Dr. Lencioni told Clinical Oncology News. “Of course, these early findings are just the first step and research is ongoing.” Perhaps most exciting is the potential for IRE to manage unresectable, locally advanced pancreatic cancer, Dr. Lencioni said. “Thermal ablation has been out of the question for treating pancreatic cancer because of the potential of damage to structures in the pancreatic area,” Dr. Lencioni said. “But our very early clinical experience suggests IRE can be conducted in these patients.” Dr. Narayanan’s own unpublished anecdotal experience using IRE in 15 pancreatic cancer patients, including

than with other patient groups because patient characteristics or cancer stage changed between work-up and treatment to include multiple new areas of metastasis or because access to the lesion was considered to be unsafe,” Dr. Narayanan said.

‘I am concerned about complications of HIFU, given that skin burns and fistulae have been reported in the limited literature that is available.’ —Eileen O’Reilly, MD “I don’t see IRE as a replacement for existing treatments, but rather as a potential treatment for previously untreatable tumors,” Dr. Lencioni added, noting the procedure is also more expensive than other ablative techniques. “Image-guided thermal ablation has shown excellent results in a range of cancers, so IRE will likely be used only for those cancers where these approaches have proven less successful. However, if emerging study results suggest an added benefit with IRE even in conventional-

‘I don’t see IRE as a replacement for existing treatments, but rather as a potential treatment for previously untreatable tumors.’

15% of patients and stopped tumor progression in 57% of patients, although none experienced complete response (Cancer Treat Rev 2012;38:346-353, PMID: 21924838). HIFU also has been tested in the treatment of prostate, breast, uterine, liver, kidney, bone and brain tumors, Dr. Orsi said. Dr. O’Reilly said outcomes data are needed to demonstrate whether the benefits of HIFU outweigh the risk for adverse events and to identify what incremental benefits HIFU may add over other conventional treatments.

Nonresectable pancreatic head tumor obstructing the common bile duct and pancreatic duct. Tumor surrounds the superior mesenteric vein at the junction with the splenic vein. Para-aortic and celiac lymph nodes and a small liver metastasis.

—Riccardo Lencioni, MD seven tumors located in the pancreatic head, confirmed the safety of the technology when used near adjacent critical structures. Treatment was associated with minor complications such as a hematoma, pneumothorax post-intubation and a single case of post-procedure pancreatitis. Despite the enthusiasm surrounding IRE, Dr. Narayanan said, “There are lots of challenges with the procedure.” The treatment involves placing multiple needles in parallel around the tumor in order to administer sufficient levels of electrical pulses, and its complexity translates into a steep learning curve. Moreover, the placement of multiple needles means tumor access is critical. “In the pancreatic cancer population, we’ve aborted more IRE procedures

zone,” said Dr. Orsi, who reviewed existing data on HIFU at the meeting. Cumulative data from nearly 200 HIFU-treated pancreatic cancer patients, from China, showed HIFU significantly decreased pain, led to a partial tumor response in approximately

ly treatable tumors, it could begin to play an increasingly important role.” Another technology touted at the meeting for its ability to treat tumors deemed unablatable with conventional technology is HIFU. This modality uses highly focused, high-temperature ultrasonic waves to coagulate target tissue. According to Franco Orsi, MD, the director of interventional radiology at the European Institute of Oncology in Milan, HIFU is more precise than RFA, MWA or cryoablation. “The treatment zone with every other ablative modality is limited by the fixed location of the delivery instrument, whereas with HIFU, because it is so focused, you can shape your ablation

“Moreover, I am concerned about complications of HIFU, given that skin burns and fistulae have been reported in the limited literature that is available. It is likely there is a learning curve with this technology, but that remains to be determined,” she said. For both new technologies, Dr. O’Reilly said, “Until randomized, controlled studies are conducted, it will remain unclear what their benefits truly are.” —David Wild Dr. Narayanan is a consultant for Angiodynamics. Drs. O’Reilly, Lencioni and Orsi have no conflicts of interest to disclose.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

‘Fusion Imaging’ May Improve Tumor Diagnosis, Treatment Different diagnostic modalities fused to improve accuracy, particularly for smaller lesions Chicago—Clinicians can now overlay two or more imaging modalities, manipulate them simultaneously “on the table” and potentially improve tumor diagnosis and treatment, an expert told attendees of the 2012 World Conference on Interventional Oncology. “Medical GPS, or fusion imaging, can increase the accuracy of image-guided tumor biopsy and ablation and help direct local chemoembolization, and if treatment needs to be modified during a case, this can be done more accurately than by using a single imaging modality alone, effectively closing the gap between diagnosis and therapy,” said Bradford Wood, MD, chief of interventional radiology and director of the Center for Interventional Oncology at the National Cancer Institute in Bethesda, Md. Fusion systems superimpose two or more images from separate modalities, stretching them as necessary and matching them in real time according to the location of sensor coils embedded in needles or ultrasound (US) cameras. The coils are placed on or inside a biopsy needle, an US transducer, a guide wire, stent graft, catheter, scalpel, steerable endoscope or on the patient’s skin. In the case of a sensor-enabled US transducer, the device facilitates multiplanar, real-time reconstruction and matching of the two threedimensional data sets of images while functioning as a standard US. In a study comparing US/magnetic resonance imaging (MRI) fusion-guided prostate biopsy to standard “blind” sextant biopsies, fusion guidance nearly doubled the cancer detection rate for a subset of patients (J Urol 2011;186:12811285, PMID: 21849184). Fusion guidance also is associated with more accurate needle positioning and potentially fewer complications than using a single imaging modality (J Vasc Interv Radiol 2011;22:515-524, PMID: 21354816). The cost savings of conducting procedures under US using fused and previously obtained MRIs also are significant, Dr. Wood added. Furthermore, fusion guidance leverages the advantages of each modality, he said. “One can combine the spatial resolution of CT [computed tomogramphy], the metabolic and functional data provided by real-time PET [positron emission tomography] guidance, and the temporal resolution and real-time feedback of US,” Dr. Wood said. According to Eileen O’Reilly, MD, a gastrointestinal oncologist at Memorial Sloan-Kettering Cancer Center and an associate professor at Weill Cornell Medical College, both in New York City, single-modality imaging is adequate

Fusion systems superimpose two or more images from separate modalities, matching them in real time. when lesions are clearly visible and easily accessible. However, in the case of smaller lesions, fusion imaging has the potential to affect both surgical and medical treatment.

“We’ve entered the era of personalized treatments in medical oncology, and biopsies are recommended not only for diagnosis, but sometimes for refining the treatment plan also, so there are

potentially broad applications for this technology,” Dr. O’Reilly told Clinical Oncology News. —David Wild The NIH, Dr. Wood’s employer, and Philips Healthcare have a research and development agreement and may share intellectual property in the field. Dr. O’Reilly has nothing to disclose.

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

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

Expiration Date: August 22, 2013

Chair

Learning Objectives

Julie M. Vose, MD, MBA

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

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

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

Nebraska Medical Center Omaha, Nebraska

Faculty

John P. Leonard, MD

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

Myeloma

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

Professor of Medicine

Intended Audiences

Weill Medical College of Cornell University

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

Clinical Director, Center for Lymphoma and

NewYork-Presbyterian Hospital New York, New York

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

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

Course Format Interactive Web-based monograph

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

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

Statement of Need

Method of Preparation

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

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

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

This activity is supported by educational grants from Genentec

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

CURRENT PRACTICE

DRUG COSTS continued from page 1

with anticancer drugs,” said Ian Tannock, MD, PhD, a professor of medical oncology at Princess Margaret Hospital in Toronto, Canada. He discussed the cost of cancer drugs at the recent annual meeting of the American Society of Clinical Oncology (ASCO). A study published in 2004 showed that the near doubling of median survival in patients with colorectal cancer has been accompanied by a 340-fold increase in drug costs in the Western world (N Engl J Med 2004;351:3317-319, PMID: 15269308). Drug prices h have risen sharply since 2004. “Some of the workhorses that provide real value are priced relaatively inexpensively. Paclitaxel and a trastuzumab (Herceptin, Genentech) are under $5,000 a month h, whereas the new drugs are com ming in at $10,000 a month,” said Thomas Smith, MD, pointing to t vemurafenib (Zelboraf, Genen ntech) and crizotinib (Xalko ori, Pfizer) as examples. “Som me drugs are over $100,000 for a one-time administration.” Dr.

