The October 2012 Digital Edition of Clinical Oncology News

In recent years, the FDA has approved a number of cancer drugs

based on small improvements in sur-vival. 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

At ASCO 2012, HopeRugo, MD, professor

of medicine at the Uni-versity of California inSan Francisco, presentedthe results of a random-ized study comparing two new drugs, ixabep-ilone 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” che-motherapy of weekly paclitaxel plus

Cancer Drug Costs Under ScrutinySome newer agents provideonly marginal gains

Vogl, NY...

Weekly Pac-Bev Should Not Be Abandoned CALGB confirms long breast cancer remissions

At the annual meeting of the American S i f Cli i l O l i J

cancer were presented: bevacizumab b d i (TML S d ) flib

Drug Trials: Often LongOn Hype, Short on GainsThe delusion of ‘significance’ in drug trials

By the NUMBERS: ‘Upcoding’

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.

$11 billionAmount Medicare has been overbilled by physicians in the past decade.

15Number of states that can expect asurge in Medicare audits.

95Percent of consultations billed at the highest level that are miscoded.

-25Billing code modifier targeted by the U.S.Justice Department in its ‘yearly work plans.’

$4.1 millionAmount that Georgia Cancer Specialists, an Atlantaoncology practice, recently agreed to pay for violating the False Claims Act.

$12.8 billionTotal amount the U.S. Justice Department has recovered under the act since January 2009.

see VOGL, page 10 �

see DRUG COSTS, page 20SS �

Vitamin D levels in early, primary breast cancer . . . . . . . . . . . . . . . . . . 14

Bortezomib induction plus post-transplant maintenance examined . . . . . . . . . . . . . . 25

EXPERT COMMENTARIES FROM SITEMAN CANCER CENTER

Keith Stockeri-Goldstein, MD

AntonellaRastelli, MD

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

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

INSIDE

Steven Vogl, MD

Independent News on Advances in Hematology/Oncology

CLINICALONCOLOGY.COM • October 2012 • Vol. 7, No. 10

40th

Anniversary Year

1972–2012

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

Society for Clinical Oncology in June,the results of three potentially

practice-altering Phase III trials in meta-static colorectal

beyond progression (TML Study), afliber-cept (VEGF-Trap) added to second-line

FOLFIRI (the VELOUR study), andregorafenib after progression fol-

lowing standard therapies (theCORRECT study).

“Significant benefits in over-all survival [OS] and progres-sion-free survival [PFS]”

declared the conclusionsfor all three trials. And

that was certainly true.

P Value

Pro

ba

bil

ity

see SIGNIFICANCE, page 5 EE �

Observed size of effect

MCCON494.indd 1 8/6/12 2:49 PM

EDITORIAL BOARD

Solid TumorsBone Metastases

Allan Lipton, MD Milton S. Hershey Medical Center,Penn State University Hershey, PA

Breast Cancer

Andrew Seidman, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Maura N. Dickler, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Gastrointestinal Cancer

Edward Chu, MDUniversity of PittsburghCancer Institute,University of PittsburghPittsburgh, PA

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

Leonard Saltz, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Gastrointestinal Cancer and Sarcoma

Ephraim Casper, MDMemorial Sloan-KetteringCancer Center,Weill Cornell Medical CollegeNew York, NY

Genitourinary Cancery

Ronald M. Bukowski, MDTaussig Cancer Center,Cleveland Clinic FoundationCleveland, OH

Gynecologic Cancery g

Maurie Markman, MDCancer Treatment Centers of AmericaPhiladelphia, PA

Lung, and Head and Neck Cancersg,

Edward S. Kim, MDUniversity of Texas,MD Anderson Cancer Center Houston, TX

Lung Cancer, Emesisg ,

Richard J. Gralla, MDHofstra North Shore-Long Island Jewish School of Medicine,Monter Cancer Center North ShoreUniversity Hospital and Long Island Jewish Medical Center Lake Success, NY

Prostate Cancer

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

Hematologic MalignanciesJennifer R. Brown, MD, PhDDana-Farber Cancer Institute,Harvard Medical School Boston, MA

Harry Erba, MD, PhDUniversity of MichiganAnn Arbor, MI

Shaji Kumar, MDMayo ClinicRochester, MN

Richard Stone, MDDana-Farber Cancer Institute,Harvard Medical School Boston, MA

Syed A. Abutalib, MDCancer Treatment Centers of AmericaZion, Illinois

Community OncologyJohn W. Finnie, MDMercy Medical CenterSt. Louis, MO

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

Steven Vogl, MDMedical OncologistNew York, NY

Symptom Control and Palliative Care

William S. Breitbart, MDMemorial Sloan-KetteringCancer Center New York, NY

Steven D. Passik, PhDVanderbilt University Medical Center Nashville, TN

Joseph V. Pergolizzi Jr., MDJohns Hopkins University School of MedicineBaltimore, MD

Russell K. Portenoy, MDBeth Israel Medical Center New York, NY

Charles F. von Gunten, MDUniversity of California,San Diego, CA

Infection ControlSusan K. Seo, MDMemorial Sloan-Kettering Cancer Center New York, NY

Oncology Nursing

Betty Ferrell, RN, PhDCity of HopeNational Medical Center Duarte, CA

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

Pharmacy

Cindy O’Bryant, PharmDUniversity of ColoradoCancer Center Denver, CO

Sara S. Kim, PharmDThe Mount SinaiMedical Center New York, NY

BioethicsJoseph P. DeMarco, PhDCleveland State University Cleveland, OH

Paul J. Ford, PhDCleveland Clinic FoundationLerner College of Medicineof Case Western ReserveUniversityCleveland, OH

Policy and ManagementMary Lou Bowers, MBAThe Pritchard GroupRockville, MD

Rhonda M. Gold, RN, MSNThe Pritchard GroupRockville, MD

Editorial Philosophy

The Editorial Board of Clinical Oncology News is instrumental in guiding the content that appears in the magazine. A significant proportion of the news coverage comes from studies presented at cancer conventions and meetings. Prior to these meetings such as the ASCO annual meeting, board members are asked to identify abstracts that should be covered in their area of specialty. They then review the articles before they are published. Board members, in their area of specialty, are also consulted about review article topics, and whether or not to cover specific trends, studies that appear in peer-reviewed journals, reports from government agencies, etc., and review the articles before they go to print.

Additionally, all news articles that appear in Clinical Oncology News are sent to the ssources 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.

Mission Statement

The 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 avaluable source for oncologists and hematologists in providing the best possiblecare for their patients.

CLINICAL ONCOLOGY NEWS • OCTOBER 2012 3CURRENT PRACTICE

Over the past decade, there has been a proliferation of peer-reviewed

medical publications that use informa-tion available in large public databases such as the Surveillance, Epidemiology, and End Results (SEER)-Medicare data-base.1 These papers have focused on a variety of outcomes, including the qual-ity 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 rele-vance of certain reports using thesedatabases may sometimes be ques-tioned, such as in a study that attempt-ed to suggest that one group of medi-cal professionals appeared to providea superior level of care compared withanother among a specific patient pop-ulation,2 it is clear that appropriateexamination of these large data sets hasthe potential to address important clin-ical and societal issues.