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Cost-Effectiveness Although drug costs have risen, costeffectiveness has declined. In many countries, cost-effectiveness is measured in cost per life-year gained. “If you live in Paris, Chicago or Toronto, it’s been suggested that the publicly funded health care system can generally afford up to $60,000, but not more than $100,000 per life-year saved,” said Dr. Tannock. He highlighted estimates of cost per life-year gained for several drugs: $10,000 for statins, $500 to $1,000 for CMF (cyclophosphamide, methotrexate and fluorouracil), and $15,000 to $45,00 for adjuvant trastuzumab.

was involved in the study. “If you look at these hazard ratios in relation to cost, there is absolutely no relation at all.” Physicians are encouraged to prescribe these costly cancer drugs. The “buy and bill” approach for reimbursement provides incentives for medical oncologists to use expensive medications when less costly alternatives that deliver similar results are available (Health ( Aff 2012;31:780-785, PMID: 22492895). “We as oncologists are encouraged constantly and sometimes directly to prescribe more expensive drugs. Some people get direct reward for that,” said Dr. Tannock. In another study that has yet to be published, researchers identified 25 new drugs approved by the FDA for 17 malignant diseases between 2000 and

A recent study found no correlation between market pricing of new anticancer drugs and the magnitude of clinical benefit.

‘There were relatively small benefits that translate usually into absolute benefits of a few months, at most, in survival. If you look at these hazard ratios in relation to cost, there is absolutely no relation at all.’ —Ian Tannock, MD, PhD Smith, the director of palliative medicine at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Baltimore, also spoke at the ASCO meeting.

at [scientific meetings], at an extremely high price,” said Dr. Tannock. Ipilimumab (Yervoy, Bristol-Myers Squibb) was approved for melanoma based on a median 3.5-month increase in overall survival and a full course of therapy costs $120,000. Vismodegib (Erivedge, Genentech) was approved for advanced basal cell carcinoma based on tumor shrinkage rates of 30% and 43% in people with metastatic and locally advanced forms of the disease, respectively, with a full course of therapy costing $75,000. Pemetrexed (Alimta, Eli Lilly) was approved for maintenance therapy of nonsq nonsquamous non-small cell lung cancer based on a three-month improvement in median overall survival and d the cost of therapy

Many of the newer oncologic drugs do not meet the threshold for what would be considered cost-effective. They often “provide extremely small gains, despite some of the hype we hear in the sessions

runs between $20,000 and $30,000. So, how are drug pricees determined? A recent sstudy found no correlaation between market prricing of new anticancerr drugs and the magnitudee of clinical benefit. The study lo ooked at three groups of agents apprroved by the FDA since 2000 and found that new agents with specific moleculaar targets are clinically the most benef beneficial, but their monthly market prices are not significantly different from the price of other anticancer agents ((J Clin Oncoll 2011;29:2543-2549, PMID: 21606435). For example, the overall survival hazard ratio (HR) was 0.69 for a group of targeted agents with a monthly cost of $5,375 and the HR was 0.84 for a group of chemotherapeutic agents at a monthly cost of $6,584. “There were relatively small benefits that translate usually into absolute benefits of a few months, at most, in survival,” said Dr. Tannock, who

2010 and estimated the cost per lifeyear gained. Only 37% of the new agents had a cost per life-year gained less than $100,000.

Determining a Price Tag Everyone expects drug companies to be able to make a profit—private companies aim to maximize profit. When Clinical Oncology News asked various companies how they determine the price of drugs, a variety of answers were provided but all of the companies said pricing was set to support investment in future research. “At Genentech, we choose prices for our medicines that allow us to continue discovering new medicines for people with serious diseases such as cancer and Alzheimer’s disease,” said Charlotte Arnold, a spokesperson for Genentech, in an email. “Things we consider when choosing a price [include] how well the medicine works; what other medicines are used to treat the same disease; the amount of money we will

Not receiving Clinical Oncology News s? Like to? Clinical Oncology News s is distributed free of charge to selected oncology and hematology/oncology physicians. We use addresses provided by the AMA and AOA. You don’t need to be a member of these organizations, but they need to have your address and specialty information. To be sure this information is up to date, please call the AMA at (800) 262-3211 or AOA at (800) 621-1773. You can tell them whether you prefer to have Clinical Oncology News s mailed to you at your office or home. You can also visit www.clinicaloncology.com/Subscription.aspxfax to subscribe directly.

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CURRENT PRACTICE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

need to continue discovering new medicines for life-threatening diseases; [and] how to ensure that our medicines get to the people who need them, even if they can’t afford them.” The monthly cost of the new HER2targeted agent pertuzumab (Perjeta, Genentech) for breast cancer is $5,900. “When determining a price for Perjeta, we took into consideration that it would be used with Herceptin, and priced Perjeta (as a single agent) less than many other recently approved cancer medicines,” said Ms. Arnold. “The monthly cost of Herceptin is $4,500. Most patients will take the combination of Perjeta and Herceptin until their disease worsens, which is about 18 months. The estimated cost for a course of treatment with Perjeta and Herceptin for 18 months is approximately $188,000.” The combination of pertuzumab, trastuzumab and docetaxel improved progression-free survival by roughly six months compared with trastuzumab and docetaxel. Amy Sousa, a spokesperson for Eli Lilly, said Lilly priced “medicines based on the value they bring to patients” and that “pricing also ensures that Lilly is able to invest in research and development of new medicines to meet the medical needs of patients in the future.” Sarah Koenig, a spokesperson for Bristol Myers Squibb, explained that the company priced its drugs on a number of factors including “the value they deliver to patients, the scientific innovation they represent and the cost to develop them.” All three companies pointed out that they provide patient assistance programs.

Drug Approval Process While company pricing and physician behavior are each a part of the skyrocketing drug cost problem, the process by which drugs are approved in the United States can also be seen as playing a role. Historically, the FDA and the European Medicines Agency (EMA), the European equivalent of the FDA, have approved drugs based on any significant difference in survival. This has encouraged larger and larger trials to demonstrate what some would say are clinically meaningless, but statistically significant differences (J ( Natl Cancer Inst 2010;103:1-5). Erlotinib was approved in combination with gemcitabine for patients with advanced pancreatic cancer after a clinical trial showed it improved survival by 10 days compared with gemcitabine alone ((J Clin Oncol 2007;25:1960-1966, PMID: 17452677). The FDA evaluates drugs for safety and efficacy compared with placebo, and it considers neither cost nor comparative efficacy against other treatments in determining what drugs get the green light. In England, after the EMA has approved a drug, the National

Institute for Health and Clinical Excellence (NICE) considers all these factors in calculating what it will cover. After concluding patients would derive minimal benefits at an excessive cost, NICE has rejected a number of cancer drugs that are regularly prescribed in the United States. The rejection list includes erlotinib (Tarceva, OSI/Genentech) for maintenance therapy of non-small cell lung cancer and lapatinib (Tykerb, GlaxoSmithKline) in combination with capecitabine (Xeloda, Roche) for women with advanced or metastatic HER2-positive breast cancer.