One interesting example of the stra-tegic approach to employing nationaldatabases is their use to explore the real-world impact of a new oncologic thera-peutic paradigm that has been intro-duced into clinical practice. It is wellrecognized that the so-called evidence-based clinical trials usually requiredand cited for regulatory approval rare-ly accurately reflect the quite heteroge-neous population encountered in typical clinical practice. For example, the elder-ly are almost always profoundly under-represented in such trials, and patientswith very common and clinically

relevant comorbidities, such as medica-tion-dependent diabetes, hypertension and heart disease, are frequently exclud-ed from study entry.

Therefore, the overall clinical rele-vance (both efficacy and toxicity) of even the most “positive” evidence-based stud-ies to the community of patients actually encountered in the real world of oncolo-gy practice—for example, elderly patients

with pre-existing comorbid medical con-ditions—may be questionable. The exam-ination of national databases may pro-vide 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 data-bases in any published analysis is the absence of investigator control of disease management (e.g., number of adminis-tered treatment cycles, initial dose and subsequent dose modifications) as well as the relatively poorly characterized clinical features of the patient popula-tion (e.g., severity of comorbid condi-tions), since in such reports it is actually a specific strength of the process. Funda-mentally, what is being measured here is the true heterogeneity and complex-ity of the real world of cancer care and not the highly artificial environment of the severely eligibility-restricted, care-fully selected and homogeneous group-ing that characterizes many, if not most, patient populations entered into con-trolled clinical trials.

Of course, an alternative and admit-tedly more cynical view of the situation

would be that some or many clinical tri-als are specifically designed (manipulat-ed?) to maximize the opportunity for a “statistically significant” favorable out-come, 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-

mary management of metastatic colorec-tal 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 combi-nation (with either irinotecan or oxali-platin) 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 over-all 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 bevacizum-ab experienced a greater risk for gas-trointestinal 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 toxici-ty 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 con-fines of clinical trials provide a far more

meaningful assessment of both the poten-tial benefits and risks associated with using such therapies. Furthermore, this examination focused on the Medicare patient population, a group likely to rep-resent a substantial proportion of individ-uals with colorectal cancer being consid-ered for systemic antineoplastic therapy.

Finally, one can argue that when dis-cussing particular therapeutic optionswith patients, the data in this type of report are as relevant as, if not more rel-evant than, those relied upon by any reg-ulatory agency to formally approve theagent for use in routine clinical care.

References

1. Chagpar R, Xing YH, Chiang Y-U, et al.Adherence to stage-specific treatmentguidelines for patients with colon cancer.J Clin Oncol. 2012;30:972-979, PMID:22355049.

2. Silber JH, Rosenbaum PR, Polsky D. Doesovarian cancer treatment and survival differby 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-linecombination chemotherapy for Medicarepatients with stage IV colorectal cancer.J Clin Oncol. 2012;30:608-615, PMID:22253466.

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

Maurie Markman, MDSenior Vice President of Clinical Affairs andNational Director for Medical Oncology,Cancer Treatment Centers of America, Philadelphia

EDITORIAL BOARD COMMENTARY

on Dr. Markman’s column?

Please write to Clinical Oncology News managing editor

Gabriel Miller at

[email protected]

Comments or feedback

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.

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) ispublished monthly by McMahon Publishing,545 West 45th Street, New York, NY 10036. Corp. Office, 83 Peaceable Street, Redding CT 06896Copyright© 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

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4 CLINICAL ONCOLOGY NEWS •OCTOBER 2012CLINICAL ONCOLOGY NEWS

All three studies had OS and PFS P val-ues well below 0.05.

But whether they continued a patienton bevacizumab (Avastin, Genentech)beyond progression, added afliber-cept (Zaltrap, Sanofi and Regeneron)to FOLFIRI after progression on oxali-platin (Eloxatin, Sanofi-aventis) or pre-scribed regorafenib (Bayer HealthCare)after failure on other standard therapies,each of these trials bought their patients exactly the same amount of additionaltime, 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 Gastro-intestinal Oncology Service at MemorialSloan-Kettering Cancer Center (MSKCC)in New York City.

“Is this the kind of goal we shouldbe aiming for? If you tell patients thatthere are significant survival benefitsto a drug, and you stop there, I assureyou that they are not thinking that they will get an average of six weeks more tolive,” Dr. Saltz said.

Of course, the term significant shouldalways be modified by the all-impor-tant adverb statistically when report-ed at meetings like American Society of Clinical Oncology (although that’s notalways the case), but when results likethese get translated to headlines thatpatients (and even community oncol-ogists) read, that modifier often dis-appears. Instead, you’ll read “afliber-cept significantly improved survival inmetastatic colorectal cancer” in pub-lications like Medical News Today, andit 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 self-serving term of significant benefit, andstress much more clearly when we aretalking about statistical significance—andexplain to the public what that means. Weshould also move toward taking a harderlook at what constitutes a clinically signif-yicant benefit to the patient. And I wouldlike to see us call our shots better inadvance,” he says. “If we told the averageobserver—patients, regulators, the gener-al public—that we’re planning a study thatwill cost tens to hundreds of millions of dollars to see if an agent improves surviv-al by less than a couple of months, they’dbe very disappointed. But that’s becomeour game plan. We power these trialswith thousands of patients so as to be ableto pick up those small differences.”

Many oncology trials today are over-powered, agreed Donald Berry, PhD,

professor of biostatistics at the Univer-sity of Texas MD Anderson Cancer Cen-ter, in Houston, who founded MD Ander-son’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 signifi-cance from modest amounts. If you ran a 100,000-patient trial, you could see P val-ue 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 thana 5% chance that the difference between two medications—whatever it is—is not real, that it’s just chance. If there’s a four-week 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 dif-ference I’m seeing is not by chance. It doesn’t tell me if those additional four weeks are clinically significant.”

“P“ values are even more complicated

SIGNIFICANCEcontinued from page 1 ��

see SIGNIFICANCE, page 6 EE �

CHEMOTHERAPY FOUNDATION SYMPOSIUMINNOVATIVE CANCER THERAPY FOR TOMORROW®

November 7-10, 2012, New York City

Practical Applications for the Practicing Oncologist

New Agents, Clinical Trials, Emerging Developments

ScheduleNov. 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 HighlightsWednesday, November 7

Keynote SpeakerNorman Wolmark, MD

Thursday, November 8Ezra M. Greenspan Memorial Lecture

José Baselga, MD

Wednesday, November 7Pediatric Oncology

Therapeutic Advances in Cancers of Childhood

Saturday, November 10Oncology Nurses, Physician Assistants, Case Managers, Pharmacists

Therapeutic Advances, Treatment Related Complications,

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Register on line at www.chemotherapyfoundationsymposium.orgContact: [email protected], (212) 866-2813

The Greenspan Meeting XXX

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Presented by The Chemotherapy Foundation

in collaboration with the Tisch Cancer Institute

of the Mount Sinai School of Medicine


than that,” said Dr. Berry. “No one under-stands P values, because they are funda-mentally non-understandable.” (He elab-orates on this problem in “Multiplicitiesin Cancer Research: Unique and Neces-sary Evils,” a commentary in August inthe Journal of the National Cancer Insti-tute [2012;104:1125-1133].)

Of course, if you could offer any patientwith any form of metastatic cancer anadditional 1.4 months—or four weeks,or four days—of life with no downside,

it would be a no-brainer. “If I could pre-scribe wearing green socks and it wouldgive my patients an additional fourweeks of life, of course they would alldo it,” says Deborah Schrag, MD, MPH,a gastrointestinal cancer specialist at theDana-Farber Cancer Institute in Boston.“But the challenge is that there are toxic-ities associated with any treatment, andthe hard question to ask is how to weighthe risks and benefits and decide ‘Is thistreatment worth it?’”

Also, average benefits don’t tell thewhole story. Each patient receiving a drug with a median OS benefit of 1.4months doesn’t get six weeks past-ed magically onto his or her life span.“Some patients won’t respond to anintervention at all and achieve no ben-efit, whereas others may achieve sub-stantial benefit,” Dr. Schrag said. “Thetrick is that we don’t know how to fig-ure out who is who ahead of time andwe need to get a whole lot more strate-gic about distinguishing between stud-ies with a lot of benefit for a few, andstudies with a little benefit for many.”

“What patients count on is improvedexperience with illness—hopefully pro-longed survival with enhanced quality of life,” said Peter B. Bach, MD, attend-ing physician and director of the Cen-ter for Health Policy and Outcomesat MSKCC. “The problem with trialdesign is that we don’t subtract away the things we could subtract away.Even treatments with no toxicities haveinconveniences, and most cancer treat-ments have much more than that. If we‘netted out’ the downsides, that mighthelp patients better understand the trueclinical significance of a study result.”

For example, regorafenib was associat-ed with hand–foot–skin reactions in 17%of patients, fatigue in 15% and diarrhea in

8%. “If you have 10 days spent being very uncomfortable, or worse, because of tox-icities, 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 adjust-ments more clearly.”

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 medi-an 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 metastat-ic colorectal cancers that the CORRECT (Colorectal Cancer Treated With Rego-rafenib or Placebo After Failure of Stan-dard Therapy) trial found.

Still, in many cases, what gets present-ed at these meetings, and trumpeted to the world, are incremental improve-ments. “We tend to accept these incre-mental 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 sig-nificant P-value, and make money, than to try an innovative idea and see if you can really move the bar. I fear we’re disincen-tivizing 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 can-cer 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. Ber-ry. “But most of the advances in breast cancer have been incremental. But if you ‘daisy-chain’ those advances, put togeth-er they have decreased mortality risk and recurrence risk by over 50%. Individually,

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

there’s no good reason to believe it will—yet it will likely become a standard prac-tice,” 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 unsustain-ably expensive system that is using hun-dreds of thousands of dollars’ worth of drugs per patient for not much benefit.”

It’s human nature for patients to

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 oncol-ogy 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 driv-en,” says Dr. Adjei. “You have compa-nies 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

to get them on the market. Investigatorshave 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 compa-ny is not nearly as much of a conflict of interest as is the whole way we advance academically. No one will publish a neg-ative study, so you have to have posi-tive studies to get promoted. And we in oncology want to show that we’re mak-ing progress, ‘winning the war on can-cer,’ so we talk it up.”

There are no easy solutions to any of this, but it’s a conversation that oncolo-gy must have. “For starters, it would be good if we, as a community, could agreeon what is a clinically significant find-ing,” said Dr. Saltz. “If I said that I could reliably improve median survival by one month at $1 billion per patient with seri-ous 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 twoscenarios, 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 toturn to something like what the Unit-ed Kingdom has put in place, with its National Institute for Health and Clin-ical Excellence. “We need a consensus panel, with some teeth in it, that will setgoals and standards for trial outcomes and drug approvals.”

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 sur-vival benefit.’ We know that’s going to bemisinterpreted. The public is reading our literature now, the Internet has put every-thing 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

SIGNIFICANCEcontinued from page 5 �

‘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’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

Clinical Oncology Newswelcomes letters to the editor.

Do you have thoughts on this column?

Please send comments to

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6 CLINICAL ONCOLOGY NEWS • OCTOBER 2012CURRENT PRACTICE

Chicago—Urea-based skin creams canreduce the incidence of hand–foot skinreactions (HFSR) in patients treated withsorafenib (Nexavar, Bayer), according toresults from a large Phase II, open-label,randomized study. An example of thisskin cream is Eucerin (Beiersdorf, Inc), a commonly available product.

The finding, reported at the annualmeeting of the American Society of Clini-cal Oncology (abstract 4008), has already spurred practitioners to make changes.

“I would definitely recommend Eucerincream in patients who are on sorafenib,”said Ed Chu, MD, chief of Hematology/

Oncology and deputy director of the Uni-versity of Pittsburgh Cancer Institute,who was not involved with the study. “Itmight also be interesting to use Eucerincream with other drugs that are associat-ed with hand–foot syndrome, such as theoral 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 sorafenibfor unresectable hepatocellular carcino-ma and 30% of patients who receive thisdrug for advanced renal cell carcinoma.

Investigators of the new study, whichwas conducted at 64 centers in China,enrolled patients with advanced hepato-cellular carcinoma who were sorafenib-naive. Approximately 900 patients weregiven sorafenib and randomized to con-comitant best supportive care (BSC) orBSC plus urea-based skin cream. Thetreatment arms were well balanced interms of baseline patient characteristics.

Patients who were treated with the skincream had a significantly lower incidenceof all-grade HFSR within 12 weeks (56.0%vs. 73.6%; P<0.0001), as well as grade 2/3HFSR (20.7% vs. 29.2%; P=0.004). Theprophylactic use of urea-based creamimproved health-related quality of life,reducing symptom burden and the effectof symptoms on daily activities. Grade 2HFSR is characterized by skin changes,such as peeling, blisters, bleeding, ede-ma or pain that does not interfere with

function. Grade 3 HFSR is ulcerative der-matitis 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 Oncolo-gy 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 Shang-hai, China, who presented the research at the meeting, said the study was limit-ed in that it did not document the extent to which the patients used the moisturiz-ing skin cream.

—Kate O’Rourke

Dr. Chu, Weekes and Ye reported norelevant disclosures.

Effective Hand–Foot Syndrome Treatment IdentifiedPhase II, randomized trial has some clinicians changing practice

Examples of hand-foot syndrome.

SUPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS

oncologyfellowadvisor.com

ONCOLOGYFellowadvisor

Top-Tier Centers Share Tipss Share Tips

Hospitals in the United States are anxxious to be included in the annual US News and World Repport’s list of top

hospitals. To make the 2011 to 2012 cut, ccancer centershad to treat at least 254 inpatients withh high-level expertise in 2007, 2008, and 20099.1 Thefollowing are the top 10 cancer centerss in USNews and World Report, in ascending orrder of quality: University of Texas MD Andersonn Can-cer Center, Memorial Sloan-Kettering CCancer Center (MSKCC), Johns Hopkins (JH), MayoClinic, Dana Farber Cancer Institute/Briggham & Women’s Cancer Center, University ofWashington Cancer Center in Seattlee, Massachusetts General Hospital, UCSFF Medical Center, Cleveland Clinic, andd Ronald Reagan UCLA Medical Center.1

Oncology Fellow Advisor spoke witthDaniel Spratt, radiation oncology traineeat Memorial Sloan-Kettering (No. 2 on tthe

Master Work–Life Balance

T raining to be an oncologist can berough. In the face of long hours,

sleep deprivation, and patient suffer-ing, young oncologists may sacrifice hobbies, interests, and even relation-ships. Many fellows find comfort inreminding themselves that better days are ahead but experts say thatthey may be setting themselves up for disappointment.

Oncologists who cope by lookingto 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 wellnesscan 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 Divi-sion of Surgical Oncology at Universityof Texas Southwestern Medical School in Dallas, Texas. “A successful medical career at the expense of personal well-being is not at all successful.”

One in 3 oncologists will experi-ence significant career burnout—described as emotional exhaustion, depersonalization, and a sense of low personal accomplishment that leadsto decreased effectiveness at work.2

Some of its more tragic consequences



A DAY IN THE LIFE

We highlight the work of fellow-ship director Timothy Gilligan, MD. 4

FELLOWSHIP TRAINING

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

FELLOWSHIP TRAINING

Communication skills are crucial for oncology fellows. 7

For the latest oncology fellow–related information,

please visit www.oncologyfellowadvisor.com

®

is brought to you as a professionalcourtesy. This content is selected and

controlled by McMahon Publishing and isfunded by Lilly USA.

SUPPORT & INFORMATION FOR THE NEXT GENERATION OF ONCOLOGY PRACTITIONERS



Vol. 3, Issue 3

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TrainingMentorMemos

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PhysicianFinance

Top-Tier page 5

see, Work–Life page 2

To obtain educational information for oncology fellows, please visit us online:

www.oncologyfellowadvisor.com

CLINICAL ONCOLOGY NEWS • OCTOBER 2012 7SOLID TUMORS

Case Background

On June 5, 2011, William D., a 57-year-old man, presented to the local emergen-cy room with a sudden onset of hema-turia. 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 activ-ity in the retroperitoneum, the largest of which was in the periaortic area mea-suring 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 subcen-timeter pulmonary nodules. On June 7, the doctors performed a transurethral resection of the bladder tumor with evac-uation 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 sarcoma-toid carcinoma and a microscopic exam showed the presence of multiple malig-nant spindle-shaped cells with inflam-matory 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 pulmo-nary nodule. The pathology was nondi-agnostic. However, given the confirmed bladder carcinoma and the presence of pulmonary nodularity, the doctors

recommended a chemotherapy regimen for metastatic bladder cancer.

William D. was given a projected one-year survival. He was released from the hospital and returned home to consid-er his options.

Initial Intake

On June 27, 2011, William D. arrivedat Cancer Treatment Centers of Ameri-ca (CTCA) at Eastern Regional Medical Center (Eastern) in Philadelphia seek-ing a second opinion. Confused by theinconclusive results that had led to hisdiagnosis, he told the intake team at CTCA: “I need to know what to do, and what I have.”

Anthony Perre, MD, medical director of New Patient Intake, CTCA at Eastern Regional Medical Center:

“When William D. wasinitially diagnosed, the

local doctors did a CT scan and saw lymph node enlargement in the abdo-men, as well as pulmonary nodularity in the left lower lobe and the right low-er lobe. We took this information intoconsideration, but began by performing a medical history from the beginning,

and doing a fresh work-up.”Next Steps: A positron emission tomo-

graphic (PET) scan revealed the wide- spread enlargement of lymph nodes in the chest, abdomen, pelvic area, spine and lung. A magnetic resonance imag-ing scan of the brain did not reveal any presence of tumors. The team also com-pleted a full patient history from which they learned—for the first time—that Wil-liam D. had experienced left-sided cervi-cal and supraclavicular lymphadenopa-thy 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. Interven-tional radiology performed the biopsy, but the results did not confirm a pres-ence of cancer, mirroring the inconclu-sive 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.

Sramila Aithal, MD, medical oncologist and hematologist/oncolo-gist, CTCA Eastern:

“One could have pro-ceeded 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 ongo-ing for 18 years gave me a suspicion that something else was going on. I wanted

the confirmed diagnosis.“At first, the surgeon did not under-

stand why I wanted this procedurebecause we already had confirmedbladder cancer. However, once Iexplained my perspective—that carci-nosarcoma is so rare and the ongoing lymph node activity caused concern—he realized the importance and mostreadily agreed with it.

“Everyone was surprised. We alsowere very happy. Hodgkin lymphoma carries a much better prognosis thanmetastatic bladder cancer. The choiceof chemotherapy for Hodgkin lympho-ma is completely different from thatwhich is used for bladder cancer andthe chemotherapy for bladder canceris much harsher. The patient’s early-stage bladder cancer did not requireany chemotherapy.”

Dr. Perre: “Often for people withHodgkin lymphoma, a core biopsy is notenough. Dr. Aithal recommended an exci-sional biopsy of the lymph node and thisstep really made the difference, becausepathology indicated Hodgkin lymphoma.We took things a step further. Dr. Aithalknew that carcinosarcoma is rare; addi-tionally, the pathology demonstrated thatthe carcinosarcoma was not muscle-inva-sive, and metastatic disease in this cir-cumstance would have been exceedingly unusual. When we noted the lymph nodesin the left axilla, it gave us another placeto investigate, and Dr. Aithal knew thatan excisional biopsy could give us a bet-ter chance at making a definitive diagno-sis. The excisional biopsy is what result-ed in the Hodgkin lymphoma diagnosis.”

Had the Hodgkin lymphoma not beendetected, William D. would not only have received treatment for the wrong diagnosis, but also unnecessarily suf-fered the harsh side effects of advancedbladder cancer treatment.

Case Reports: Hematuria WithLymph Node Activity and Pulmonary Nodules

This 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 Newsencourages reader feedback. Please email managing editor Gabriel Miller at

[email protected].

Axillary (underarm) lymph nodes.

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


Recommended TreatmentNext Steps: It was clear that William

D. had two cancers—early-stage blad-der cancer as well as advanced Hodgkinlymphoma. Urology confirmed that hisbladder was stable and he began chemo-therapy for Hodgkin lymphoma—fourcycles of ABVD (adriamycin-bleomy-cin-vinblastine-dacarbazine) as first-line treatment for Hodgkin lymphoma.

Dr. Perre: “The new diagnosis andsubsequent treatment plan was for-mulated quickly. William D. went fromthinking he would die to understanding he could live.”

Managing Side Effects

William D. also received naturopathicrecommendations to help manage theside effects of his prescribed chemo-therapy regimen, as well as to monitorsupplement and vitamin intake and pre-vent drug–herb and drug–nutrientinteractions.