“I think the way around this [the drug cost problem] is that registration of new anticancer drugs ought to be based on value-based pricing,” said Dr. Tannock. “Every other thing we buy is related to value, but that is not the case for anticancer drugs in Western countries.” He pointed out, however, that obviously the profit motive is a powerful incentive for developing new treatments and that prices go down as drugs go off patent, making them more accessible to more people. Attempts to control pricing might lead to nonavailability of drugs, said Dr. Tannock. Some clinicians and

health economists point out that the slim profit margin of generics may be part of the drug shortage problem that has been plaguing the United States. Dr. Tannock argued that value-based pricing can work, but “you have to allow companies to recover the real cost of research.” —Kate O’Rourke Dr. Tannock disclosed an uncompensated consultant or advisory role and research funding from Bayer, Exelixis, Genentech, Johnson & Johnson, Eli Lilly and Sanofi. Dr. Smith has no relevant disclosures.

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Combo Therapy Trumps Monotherapy for Metastatic Breast Cancer From The New England Journal of Medicine

he combination of a selective aromatase inhibitor (AI) and estradiol analogue appears to be superior to an inhibitor alone as a first-line strategy to fight hormone receptor (HR)-positive metastatic breast cancer. Researchers reported significant improvements in progression-free survival (PFS) and overall survival (OS) for women receiving a combination of anastrozole and fulvestrant compared with those receiving anastrozole alone. The study was published in The New England Journal of Medicine (2012;367:435-444, PMID: 22853014). A multisite team, with principal author Rita W. Mehta, MD, assessed 694 postmenopausal women in a Phase III, randomized clinical trial. They found median PFS was 15.0 months in

the combination-therapy group versus 13.5 months in the anastrozole-alone group. The ultimate superiority of the combination strategy emerged over time. The disparity in the rate of PFS between groups grew from one year (57% of the combination vs. 56% of the anastrozole-alone group) to two years (35% and 28%, respectively) and at three years (25% and 16%). The hazard ratio for progression or death with the combination therapy was 0.80. “The hazard ratio … was notable, especially given the fact that the group receiving anastrozole alone had a higher median progression-free survival than had been projected in the design of the trial,” the investigators wrote. Median OS, a secondary outcome, was 47.7 months with combination treatment versus 41.3 months with monotherapy. “The improvement in overall survival that was observed in

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

he concept of complete estrogen receptor (ER) blockade has regained significant interest since the report of the SWOG 0226 trial demonstrating that a well-tolerated hormonal therapy combination, anastrozole plus fulvestrant (250 mg), is superior to anastrozole alone in both PFS and OS as first-line therapy for metastatic HR-positive breast cancer.1 Although it may be premature to bring this regimen to the clinic because of conflicting results from different trials,2 new research hypotheses are generated. An interesting finding from the SWOG 0226 trial is that, despite a significant prolongation of PFS and OS favoring the combination therapy, the clinical benefit rate and response rate were similar between the two

treatment arms. This result is reminiscent of what was observed in the FIRST (Fulvestrant First-Line Study) trial, a randomized Phase II trial of fulvestrant high dose (500 mg) with anastrozole as first-line treatment for advanced breast cancer, in which the time to progression was improved in the fulvestrant arm compared with the anastrozole arm (23.4 vs 13.1 months), but the response rate and clinical benefit rate were similar. 3 Because ER function is critical for the development of acquired endocrine resistance,4 one could postulate that more effective ER blockade could have delayed the onset of acquired endocrine resistance, rather than affecting the de novo endocrine-resistant tumors. Therefore,

our study has not been seen in other trials of first-line hormonal therapy for HR-positive metastatic breast cancer,” noted the Southwest Oncology Group (SWOG) Cooperative Group researchers. The study was funded by the National Cancer Institute. As with PFS, the difference in OS favoring combination treatment increased over time. At one year, OS was 91% in the combination group versus 89% in the monotherapy group; at two years, 79% and 75%; and at three years, 62% and 57%, respectively. The 350 women randomized to combination therapy and the 345 randomized to anastrozole alone each received 1 mg oral anastrozole daily. The combination-group women also received 500 mg fulvestrant intramuscularly as an initial loading dose on day 1, followed by 250 mg or low-dose fulvestrant on days 14 and 28 of the first cycle, and thereafter

every 28 days. The protocol was amended during the study to increase subsequent fulvestrant dosages to 500 mg after other investigators reported its superiority over the low-dose formulation and following FDA approval of the higher-dose formulation. The researchers also assessed women previously treated versus women not treated with tamoxifen. Overall, the advantages of combination therapy remained regardless of this classification. In other words, the interaction between treatment and use of prior adjuvant tamoxifen therapy was not significant. Only 15 women discontinued treatment due to toxic effects (11 in the combination group and four in the anastrozole-alone group). “In general, the toxic effects were mild and did not differ significantly in grade between the two groups,” the authors wrote.

tumors resistant to endocrine therapy would not derive benefit from such treatment. This is supported by the unplanned subgroup analysis in the SWOG 0226 trial, showing that the benefit of the combination therapy was restricted to those who had not received adjuvant tamoxifen, a population enriched for endocrine-sensitive disease. If the hypothesis is correct, the approach of complete ER blockade should be tested in an endocrine-sensitive population. How do we achieve the most effective ER blockade? In collaboration with the National Cancer Institute, the Alliance for Clinical Oncology Cooperative Group is planning a neoadjuvant trial that compares anastrozole with fulvestrant (500 mg), either alone or in combination with anastrozole, in the neoadjuvant setting. Endocrine-resistant tumors are identified early in treatment by a high Ki-67 level for alternative treatment strategies.5 Results of this trial will provide essential information on whether fulvestrant (500 mg) alone or in combination with anastrozole should be brought forward in the adjuvant setting.

References

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1. Mehta RS, et al. A Phase III randomized trial of anastrozole versus anastrozole and fulvestrant as first-line therapy for postmenopausal women with metastatic breast cancer: SWOG S0226 in CTRC-AACR. San Antonio Breast Cancer Symposium. 2011. San Antonio, TX. 2. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919-1925, PMID: 22370325. 3. Robertson JFR, et al. A comparison of fulvestrant 500 mg with anastrozole as firstline treatment for advanced breast cancer: follow-up analysis from the “FIRST” study. San Antonio Breast Cancer Symposium. 2010. San Antonio, TX. 4. Roop RP, Ma CX. Endocrine resistance in breast cancer: molecular pathways and rational development of targeted therapies. Future Oncol. 2012;8:273-292, PMID: 22409464. 5. Goncalves R, Ma CX, Luo J, et al. Use of neoadjuvant data to design adjuvant endocrine therapy trials for breast cancer. Nat Rev Clin Oncol. 2012;9:223-229, PMID: 22371132.

Dr. Ma reported no relevant financial disclosures.

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Tailoring Radiotherapy for Pediatric Hodgkin Lymphoma L

imited radiotherapy resulted in a high rate of two-year event-free survival (EFS) in pediatric patients with favorable-risk Hodgkin lymphoma who had a complete early response to chemotherapy, according to a study in JAMA (2012;307:2609-2616, PMID: 22735430). The findings suggest that a risk-adapted, response-based approach may be effective and well tolerated in selected patients with favorable-risk Hodgkin lymphoma. More than 90% of children with favorable-risk Hodgkin lymphoma will achieve long-term survival, the researchers reported, yet many develop toxic effects from radiotherapy. In the Phase II, multi-institutional, unblinded, nonrandomized clinical trial, the researchers identified 88 patients with Hodgkin lymphoma stage IA or IIA, fewer than three involved nodal regions, no extranodal extension and no mediastinal bulk. Patients received four cycles of vinblastine, adriamycin (doxorubicin), methotrexate and prednisone (VAMP) chemotherapy. After two cycles, the patients were evaluated for early response using computed

tomography scan and functional imaging. Patients who achieved a complete response (CR) after two cycles (n=47) received no radiotherapy; patients who achieved less than a CR (n=39) received 25.5 Gy-involved field radiotherapy. One patient who achieved less than CR withdrew consent for participation; another had early disease progression and received retrieval therapy. The estimated two-year EFS, the primary outcome measure, was 90.8% (95% confidence interval [CI], 84.7%-96.9%). Among patients who did not require radiotherapy, the primary outcome measure was 89.4% (95% CI, 80.8%-98.0%), whereas among patients who did, it was 92.5% (95% CI, 84.5%-100.0%; P=0.61). Fifty-six patients received at least five years of follow-up; rates of five-year EFS were similar in patients who did not receive radiotherapy (89.4% [95% CI, 79%-99.8%]) and those who did (87.5% [95% CI, 75.7%-99.3%]). Patients who did not receive radiotherapy and had a recurrence were retrieved with chemotherapy and radiotherapy without stem cell transplant. Therapy was well tolerated and no

major complications occurred. Commenting by email, Frederick Goldman, MD, a professor of pediatrics and director of the Blood and Marrow Transplant Program at Children’s Hospital of Alabama at the University of Alabama at Birmingham, said: “This study demonstrates the feasibility of using specific radiologic response criteria in low-risk Hodgkin disease patients as a means of reducing the amount of therapy they receive. The net result is that patients will get more tailored therapy, and that this will ultimately result in lower rates of long-term side effects.” Dr. Goldman, who was not associated with the study, co-authored an accompanying editorial (JAMA ( 2012;307:2639-2641, PMID: 22735435). “There have been studies trying to omit radiotherapy in children with Hodgkin lymphoma,” the study’s lead author, Monika L. Metzger, MD, MSc, a pediatric hematologist/oncologist at St. Jude Children’s Research Hospital in Memphis, Tenn., said in an interview. These studies, Dr. Metzger said, used riskier chemotherapeutic agents

and higher doses than those used in her study. “We can expect less long-term complications.” The principal finding of her study, said Dr. Metzger, is “that patients with certain characteristics could be cured with this low-intensity chemotherapy and no radiotherapy if they had a complete response early on in therapy. … For certain patients that meet criteria, this protocol can certainly be discussed with the family and offered to patients as an option.” “It is still too early to make conclusions but it seems quite reasonable that we may be able to eliminate radiation in a select group of low-risk Hodgkin disease patients,” said Dr. Goldman. Limitations of the study, he said, included small size and relatively short median follow-up. “It is only for a specific group of favorable-risk patients. It needs to be clear that the patient meets the criteria.” —George Ochoa Drs. Goldman and Metzger reported no relevant financial conflicts of interest.

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Trastuzumab Injection ‘Noninferior’ to IV in Breast Cancer From Lancet Oncology

t makes sense that a five-minute subcutaneous injection of trastuzumab could save time and money compared with standard 30- or 90-minute IV administration. But is this new formulation just as effective and safe for women fighting stage I to III, HER2-positive breast cancer? To find out, Gustavo Ismael, MD, and an international, multisite team studied 596 women in a neoadjuvant, Phase III, open-label randomized trial ((Lancet Oncol 2012;13:869-878, PMID: 22884505). All participants had newly diagnosed, non-metastatic primary cancer. Hoffmann-La Roche funded the study. The two primary end points of the

HannaH (enHANced treatment with NeoAdjuvant Herceptin) study were serum trough concentration (Ctroughh) of the study drug, recorded before surgery (predose cycle 8), and pathologic complete response (pCR). Women were enrolled in the study from October 2009 to December 2010 at 81 centers worldwide. Median duration of follow-up was 12 months. The pharmacokinetic profile, total pCR and overall response were secondary end points. Other secondary measures included time to response, eventfree survival, overall survival, safety and tolerability, and immunogenicity. The new subcutaneous formulation, which contains a fixed dose of 600 mg of trastuzumab, was given to 297 women. A nurse used a handheld syringe to deliver the subcutaneous injection to

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

he HannaH study demonstrates the safety and efficacy of subcutaneous trastuzumab in the neoadjuvant setting. This trial randomized stage I to III, HER2-positive breast cancer patients to receive subcutaneous versus IV trastuzumab. Subcutaneous trastuzumab was administered at a fixed dose (600 mg) in combination with hyaluronidase PH-20 (rHuPH-20), an enzyme that temporarily degrades interstitial hyaluronan in the subcutaneous space, thus increasing the volume that can be administered subcutaneously and aiding absorption of trastuzumab. This study was an international trial with the majority of patients treated in Eastern Europe, Asia, South America and

South Africa. Western European and Canadian treatment sites accounted for 19% of patients. The primary clinical end point was pCR rate. Subcutaneous trastuzumab gave a slightly higher pCR rate than IV trastuzumab (45.4% vs. 40.7%), although this difference is not significant. Virtually all (97%) of the subcutaneous trastuzumab patients achieved a therapeutic serum target level of trastuzumab. Local adverse reactions were low, with only 1% of patients developing a local cellulitis. Systemic adverse effects were comparable between subcutaneous and IV trastuzumab, although three deaths occurred on the subcutaneous arm compared

the thigh every three weeks. Administration took about five minutes. Another 299 women were randomized to a standard IV protocol and received an 8 mg/kg loading dose of trastuzumab and 6 mg/kg maintenance doses every three weeks. Participants in the subcutaneous group did not receive a loading dose. “The median time to response was six weeks in both treatment groups (i.e., after two treatment cycles), suggesting that the lack of a loading dose in the subcutaneous regimen does not compromise efficacy,” the authors wrote. Almost all participants exceeded the 20 mcg/mL Ctrough target level. Additionally, pCR occurred in 45.4% of the subcutaneous group and 40.7% of the IV group. These findings support the noninferiority of

subcutaneous trastuzumab compared with the IV formulation. Median relative dose intensity was greater than 96% in both groups, “suggesting good tolerability of subcutaneous trastuzumab,” the authors noted. The incidence of grade 3 to 5 adverse events was similar. Neutropenia occurred in 29.0% of the subcutaneous group versus 33.2% of the IV group; leukopenia developed in 4.0% versus 5.7%; and febrile neutropenia developed in 5.7% versus 3.4%. At 21%, the serious adverse event rate was higher in the subcutaneous group than in the IV group, at 12%, driven in part by infections and infestations (8.1% vs. 4.1%, respectively). None of the reported infections was associated with the site of subcutaneous injection.

with one death with IV trastuzumab. All of these deaths were attributed to comorbidities preexisting in the patients and were not related to the route of administration of trastuzumab. No cases of symptomatic congestive heart failure occurred in either arm. Clinical follow-up on this trial was short (12.4 months), but this is in keeping with the neoadjuvant trial design. This trial demonstrates the noninferiority of subcutaneous trastuzumab in the neoadjuvant setting. Although these results will likely translate into the adjuvant setting, formal demonstration of that is needed. In fact, a trial is currently being performed in Canada and Europe comparing subcutaneous with IV trastuzumab in early-stage HER2-positive breast cancer.1 Subcutaneous trastuzumab has several advantages, including requiring less time to administer than the IV drug and the possibility of selfadministration by patients. A trial comparing self-injection of subcutaneous trastuzumab through a single-use injection device with more standard administration of subcutaneous drug via medical

staff is being conducted internationally.2 The success of subcutaneous trastuzumab on the HannaH trial expands the availability of trastuzumab to countries or patients where long-term central venous access is difficult. Furthermore, it opens the possibility that other antibody drugs (both for cancer or other types of diseases) can be administered subcutaneously. Although the usage of subcutaneous trastuzumab in the United States is likely to be low, at least initially, this trial provides a very interesting alternative for patients who have problems with central venous access devices.