Renee Lang, ND,a naturopathic oncology provider:“Specifically, we focusedon managing leg cramp-ing, fatigue and mouthsores, as well as thereduction and prevention

of neuropathy.”Next Steps: In addition to some

general immune support, Edward wasprescribed coenzyme Q10 as an anti-oxidant to decrease fatigue and as a protectant against potential cardio-toxicity that can arise from the use of adriamycin.

Coping With Cancer

During his treatment, CTCA cliniciansnoted that William D. experienced mooddisturbance and heightened anxiety. Toaddress those challenges, the patientmet with a member of the CTCA mind–body medicine team, a group of licensedmental health professionals who helpsupport and maintain patients’ psycho-logical well-being. The team uses evi-dence-based therapies such as cognitive-behavior therapy (CBT), sleep hygieneand relaxation training, which can helpwith physical symptoms such as dyssom-nia, pain and nausea, as well as motiva-tional interviewing, which can help tooptimize adherence to treatmentrecommendations.

Carol Roth, LCSW, a mind–body medicine clinician at CTCA:

“Getting a cancer diag-nosis can be very trau-matic and very shocking.People have a lot of othercomplex things going on,

just by the nature of life itself, such ascomplex family and social relationshipsor demanding work and professional

relationships. And in the midst of that, a cancer diagnosis can upend a person’s life. As a result, there can be quite a bit of change in a person’s affect and their mood, and that can manifest in a vari-ety of ways.

“People can cope with stress in positive or negative ways. We help patients exam-ine their individual coping style, identi-fy their own strengths and build success-ful coping strategies to help them with the way they are feeling. We don’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-relat-ed 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.”

Outcome

Three months into treatment, a PET/CT scan demonstrated favorable response to therapy. Today, William D. is in remis-sion and under surveillance, with cystos-copies performed every three months.

Dr. Perre: “A diagnosis can cause a patient to become distraught and anx-ious. For William D., being told he would be dead in a year, and now in complete remission … he has a new lease on life. Part of what we do here is help comfort patients and provide tools to face chal-lenges, because part of the battle is spir-itual and emotional.”

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 [email protected].

FDA Drug ApprovalsRegorafenib (Stivarga, Bayer HealthCare Pharmaceuticals) was approved by

the FDA for the treatment of metastatic colorectal cancer following previous RRtreated 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 chron-ic, 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 resis-tant 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 cytoge-netic 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-con-trolled trial of 1199 patients who had received prior docetaxel, an interim anal-ysis 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 oralsuspension (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 indi-cation 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.

—from FDA press releases

Letters to the Editor

Readers respond to “Vogl, NY”column on the EMILIA trial

To the Editor:

Kudos to Steve Vogl, MD, for once again rendering his thoughtful and straight-forward opinion, in this instance regarding the EMILIA trial results and

industry’s and government’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. Vogl’s always interest-ing, thought provoking and frequently iconoclastic musings.

Marc Slatkoff, MDMedical OncologistPiedmont Hematology-Oncology AssociatesWinston-Salem, NC

To the Editor:

Thank 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, MPHProfessor of Medicine Director, Comparative Effectiveness and Outcomes Research–OncologyDuke University School of Medicine and the Duke Cancer Institute



[email protected].

What are your thoughts?

Send us your newsClinical 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

[email protected]


bevacizumab (“pac-bev”). Response and progression-free survival (PFS) were significantly inferior for the ixabepilo-ne arm, and slightly but not significantly worse for the nab-paclitaxel arm (Table 1). Unfortunately, toxicity was exces-sive 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-to-treatment failure (cessation of chemo-therapy) a median of four months before disease progression.

However, the most important obser-vation from this study was not men-tioned until the question-and-answer period: that the “control” group dupli-cated the extraordinarily long PFS of 11.5 months for weekly pac-bev origi-nally reported by Kathy Miller, MD, in ECOG 2100 (Table 1).2

Genentech/Roche clearly erred in the development of bevacizumab for meta-static 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 chemo-therapy studies of bevacizumab with dif-ferent 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 sur-vival, leading the FDA to withdraw its approval for the use of bevacizumab for metastatic breast cancer.

How To Interpret the Extraordinarily Long PFS ofPaclitaxel-Bevacizumab

The near doubling of median time to progression from six to 11.5 months with-out prolongation of median- or long-term survival is an incremental benefit. The assumption, which still needs to be vali-dated prospectively, is that delaying dis-ease progression prevents worsening of symptoms and improves quality of life,

even if it does not prolong life. Among women with symptomatic metastat-ic breast cancer who improve or resolve their symptoms on paclitaxel plus beva-cizumab, delaying disease progression by 5.5 months must be a substantial benefit provided disease progression is accom-panied by worsening of symptoms. As a compassionate physician, my goal in treating metastatic breast cancer is con-trol 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 Pacli-taxel Plus Bevacizumab?

The addition of bevacizumab to week-ly paclitaxel is not a “home run.” A “home run” would be a therapy that produced either some cures, a lot of long com-plete remissions—especially if they are unmaintained or maintained with min-imal toxicity—or completely controlled symptoms for long periods with minimal levels of toxicity.

Nonetheless, in 2012, I know of no otherchemotherapy for HER2-negative breast

cancer that produces such long remis-sions, and, until something better comes along, I intend to offer it to my patients

as first-line chemotherapy for metastat-ic 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 aMore Toxic, Less Effective Formulation?

It is unclear whether this is the case. In a metastatic disease population of 454 women (60% with prior chemothera-py for metastatic disease, 78% recruited from Russia or Ukraine), William Grad-ishar, MD, a professor of hematology and medical oncology at Northwestern Uni-versity in Chicago, reported in 2005 that nab-paclitaxel is more active and less tox-ic 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 progres-sion (37 vs. 23 weeks) were modest.3

A subsequent four-arm Phase II study, also largely recruited in the former Sovi-et Union, made “Phase III-type” compar-isons with only 75 patients in each of the

four arms. Every-three-week nab-pacli-taxel seemed neither more nor less effec-tive than every-three-week docetaxel,

but weekly nab-paclitaxel at 100 or 150mg/m2 seemed more effective, with over-all response rates of 63% and 74% versus39% with docetaxel, and longer medi-an PFS (7.5 and 14.6 vs. 7.8 months fordocetaxel). The confidence intervals forthese figures were broad and these resultswere not exactly reproduced by indepen-dent radiologic review. Grade 3/4 neu-tropenia went from 25% at 100 mg/m2

weekly to 46% at 150 mg/m2 nab-pacli-taxel weekly to 94% with every-three-week docetaxel.4

I suspect it was the very long PFSon the high-dose weekly arm in thissmall study that led Abraxis to con-vince the Cancer and Leukemia Group B(CALGB) to use this dose in study 40502.

Was PositiveInteraction of Nab-Paclitaxel With Bevacizumab Lost BecauseDoses Were Missed?

In CALGB 40502, there was muchmore hematologic and neurologic toxic-ity with nab-paclitaxel than with solvent-based paclitaxel, leading to many moredose reductions—and presumably, inter-ruptions—as well as early discontinua-tion of therapy (Table 1). Because thereappears to be a special interaction of bev-acizumab with weekly paclitaxel, if tox-icity led to a significant number of misseddoses of weekly nab-paclitaxel, the spe-cial interaction may have been lost as anunexpected result of the loss of week-ly scheduling. In addition, no favorableinteraction in terms of duration of diseasecontrol can be expected if chemotherapy has been discontinued for toxicity. Unfor-tunately, we may never know whether a lower planned weekly nab-paclitaxeldose produces longer remissions, sinceit seems unlikely that this study will berepeated at a lower nab-paclitaxel dose.

According to Dr. Rugo, the pharma-ceutical company, Abraxis/Celgene,

Table 1. Two Randomized Trials of Paclitaxel Plus Bevacizumab

ECOG E2100 CALGB 40502

Paclitaxel (n=326)

Paclitaxel + Bevacizumab (n=347)


Nab-Paclitaxel + Bevacizumab (n=271)

Median PFS, mo 5.9 11.8 10.6 9.2

Median TTF, mo 5.1 7.1 7.1 5.4

Median OS, mo 25.2 26.7 26 27

ORRa 25% 49% 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. Among measurable disease patients only.

Steven Vogl, MDMedical Oncologist, New York City

EDITORIAL BOARD COMMENTARYVOGLcontinued from page 1 ��


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


[email protected]

What areyour thoughts?

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.

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.


chose the dose of nab-paclitaxel. Insteadof developing nab-paclitaxel as an easierto administer, less toxic, yet still effectiveformulation of an effective drug, Abrax-is chose to push for higher doses, ignor-ing earlier CALGB data that higher dos-es of paclitaxel are not more effective inttreating metastatic breast cancer, but arestill more toxic.5

Perhaps Abraxis did not yet know theresults of a large randomized Phase IIstudy the company supported in theUnited States that looked at bevacizum-ab with three schedules of high-dosenab-paclitaxel.6,7 In this study, 37% of the209 enrolled patients had their therapy stopped because of toxicity. One arm—260 mg/m2 nab-paclitaxel given every 14days—was closed to accrual early due toexcessive toxicity after only 54 patientshad been entered.

Table 3 focuses on the 79 patients in thisstudy assigned to weekly nab-paclitaxelplus bevacizumab at 130 mg/m2 per weekwithout planned interruption. Althoughobjective response was a respectable 45%,median duration of treatment was only 4.1 months (six three-week cycles), muchshorter than the median time to diseaseprogression of nine months. Hematolog-ic and neurologic toxicity were at levels Iconsider excessive for the palliative treat-ment of incurable cancer (Table 3).

By pushing to such high doses and highlevels of toxicity, the duration of paclitaxeltherapy was shortened and the favorableinteraction with bevacizumab was proba-bly impaired. Doses that were skipped fortoxicity or not given because chemother-apy was stopped could not possibly inter-act favorably with bevacizumab.

Where Do We Go From Here?

It would be reassuring to have stud-ies to demonstrate that adding bevaci-zumab improves patients’ time with a high quality of life. I frankly doubt itis worth committing large numbers of patients and years of effort to provethis. A more reasonable and hopefulplan would probably be to use pac-bev as a control arm with which to com-pare promising therapies in the future,measuring symptoms and quality of lifeboth on study and after the study peri-od. If pac-bev prolongs time to progres-sion, then patients will be “on study”longer, and we will need to comparetheir symptoms and quality of life bothearly and late in their pac-bev thera-py to the quality of life of the patientson comparator therapies over the same

time period. These comparator patients may already have switched to second- or 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 toxic-ities assumes great importance in trial design and dose selection—a good thing, I would argue.

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 neu-ropathy forces cessation of the paclitax-el component, or at some time point afterstable 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 diseasecontrol that bevacizumab adds to initialchemotherapy for metastatic breast can-cer 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) com-pared 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 Annu-al Meeting of the American Society of Clin-ical Oncology; June 1-5, 2012; Chicago, IL.Abstract CRA1002.

2. Miller K, Wang M, Gralow J, et al. Paclitax-el 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 albu-min-bound paclitaxel compared with poly-ethylated castor oil-based paclitaxel inwomen 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 sur-vival with nab-paclitaxel compared with docetaxel as first-line therapy for metastat-ic breast cancer. J Clin Oncol. 2009;27:3611-3619, 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 nanoparticlealbumin-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. Ran-domized Phase II trial of weekly vs. q 2-weekly vs. q 3-weekly nanoparticle albu-min-bound paclitaxel with bevacizumab as first-line therapy for metastatic breast can-cer. Presented at the San Antonio Breast Cancer Symposium; December 6-10, 2011;San Antonio, TX. Abstract P1-14-01.

Table 2. Toxicity in CALGB 40502


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 2% 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.on days 1, 8 and 15 every 28 d.

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 3/4neurotoxicity)

Median duration of treatment, mo 4.1 (6 cycles of 21 d each)

Toxicity

Neurotoxicity grade >3, % 43

Sensory neuropathy grade >2, % 70

Neutropenia grade >3, % 30

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-weeklynanoparticle albumin-bound paclitaxel with bevacizumab as first-line therapy for metastatic breastcancer. Presented at the San Antonio Breast Cancer Symposium; December 6-10, 2011; San Antonio, TX. Abstract P1-14-01.Abstract P1 14 01.

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.

Send us your newsClinical Oncology News appreciates news tips and suggestions for coverage from readers.

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Regimen Shows Promise in Older Patients With Hodgkin Lymphoma

Age is an independent, poor prog-nostic feature in Hodgkin lym-

phoma.1 The ABVD regimen may be excessively toxic in older adults; in one retrospective cohort study, the treat-ment-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 (bleo-mycin, etoposide, doxorubicin, cyclo-phosphamide, vincristine, procarba-zine and prednisone) or COPP-ABVD (cyclophosphamide, vincristine, pro-carbazine and prednisone alternating with doxorubicin, bleomycin, vinblas-tine 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 pro-spectively enroll older patients with Hodgkin lymphoma and assess the

efficacy and safety of the VEPEMB regimen. Patients underwent a pro-spective 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 experimen-tal regimen, were treated at physi-cian 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 like-ly to achieve CR. The treatment-relat-ed septic death rate was 3%. In an eval-uation of the entire cohort (including those treated with other regimens), factors predictive of achieving CR included hemoglobin, comorbidities, dependence on instrumental activi-ties of daily living, Eastern Coopera-tive Oncology Group performance sta-tus and albumin.

There is growing evidence of the importance of incorporating princi-ples of geriatric assessment into the

oncologic assessment of older adults.4

Geriatric assessments include eval-uation of comorbidities, functional status, cognition, depression, nutri-tional status, falls and social support. Geriatric assessment is predictive of grade III/IV toxicity of chemothera-py 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 approach-es should incorporate geriatric princi-ples, as was done in this study, both for selecting therapy for subgroups of older adults, but also subsequently as predic-tors of toxicity and outcomes to facil-itate decision making for clinicians, patients and their caregivers.

References

1. Hasenclever D, Diehl V. A prognosticscore for advanced Hodgkin’s disease.International Prognostic Factors Projecton 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

Hodgkin’s lymphoma patients older than45 years. Pathol Oncol Res. 2012;18(3):675-680, PMID: 22234624.