References 1. Clinicaltrials.gov identifier: NCT01401166. http://clinicaltrials.gov/ ct2/show/study/NCT01401166. Accessed September 11, 2012. 2. Clinicaltrials.gov identifier: NCT01566721. http://clinicaltrials.gov/ ct2/show/study/NCT01566721. Accessed September 11, 2012.

Dr. Bose reported no financial disclosures relevant to this study.

Lymphomas John Sweetenham, Jame Abraham (Editor) See page 27

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS â&#x20AC;˘ OCTOBER 2012

Regimen With Bortezomib Effective in Multiple Myeloma From the Journal of Clinical Oncology

ortezomib (Velcade, Takeda/Millennium) achieved promising results during an open-label, Phase III clinical trial designed to assess its utility both at induction, as part of a combination regimen, and as maintenance therapy in patients with newly diagnosed multiple myeloma. A summary of the trialâ&#x20AC;&#x2122;s findings was published in the Aug. 20 issue of the Journal of Clinical Oncology (2012;30:2946-2955, PMID: 22802322). Designed and performed by the Dutch-Belgian Hemato-Oncology Cooperative Group (whose acronym is HOVON) and the German Multicenter Myeloma Group (GMMG), the

trial, led by Pieter Sonneveld, MD, PhD, compared VAD (vincristine, doxorubicin and dexamethasone) to PAD (bortezomib, doxorubicin and dexamethasone) as induction therapy in 827 adult patients newly diagnosed with the disease. Both regimens were followed by high-dose melphalan and autologous stem cell transplantation, but patients who received the VAD regimen at induction received maintenance therapy of thalidomide (50 mg per day) for two years, whereas those in the PAD arm received maintenance therapy with bortezomib (1.3 mg/m2 once every two weeks) for the same duration. After a median follow-up of 41 months, complete response (CR) was significantly higher following PAD

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

number of randomized trials have evaluated the role of maintenance following high-dose chemotherapy and autologous stem cell transplantation for patients with untreated multiple myeloma. In the era of novel agents, thalidomide was found to improve eventfree survival (EFS) in several trials and OS in one.1 Maintenance with thalidomide has been hampered by significant toxicities, most importantly problems with peripheral neuropathy that prevent long-term use of this agent. More recently, the use of lenalidomide maintenance following autologous stem cell transplant was reported in two prospective randomized trials.2,3 These studies both demonstrated an improvement in EFS and one trial also showed improved OS for patients randomized to

lenalidomide maintenance. The Phase III HOVON-65/GMMGHD4 trial by Sonneveld and colleagues examines the efficacy of bortezomib induction and post-transplant maintenance compared with alkylator-based induction and thalidomide maintenance. There are a number of important findings from this trial, however it does not answer the question of whether bortezomib maintenance is superior to thalidomide maintenance after stem cell transplantation. The Sonneveld trial demonstrates an improved EFS and OS in the patients receiving bortezomib induction and maintenance, but it is unclear whether the benefit over the alkylator arm was related to bortezomib induction, maintenance or a combination of the two.

induction and bortezomib maintenance (49%) than it was with VAD induction and thalidomide maintenance (31%; P<0.001). Similarly, progression-free survival (PFS) was also higher in the PAD-bortezomib maintenance arm (35 months) than it was in the comparator arm (28 months; P<0.002). Additionally, in high-risk patients having increased creatinine levels (>2 mg/dL), the PAD-bortezomib regimen significantly improved PFS from a median of 13 to 30 months ( 0.004) and overall survival (OS) (P= from a median of 21 to 54 months ( <0.001). (P There was a significant difference with regard to treatment adherence between the two study groups, however. Of those in the VAD-thalidomide

group who remained in the trial following induction therapy, 22% (77 of 347) went off protocol following high-dose melphalan because of allogeneic stem cell transplantation (21%), persistent toxicity (3%) or other reasons (13%), which in some cases included death and/or noncompliance. In the PADbortezomib group, 35% (123 of 352) of the remaining patients went off protocol because of allogeneic stem cell transplantation (8%), persistent toxicity (13%) or other reasons (14%), which included death and/or noncompliance. Most instances of persistent toxicity reported in the PAD-bortezomib arm involved polyneuropathy. According to the study design, persistent toxicity was an exclusion criterion for starting maintenance therapy.

Of patients in the bortezomib arm, 13% did not start maintenance therapy primarily due to treatment-emergent peripheral neuropathy. One of the findings of the lenalidomide maintenance trials was an increase in second primary malignancies (SPMs) in the patients randomized to lenalidomide maintenance. In these two lenalidomide trials the incidence of SPMs was approximately 8% in the lenalidomide patients and 3% to 4% in the placebo arms. Including SPMs in the EFS calculations still shows a benefit for lenalidomide maintenance, and additional studies are ongoing trying to determine the mechanism of this risk and whether it is a reproducible signal. Although not reported in the current paper by Sonneveld, there was no increased risk for SPMs associated with the bortezomib arm in data presented at ASH in December 2011.4 There is adequate data to support maintenance therapy following autologous transplantation but what is the optimal induction before autologous transplant and what is the appropriate maintenance therapy? Should a different class of drugs be used for induction

and maintenance? Is there a role for consolidation after transplant and before maintenance therapy? Ongoing studies will help answer these important questions, which should lead to longer remissions and survival for patients with myeloma.

References 1. Attal M, et al. Maintenance therapy with thalidomide improves survival in patients with multiple myeloma. Blood. 2006;108:3289-3294, PMID: 16873668. 2. Attal M, et al. Lenalidomide maintenance after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:17821791, PMID: 22571202. 3. McCarthy PL, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012;366:17701781, PMID: 22571201. 4. Miguel JFS, et al. Risk of second primary malignancies (SPMs) following bortezomib (Btz)-based therapy: analysis of four Phase III randomized controlled trials in previously untreated or relapsed multiple myeloma (MM). ASH Annual Meeting Abstracts 118:2933, 2011.

Dr. Stockerl-Goldstein discloses that he is a member of the speakersâ&#x20AC;&#x2122; bureaus for Celgene, Millennium and Onyx.

Having trouble keeping up with all of the oncology and medical journals that cross your desk? On a monthly basis, Clinical Oncology News highlights key studies from the journals and provides guest clinician perspectives to help you stay up to date. We hope you find this a useful tool.

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CLINICAL ONCOLOGY NEWS • OCTOBER 2012

More Evidence ACE Inhibitors Protect Against Radiation Pneumonitis From the International Journal of Radiation Oncology, Biology, Physics

he protective effect conferred by angiotensin-converting enzyme (ACE) inhibitors against grade 2 pneumonitis in lung cancer patients treated with thoracic irradiation, which had been an interesting laboratory finding, has now been confirmed in the clinical setting. In a retrospective study reported in the International Journal of Radiation Oncology, Biology, Physics (2012;84:238-243, PMID: 22300564), 62 of 162 (38%) men with stage I to III small-cell or non-small cell lung cancer also took ACE inhibitors at the time of radiation treatment. This group experienced a significantly lower incidence of grade 2 or greater

pneumonitis, at 2% compared with those patients who did not take ACE inhibitors, at 11% ((P=0.032). “Our findings suggest that concurrent use of ACE inhibitors reduces the risk for radiation pneumonitis in subjects undergoing radiation therapy for lung cancer,” the researchers concluded. Jordan Kharofa, MD, was first author of the study. In contrast, the researchers found that nonsteroidal anti-inflammatory drugs, statins, angiotensin receptor antagonists and inhaled glucocorticoids imparted no such significant protective effect. Age appears to play a role as well. A significantly higher proportion of patients 70 years and older experienced grade 2 or greater pneumonitis (16%) versus younger patients (2%;

EXPERT INSIGHT Jeffrey D. Bradley, MD Staff Physician, Siteman Cancer Center and Barnes-Jewish Hospital S. Lee Kling Professor of Radiation Oncology, Washington University School of Medicine in St. Louis

harofa et al from the Medical College of Wisconsin report on a population of lung cancer patients receiving curative radiation therapy at the Zablocki VA Medical Center in Milwaukee, and suggest that the incidental use of ACE inhibitors may decrease the risk for developing radiation pneumonitis. I want to believe these data. Perhaps I want to believe it because we have not identified therapies that mitigate the risk for radiation pneumonitis other than attempting to reduce the dose of radiation delivered to normal lung.