3. Ballova V, Rüffer JU, Haverkamp H, et al.A prospectively randomized trial carriedout by the German Hodgkin Study Group(GHSG) for elderly patients with advancedHodgkin’s disease comparing BEA-COPP baseline and COPP-ABVD (study HD9elderly). Ann Oncol. 2005;16(1):124-131, PMID: 15598949.

4. Dale W, Mohile SG, Eldadah BA, etal. Biological, clinical, and psychoso-cial correlates at the interface of cancerand aging research. J Natl Cancer Inst.2012;104(8):581-589, PMID: 22457474.

5. Hurria A, Togawa K, Mohile SG, etal. Predicting chemotherapy toxici-ty in older adults with cancer: a pro-spective 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 tox-icity in older patients: The Chemother-apy Risk Assessment Scale for High-Age 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 geri-atric assessment is more effective thanclinical judgment to identify elderly dif-fuse large cell lymphoma patients whobenefit from aggressive therapy. Cancer. 2009;115(19):4547-4553, PMID: 19562776.

8. Smith BD, Smith GL, Hurria A, HortobagyiGN, Buchholz TA. Future of cancer inci-dence in the United States: burdens uponan aging, changing nation. J Clin Oncol.2009;27(17):2758-2765, PMID: 19403886.

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

From Blood

Amulti-drug chemotherapeutic reg-imen containing vinblastine,

cyclophosphamide, prednisolone, pro-carbazine (Matulane, Sigma Tau), eto-poside, mitoxantrone and bleomycin has been shown to be effective in olderadults with Hodgkin lymphoma (withthe exception of procarbazine, allare available in generic form in the United States).

The U.K.-based Phase II clinical tri-al, part of the SHIELD (Study of Hodg-kin In the Elderly/Lymphoma Data-base) study, was designed to expandon the findings of the Italian Lym-phoma Group, which first developed

and studied the regimen in elderly patients with the disease in the ear-ly 2000s (Ann Oncol(( 2004;15:123-128; PMID: 14679131). The results of the present study on the regimen, known collectively as VEPEMB, were pub-lished in the June 21 issue of the jour-nal Blood (2012;119:6005-6015; PMID: d22577177).

In the SHIELD study, 103 patients (median age, 73) with Hodgkin lym-phoma were treated with VEPEMB and another 54 were registered (off-study) prospectively and treated with ABVD (doxorubicin, bleomycin, vin-blastine and dacarbazine)—a regi-men that is considered the gold stan-dard for treatment of younger patients with Hodgkin lymphoma—or CLVPP

(chlorambucil, vinblastine, procarba-zine hydrochloride and prednisolone). Additionally, 18 patients also were reg-istered (off-study) prospectively and administered alternative treatments, such as radiotherapy, surgery or CHOP (cyclophosphamide, doxorubicin, vin-cristine and prednisolone).

Among the patients in the VEPEMB arm, 31 had early-stage disease (stag-es 1A or 2A); these patients received three cycles of VEPEMB followed by radiotherapy. After a median follow-up 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 tri-al included neutropenic sepsis and pyrexia. The ABVD regimen “dem-onstrated substantial toxicity,” the authors noted.

Tanya M. Wildes, MDStaff Physician,Alvin J. Siteman Cancer Center at Barnes-Jewish Hospital andWashington University School of Medicine in St. LouisAssistant Professor of Medicine,Washington University School of Medicine in St. Louis

EXPERT INSIGHT

12 CLINICAL ONCOLOGY NEWS • OCTOBER 2012HEMATOLOGIC DISEASE

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Vitamin D Linked to Breast Cancer Survival, Tumor Size

This study adds to the growing lit-erature on the association of vita-

min D and cancer, and reminds us that the vitamin D signaling pathway remains an elusive system. The inves-tigators 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 relation-ship 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 entire-ly surprising considering the extraor-dinarily complex signaling pathway of

vitamin D which, besides regulating thehomeostasis of calcium and ph ospho-rus, exerts a paracrine effect on almostevery cell in the body, including breastcells. Breast cells in fact possess theenzyme that converts the precursor of 25(OH)D into its active form 1,25-dihy-droxyvitamin D, which in turn regu-lates a cascade of other pathways.

Unfortunately, it is still unclearwhether there is a causal effect of vita-min D on cancer, and if anything, thisstudy advises caution before encour-aging vitamin D supplementation tofurther the goal of preventing cancer.There is an abundance of studies show-ing that all-cause mortality is increased with lower vitamin D levels; however,we still do not know what is the safeupper limit of normal. For instance,the National Health and Nutrition

Examination Survey III study suggeststhat 25(OH)D levels above 50 ng/mL may be associated with an increased all-cause mortality in women,1 and thatlung cancer and other digestive systemcancers 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. ArchIntern Med. 2008;168:1629-1637; PMID:18695076.

2. Freedman DM, Looker AC, Abnet CC, etal. Serum 25-hydroxyvitamin D and cancer mortality in the NHANES III study (1988-2006). Cancer Res. 2010;70:8587-8597;PMID: 20847342.

Dr. Rastelli reported no relevant financial disclosures.

Chicago—A Phase III trial has shownthat regorafenib (Bayer) is a new poten-tial therapeutic option for patients withadvanced gastrointestinal stromal tumor(GIST) resistant to tyrosine kinase inhib-itors (TKIs). In late August, Bayer sub-mitted a New Drug Application for rego-rafenib in GIST.

“Regorafenib has the potential to ful-fill an unmet need for patients withadvanced GIST progressing after ima-tinib and sunitinib and potentially rep-resents a new standard of care for thispatient population,” said George Deme-tri, MD, director of the Center for Sarco-ma 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 dis-ease, drug resistance remains a chal-lenge. Regorafenib is a structurally dis-tinct 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 suni-tinib. The double-blind trial involv-ing 17 countries across Europe, North America and Asia-Pacific, randomized 199 patients in a 2:1 ratio to regorafenib or placebo, each with best support-ive 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 surviv-al was 4.8 months in patients receiving regorafenib compared with 0.9 months in

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

Regorafenib Offers New Option for Refractory GISTDouble-blind study of 199 patients

From Carcinogenesis

Vitality and vitamin D very likely could be linked for women diag-

nosed with early, primary breast can-cer, according to a study. Higher serum 25-hydroxyvitamin D3 (25[OH]D) lev-els 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 remark-able 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).

Lower vitamin D levels at time of diag-nosis did not significantly correlate with lymph node invasion, receptor status or tumor grade.

This finding suggests a possible mechanism of action: “Our own obser-vations, 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 pri-mary, non-metastatic breast cancer at University Hospitals Leuven in Bel-gium between June 2003 and Febru-ary 2010.

In terms of survival, a serum vita-min D level greater than 30 ng/mL

conferred a significant benefit for overall survival (OS; P=0.0101) and significant disease-specific survival (DSS; P=0.0192).