Guerrero et al from the University of Texas MD Anderson Cancer Center in Houston, recently reported a provocative article suggesting that elevated levels of exhaled nitric oxide (NO) also are predictive of radiation pneumonitis.1 They used a simple, cheap, commercially available device, tested it prospectively, and provided a strong indication that exhaled NO is predictive of this toxicity. Regardless, the only treatment intervention for patients with increased exhaled NO is to reduce the volume of normal lung receiving radiation. Like these ACE inhibitor data, the

P=0.005). In fact, 11 of the 12 pneumonitis events in the study occurred in this older age group. Again, ACE inhibitors ameliorated this risk; symptomatic pneumonitis occurred in 4% of ACE inhibitor users versus 23% of non-users aged 70 years or older. Only one dosimetric parameter emerged as a significant factor associated with grade 2 or greater pneumonitis for all patients. Specifically, a V5 (volume of lung receiving at least 5 Gy irradiation) of 50% or greater significantly predicted this adverse effect (13% versus 4%; P=0.04). Median survival did not differ significantly between those on ACE inhibitors (19 months) and others in the study (22 months). ACE inhibitor therapy might decrease pulmonary fibrosis and collagen

accumulation in the lungs following thoracic irradiation, according to experimental evidence, but the precise mechanism remains a mystery. Changes in blood flow or reduction of pulmonary hypertension are other possibilities. All patients were men treated at the Clement J. Zablocki Veterans Affairs Medical Center in Milwaukee from 2004 to 2009. Median age was 65 years. Nearly two-thirds of patients had stage III lung cancer (64%) and received concurrent chemotherapy (61%). Despite encouraging preclinical findings, the current study is only the fourth published clinical study to evaluate ACE inhibitors’ mitigation of radiation pneumonitis. The other three clinical reports also were retrospective. Prospective evaluation is warranted in the future, the authors noted.

exhaled NO data needs to be verified. Plans are under way to test this prognostic marker in clinical trials. I was peripherally involved with RTOG (Radiation Therapy Oncology Group) 0123, a prospective Phase II study that administered captopril in an effort to provide clinical evidence that ACE inhibitors reduced risk for radiation pneumonitis. The idea was a result of the preclinical laboratory work of Dr. Bill Ward at Northwestern University. The trial’s PI was Dr. Bill Small, a mentee of Dr. Ward’s who was committed to testing this hypothesis clinically. Unfortunately, RTOG 0123 was closed prematurely due to lack of accrual. It was very difficult to enroll lung cancer patients in this trial. The list of contraindications to ACE inhibitor therapy include common problems in elderly lung cancer patients, including hypertrophic cardiomyopathy, valvular heart disease, renal artery stenosis, abnormally low blood pressure, liver problems,

kidney disease, connective tissue disorders, hyponatremia, hyperkalemia and/ or low neutrophil counts. The Kharofa et al study carries all the major problems associated with retrospective studies. Retrospective findings should really only serve as ideas for prospective testing. However, in this case I don’t think a prospective clinical trial testing the value of ACE inhibitors in reducing radiation pneumonitis risk will be attempted again. Research dollars are in short supply and are prioritized for interventions that may improve survival in this frustrating disease.

Reference 1. Guerrero T, Martinez J, McCurdy MR, et al. Elevation in exhaled nitric oxide predicts for radiation pneumonitis. Int J Radiat Oncol Biol Phys. 2012;82:981-988, PMID: 21377296.

Dr. Bradley reported no relevant financial disclosures.

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Carfilzomib: Despite Risks, Significant Impact Likely Up-front role a possibility; reimbursement, convenience remain questionable

n late July, the FDA approved carfilzomib as a monotherapy for patients with relapsed and refractory multiple myeloma. Interviews with several hematology/oncology experts suggest that the drug will have a significant impact on the treatment of this challenging malignancy. Onyx Pharmaceuticals, which will market the drug as Kyprolis, had asked that carfilzomib be approved for patients with multiple myeloma (MM) who are refractory to their most recent treatment and who had received at least two prior lines of therapy that included the proteasome inhibitor bortezomib (Velcade, Millennium) and an immunomodulatory agent—either thalidomide or lenalidomide (Revlimid, Celgene). The FDA granted that indication—a decision that followed an 11-0 recommendation for approval by the agency’s Oncologic Drugs Advisory Committee (ODAC). A single-arm, Phase II study (003A1) in 266 patients with relapsed and refractory multiple myeloma was the central trial in carfilzomib’s new drug application. The overall response rate (ORR) was 22.9%, with a median response duration of 7.8 months. Additionally, 62% of responding patients maintained response for at least six months and 27% for at least 12 months. Response did not differ by baseline demographics, disease-related or treatment-related characteristics, including whether patients were refractory to both bortezomib and lenalidomide. These results compare favorably to reports of single-agent therapies in patients with relapsed and refractory MM. The drug was well tolerated. Prior to the ODAC meeting, the FDA distributed a briefing document suggesting the drug’s benefit might not outweigh the risks, especially cardiac risks. In the 0031A1 study, according to the briefing document, seven deaths that occurred in the carfilzomib arm most likely were caused by cardiac toxicities. At the ODAC meeting, however, a non-voting participant from the FDA downplayed this data, saying the lifethreatening heart-, lung- and liver-related adverse events (AEs) documented in the clinical trial were seen in only 4% of patients. The FDA participant pointed out that the single-arm design of the carfilzomib study made it difficult to correlate the deaths directly to the drug therapy, adding that it was not clear what the disease, previous therapy or the study drug itself might have played in the AEs documented in the study. Moreover, Onyx presented data that cardiac toxicities were common in

Multiple myeloma cells.

‘It was really unclear whether there was any cause and effect between the carfilzomib [study arm] and cardiac toxicity.’ —Wyndham Wilson, MD, PhD patients with heavily pretreated MM. “It was really unclear whether there was any cause and effect between the carfilzomib [study arm] and cardiac toxicity,” said Wyndham Wilson, MD, PhD, ODAC chairman and chief of lymphoma therapeutics at the National Cancer Institute. He said he had no hesitation voting yes.

Option for Refractory Patients Shaji Kumar, MD, an MM expert at Mayo Clinic in Rochester, Minn., said that carfilzomib “adds one more option for patients who have exhausted currently available therapies” and carries an added benefit: “It causes very little neuropathy,” he stressed. This AE can range from tingling and numbness in the fingers and toes, to painful neuropathy and autonomic neuropathy. The condition is a common dose-limiting toxicity of several MM therapies, including bortezomib, thalidomide and vincristine. In the case of IV bortezomib, the drug is associated with a 53% rate of peripheral neuropathy, 16% of which is grade 3/4, according to the drug’s prescribing information. In the carfilzomib study, 12.4% of patients had treatment-emergent peripheral neuropathy, with only 1.1% being grade 3, and grade 4 neuropathy was nonexistent. No patients

discontinued treatment because of neuropathy. (See Table for other AEs linked to discontinued treatment.) “Neuropathy is a problem that, although not life-threatening, is very vexing,” said Ravi Vij, MD, an associate professor of medicine in the Division of Oncology at Washington University School of Medicine, in St. Louis, who was heavily involved with the

carfilzomib trials. Lenalidomide, in contrast, is rarely associated with mild neuropathy, he added. If neuropathy does set in, Dr. Vij said, it often takes weeks or months to resolve and good supportive-care treatments do not exist. Dr. Vij added that physicians also should keep an eye out for dyspnea as a possible side effect associated with carfilzomib therapy. He said that 33.8% of patients in the 003A1 study experienced dyspnea of any grade; 3% experienced grade 3 and 0.04% experienced grade 4. “When people use carfilzomib in the community, they will need to be a little vigilant about dyspnea,” he stressed. Prior to the drug’s approval, some analysts speculated that the FDA might impose a postmarketing program to help ensure the safe and effective use of carfilzomib. Something of the sort did occur; as a condition of carfilzomib’s accelerated FDA approval, Onyx Pharmaceuticals is required to provide additional clinical data about the drug. According to the manufacturer, such studies are now under way.

Strength in Numbers Both Drs. Kumar and Vij said that carfilzomib is likely to be used in combination with at least dexamethasone or even with lenalidomide and dexamethasone. Two- and three-drug combinations are common in MM, they noted. Their views, stated just prior to the drug’s approval, proved to be partly prescient; the FDA-approved drug label recommends that patients should be premedicated with dexamethasone before each infusion to lower the risk for infusion reactions.

Table. Discontinuations in Multiple Myeloma Patients Due to Adverse Events Adverse Event

Incidence (N=526) (%)a,b,c 10 (2)

Pneumonia

10 (2)

Cardiac failure (congestive)

9 (2)

Renal failure (acute)

9 (2)

Blood creatinine increased

7 (1)

Pyrexia

6 (1)

Cardiac arrest

5 (1)

Thrombocytopenia

5 (1)

Excludes adverse events attributed to progressive multiple myeloma disease (e.g., disease progression, hypercalcemia, spinal cord compression).

Patients may be counted in more than one adverse-event category

Data culled from several Phase II studies; not limited to the 003A1 trial.

HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Dr. Kumar added that he also sees a role for carfilzomib in up-front therapy, “but obviously there are no Phase III trials that have been done, so there is not going

have to come back two days every week, whereas Velcade, depending on what schedule you are using, can be two days per week or one day per week,” Dr.

‘I don’t think there is going to be one answer that fits all in how this drug will be used.’ —Shaji Kumar, MD to be an approval in that setting,” he said. “It is something that needs to be studied.” A recent Phase I/II study suggested that up-front combination therapy might indeed be a viable option. The study evaluated carfilzomib in tandem with low-dose dexamethasone and lenalidomide. Of 36 patients newly diagnosed with MM completing eight or more cycles of therapy, 42% reached stringent complete responses. The 24-month progression-free survival estimate was 92%, the investigators reported ((Blood d 2012 June 4 [Epub ahead of print]. The results were first presented at the 2011 annual meeting of the American Society of Hematology, in San Diego; abstract 631.) How the drug will be used also will depend on whether insurers will pay for it, which is dependent on the FDA label and compendia listing, Dr. Kumar noted. The cost of the drug and schedule also will influence use. Convenience also may play into treatment decisions. “With carfilzomib you

Kumar said. “I don’t think there is going to be one answer that fits all in how this drug will be used.”

Oncology Pharmacist’s View Ali McBride, PharmD, MS, a clinical pharmacy specialist at the Arthur G. James Hospital at Ohio State University in Columbus, said he agreed that several questions remain as to how the drug will be used in clinical practice, including whether the drug has potential for up-front therapy. The proper sequencing of carfilzomib also remains to be determined, he noted. “If you give bortezomib first, can you then use carfilzomib if the patient fails to respond? Or do you use carfilzomib as initial therapy followed by bortezomib?” All of these various clinical scenarios “may be in the mix in terms of potential ways to maximize patient response,” he noted. Dr. McBride pointed to a recent study ( (Blood 2012;119:5661-5670, PMID: 22555973) as evidence that using

carfilzomib first may be the preferred strategy. In the multicenter, open-label Phase II trial, 129 bortezomib-naive patients with relapsed/refractory MM were treated with IV carfilzomib in two cohorts. Patients in cohort 1 were given 20 mg/m2 of the drug for all treatment cycles; cohort 2 received 20 mg/ m2 for cycle 1 and then 27 mg/m2 for all subsequent cycles. The clinical benefit response (overall response rate plus minimal response) was 59.3% in cohort 1 (95% CI, 45.7%-71.9%) and 64.2% in cohort 2 (95% CI, 51.5%-75.5%), according to the study, which included Dr. Vij as a coinvestigator. Consistent with the FDA trial data, carfilzomib elicited a relatively low incidence of peripheral neuropathy (17.1% overall, with one grade 3 and no grade 4), the investigators reported. The lower rate of peripheral neuropathy seen in clinical trials of carfilzomib is significant, Dr. McBride stressed. “It may prove to be one of the guiding points in choosing this drug over bortezomib,” he said. He noted, however, that there are now data to suggest that a subcutaneous (SQ) formulation of bortezomib causes very low rates of peripheral neuropathy. In one study ((Lancet Oncol 2011;12:431-440, PMID: 21507715), peripheral neuropathy of any grade occurred in 38% of patients given SQ bortezomib vs. 53% treated with an IV formulation ((P=0.044). “It will be interesting to see what the head-to-head numbers on peripheral

neuropathy are in these patients,” Dr. McBride said. As far as reimbursement—always a key consideration with newly approved agents—Dr. McBride said it is a bit too soon to speculate on any issues that may arise. “As usual it will be a payer-driven decision,” he said. “The big issue, at least initially, is to remember that you will only be able to use the drug in the relapsed/refractory setting. Payers will most likely be very firm in paying only for that indication.” Dr. McBride added a final note of caution based on the data from the 266-patient carfilzomib study: The trial did not establish whether the drug prolongs patients’ lives or increases progression-free survival, both of which are considered to be important markers of clinical response. Still, carfilzomib’s approval “is an important addition to our armamentarium for multiple myeloma—especially given its role in patients who are running out of other treatment options.” —Kate O’Rourke, with additional reporting by David Bronstein Dr. Vij is on the advisory board of Onyx and Celgene and has received grant funding from the companies. Dr. Kumar is the principal investigator on clinical trials supported by Celgene, Cephalon, Genzyme, Millennium and Novartis. Drs. Wyndham and McBride reported no relevant financial conflicts of interest.

Vitamin D Reduces Aromatase Inhibitor–Induced Joint Pain Chicago—High-dose vitamin D is effective at combating joint pain, a common side effect of aromatase inhibitor (AI) therapy, according to a randomized clinical trial presented at the recent annual meeting of the American Society of Clinical Oncology (abstract 9000). “Six months of vitamin D3 at a dose of 30,000 IU per week is safe in women starting an AI for adjuvant treatment of breast cancer, is associated with less worsening of AI-related musculoskeletal symptoms, and is associated with fewer overall adverse quality-of-life events,” said Qamar Khan, MD, an associate professor at the University of Kansas Medical Center in Wichita, who led the study. According to Dr. Khan, approximately 50% of breast cancer patients taking adjuvant AIs for breast cancer report new or worsening musculoskeletal pain ((J Clin Oncol 2010;28:4120-4128, PMID: 20585090). These symptoms frequently cause women to discontinue therapy prematurely. The exact mechanism by which AIs can induce musculoskeletal symptoms is unclear, but estrogen deprivation has

been shown to cause inflammation and increase pain sensitivity. “Some of the women on AIs have MRI [magnetic resonance imaging] findings of tenosynovitis suggestive of local inflammation,” said Dr. Khan. The double-blind, randomized VITAL trial (VITamin D for Arthralgias from Letrozole) was conducted at Kansas Medical Center and the Cancer Center of Kansas, Wichita, a large community practice. The study enrolled 160 patients with postmenopausal stage I to III breast cancer who were starting on adjuvant letrozole and had deficient levels of vitamin D3. Vitamin D deficiency was defined as 40 ng/mL or lower. During the 24-week study, 160 patients received daily letrozole 2.5 mg, 1,200 mg of calcium and 600 IU of vitamin D. Eighty patients received oral vitamin D 30,000 IU per week and 80 patients received placebo. Patients were asked to refrain from taking other vitamins and supplements. Patients were excluded from the study if they had severe or debilitating musculoskeletal pain, see VITAMIN D D, page 30

SOLID TUMORS

CLINICAL ONCOLOGY NEWS • OCTOBER 2012

Evidence Grows for Dual HER2 Blockade in Breast Cancer Complete response higher with combo treatment, but not statistically significant Chicago—A growing body of evidence shows that neoadjuvant dual HER2-targeted therapy may be the future of breast cancer therapy. The most recent results are from the National Surgical Adjuvant Breast and Bowel Project B-41 (NSABP B-41) trial that compared pathologic complete response (pCR) from the combination of neoadjuvant lapatinib and trastuzumab to either agent alone in patients with HER2-positive tumors. “Combined HER2-targeted therapy produced a numerically higher pCR percentage than single-agent HER2-directed therapy, but the difference was not statistically significant,” said Andre Robidoux, MD, an oncologist at the University of Montreal Hospital Center, in Canada. He presented the study at the annual meeting of the American Society of Clinical Oncology (abstract LBA506). Although various researchers have pointed out that dual therapy will increase the price of therapy up front, it may decrease costs overall if it reduces the amount of follow-up therapy. The NSABP B-41 investigators enrolled patients with operable HER2-positive breast cancer and randomized them to one of three treatments: four cycles of doxorubicin/cyclophosphamide (AC) and paclitaxel plus trastuzumab (Herceptin, Genentech) weekly until one week before surgery; AC and paclitaxel plus lapatinib (Tykerb, GlaxoSmithKline) daily until one day before surgery; or AC and paclitaxel plus combined trastuzumab and lapatinib therapy. All three arms then received surgery and one year of trastuzumab. Rate of pCR, defined as the absence

VITAMIN D continued from page 29

a history of renal stones or a history of hypercalcemia or hyperparathyroidism. The study arms were well balanced. In patients who received extra vitamin D, vitamin D levels increased from 22 ng/mL at baseline to 53 ng/mL at week 12 and 57 ng/mL at week 57. The investigators used several tools to measure pain, fatigue and quality of life. The Simple Descriptive Pain Intensity Scale asked women to report and rate joint pain as mild, moderate, severe or disabling. The Brief Pain Inventory (Short Form) measured pain intensity and how much it interfered with items such as mood, general activity and sleep. The Health Assessment

of invasive tumor in resected breast specimens, was higher in the combination arm (62%) than the trastuzumab arm (52.5%), but the difference was not statistically significant ( =0.095). No difference was seen in (P the pCR rate between the trastuzumab alone (52.5%) and lapatinib alone arms (53.2%; P=0.99). Rates of grade 3/4 toxicities, including diarrhea, were higher in the lapatinib arms (Table), but febrile neutropenia and hepatic toxicity were similar in the three treatment groups. Combination therapy did not increase the rate of congestive heart failure compared with single-agent therapies. “These results are similar to other neoadjuvant studies of dual HER2directed therapies,” said Anne Schott, MD, an associate professor of Internal Medicine at the University of Michigan Health System in Ann Arbor, who was not involved with the study. “NeoALTTO [Neoadjuvant Lapatinib and/or Trastuzumab Treatment Optimisation] showed a nearly doubling of pCR with trastuzumab and lapatanib compared to either therapy alone. NeoSPHERE [Neoadjuvant Study of Pertuzumab and Herceptin in an Early Regimen Evaluation] also showed an increase in pCR with trastuzumab and pertuzumab [Perjeta, Genentech] compared to either treatment alone, and also showed a decent pCR rate of dual combined therapy without chemotherapy.” In the CHER-LOB trial, pCR was nearly doubled when lapatinib and trastuzumab were combined compared with either treatment alone ((J Clin Oncol

Table. Comparison of Grade 3/4 Toxicities in NSABP B-41 Trial Trastuzumab

Lapatinib

Trastuzumab and Lapatinib

Overall grade 3, %

Overall grade 4, %

Grade 3 diarrhea, %

‘Although these reports are interesting, pathologic complete response rates in this set of neoadjuvant trials do not provide sufficient evidence to consider dual targeted therapy as the standard of care for early-stage breast cancer.’ —Anne Schott, MD 2012;30:1989-1995, PMID: 22493419). “Although these reports are interesting, pCR rates in this set of neoadjuvant trials do not provide sufficient evidence to consider dual targeted therapy as the standard of care for early-stage breast cancer,” said Dr. Schott. She pointed out that a German study of seven randomized clinical trials showed that pCR is a suitable surrogate end point for patients with luminal B/ER2-negative, HER2positive (nonluminal) and triple-negative disease, but not for those with luminal B/HER2-positive or luminal A tumors ((J Clin Oncoll 2012;30:1796-1804, PMID: 22508812). In the NSABP B-41 trial, she said, 63% of patients were hormone re-

‘Vitamin D3 may be a promising intervention for musculoskeletal symptoms and possibly cancerrelated fatigue.’ —Karen Michelle Mustian, PhD, MPH Questionnaire II (HAQ II) measured the degree of difficulty that an individual had performing common activities of daily living. The Brief Fatigue Inventory asked questions related to intensity of fatigue and impact of fatigue on common activities. The first primary end point was the incidence at six months of a musculoskeletal event defined as a worsening of pain using the Simple Descriptive Pain Intensity Scale, as disability using HAQ II (+0.25) or as discontinuation of letrozole due to musculoskeletal pain. There was a trend for improvement

in this primary end point for patients receiving extra vitamin D (37% vs. 51%; P=0.069). The second primary end point was the incidence at six months of a musculoskeletal event defined as a worsening of pain using the Brief Pain Inventory (BPI; +1), disability using HAQ II or discontinuation of letrozole. There was a statistically significant improvement in patients taking vitamin D for this end point (38% vs. 61%; P=0.008). The incidence of an adverse quality-of-life event, a secondary end point, also was improved for patients taking

ceptor–positive and it is therefore unclear if the pCR benefits will translate to disease-free survival. For a definitive answer, clinicians need to wait for results from the ALTTO trial (testing combination lapatinib and trastuzumab), and APHINITY (Adjuvant Pertuzumab and Herceptin in Initial Therapy of Breast Cancer; testing pertuzumab plus trastuzumab). —Kate O’Rourke Dr. Robidoux disclosed a consultant or advisory role with GlaxoSmithKline and honoraria and research funding from GlaxoSmithKline and Roche. Dr. Schott disclosed research funding from Dompe, GlaxoSmithKline and Merck.

extra vitamin D (42% vs. 72%; P≤0.001). This secondary end point was defined as a musculoskeletal event or worsening of fatigue. Investigators who were not involved with the study were impressed by the data. “This was a very well-done study,” said Karen Michelle Mustian, PhD, MPH, an assistant professor of radiation oncology at the University of Rochester Medical Center in Rochester, N.Y. “Vitamin D3 may be a promising intervention for musculoskeletal symptoms and possibly cancer-related fatigue.” —Kate O’Rourke Dr. Khan disclosed honoraria from Abraxis BioScience and Genentech, and research funding from Abraxis BioScience, Novartis and Roche/Genentech. Dr. Mustian had no relevant disclosures.

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