In a stratified analysis, postmeno-pausal (but not premenopausal) wom-en exhibited a significant advantage in DSS, disease-free interval and dis-tant disease-free interval. Specifically, during a median follow-up of 4.7 years, the observed relapse rate among wom-en 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 demon-strated certain genetic variants are sig-nificantly associated with vitamin D sta-tus, the investigators also assessed eight potentially relevant single nucleotide polymorphisms (SNPs) in a subset of

1,338 patients with available data. How-ever, they found no significant associa-tion between these genetic factors andtumor characteristics or survival.

Although the association betweenlower vitamin D levels and greatertumor size was significant, it was “rath-er modest,” representing a potentiallimitation of the study, the researchersnoted. Analysis of breast cancer–specif-ic survival and a documented cause of death in 87% of participants who died were strengths of the study.

Future study to resolve the unan-swered question about whether vita-min D supplementation should beadministered to women to preventbreast cancer is warranted. Thesefuture findings could dictate inclusionof such recommendations in standardtreatment regimens.

Antonella Rastelli, MDStaff Physician,Siteman Cancer Center at Barnes-Jewish Hospital andWashington University School of Medicine in St. LouisAssistant Professor,Washington University School of Medicine in St. Louis

EXPERT INSIGHT

GIST cells under a microscope.

14 CLINICAL ONCOLOGY NEWS • OCTOBER 2012SOLID TUMORS

Rituximab Maintenance for Elderly With Mantle Cell Lymphoma

Patients aged 65 years and overrepresent a majority of new MCL

diagnoses, limiting use of aggres-sive treatment strategies that haveimproved outcomes in youngerpatients. The results of this study willhelp inform, but not define, therapy for older patients with MCL.

The good news was that maintenancerituximab enhanced remission dura-tion compared with IFN-α. Becausethe efficacy of IFN-α maintenance inMCL has been demonstrated previous-ly, a comparison between maintenance

rituximab and no maintenance like-ly would have demonstrated an even greater benefit. It is important to high-light 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, infec-tion, secondary malignancy and other causes, many of which were seen while patients were in remission. Although

we cannot be certain of a direct rela-tionship, the profound and sometimesprolonged suppression of the lym-phoid and myeloid cell lines associat-ed with fludarabine is highly suspect.Fludarabine-induced immune sup-pression could directly increase therisk for relapse, infection and second-ary malignancy, and it also may lim-it the ability to administer effectivetreatment at the time of relapse. Over-all, fludarabine-based therapy shouldprobably be avoided in this populationunder most circumstances.

The difficult (i.e., ugly) news aris-es when we try to interpret these results in the context of the mod-ern clinical landscape. One draw-back of large studies of rare diseases is the delay between study inception and conclusion. Such studies often answer questions that are less clinical-ly relevant by the time they are pub-lished. Perhaps due to extrapolation

from studies of elderly chronic lym-phocytic leukemia patients, most cli-nicians would already avoid fludara-bine in elderly patients with MC L, decreasing the relevance of this find-ing. Furthermore, bendamustine plus rituximab improves progression-freesurvival and has less toxicity in com-parison to R-CHOP in patients withMCL, a finding that has already affect-ed clinical practice. Whether mainte-nance rituximab will have a similarimpact after bendamustine induction therapy is unknown. However, giv-en the relatively short median surviv-al seen in elderly patients with MCLand the manageable side-effect profile associated with maintenance ritux-imab, I would advocate for rituximabmaintenance therapy in patients who respond to first-line therapy.

Dr. Carson reported no relevant financial disclosures.

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 sig-nificant difference was not expect-ed. “Eighty-five percent of patients on the placebo arm crossed over to rego-rafenib,” 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%), hyperten-sion (22.7% vs. 3%), and diarrhea (5.3% vs. 0%). However, patients were able to

continue successfully on regorafenib with study-defined dose modifications, and the rate of toxicity-related treatment dis-continuation 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 via-ble 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 refracto-ry GIST offer only best supportive care. Some clinicians might choose to con-tinue a previous TKI therapy following progression of disease or try a different,

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 researchfunding from Millennium, Novartis

and Pfizer.

From The New England Journal of Medicine

A one–two punch against mantle cell lymphoma (MCL) in older

patients has demonstrated the poten-tial 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 chemo-therapy strategy since currently only a minority of patients achieves com-plete remission (CR). Relapse or pro-gression 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, cyclophos-phamide, 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 experi-enced progressive disease (5%) com-pared with the RF-C group (14%).

Patients who responded to induction were re-randomized to maintenance therapy with either rituximab or IFN-α.

Those who received rituximab experi-enced a longer duration of remission during a median 36-month follow-up.

Hematologic toxic effects were more frequent in the R-FC group com-pared with the R-CHOP group, includ-ing grade 3 or 4 anemia, leukocytope-nia, 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 fluda-rabine-containing induction regi-men was not more effective but was more toxic than R-CHOP,” the authors wrote. “Maintenance therapy with rituximab almost doubled the dura-tion of remission in patients who had a response to induction therapy and significantly improved overall surviv-al 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 signifi-cantly 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 ritux-imab administered as maintenance therapy are important. Maintenance therapy with rituximab showed not only a progression-free survival bene-fit but also a significant survival advan-tage among patients who were suc-cessfully pretreated with R-CHOP,” the authors noted.

Kenneth Carson, MDStaff Physician,Siteman Cancer Center at Barnes-Jewish Hospital andWashington University School of Medicine in St. LouisAssistant Professor,Washington University School of Medicine in St. Louis

EXPERT INSIGHT

‘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

CLINICAL ONCOLOGY NEWS • OCTOBER 2012 15HEMATOLOGIC DISEASE

Chicago—Continuing bevacizumab dur-ing a second-line chemotherapy regimenslows the growth of metastatic colorectalcancers (mCRC), according to results of a multicenter Phase III trial.

In patients who received bevacizum-ab (Avastin, Genentech) in first-linetreatment and were then randomized toreceive either bevacizumab or no anti-angiogenesis agent during a second-linecourse of different chemotherapy, theaddition of bevacizumab significant-ly improved survival (ASCO meeting;abstract CRA3503).

“This study confirms that continu-ing bevacizumab after first progressionwhile altering chemotherapy is benefi-cial,” Dirk Arnold, MD, PhD, the medicaldirector of the Hubertus Wald TumorCenter at University Cancer Center inHamburg, Germany, said. Dr. Arnoldsuggested a new model for mCRC treatment in which angiogenesis inhi-bition is maintained through multiplelines of chemotherapy.

In the trial, 820 patients with unresect-able mCRC who had progressed withinthree months of discontinuing a first-line oxaliplatin (Eloxatin, Sanofi-aventis)- oririnotecan-based chemotherapy wererandomized to receive second-line che-motherapy with or without bevacizum-ab. In the second-line regimen, whichwas anchored with an agent not usedpreviously, bevacizumab was adminis-tered at a dose of 2.6 mg/kg per week.

The primary end point was over-all survival (OS). Secondary end points

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 first-line 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 slight-ly lower (32% vs. 34%).

Based on these results, “I expect that there will be a label change for bev-acizumab which will be bevacizum-ab beyond progression,” said Alan P. Venook, MD, a professor of hematology and oncology at the University of Califor-nia, San Francisco. Dr. Venook suggest-ed that the benefits are relatively modest

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 suggest-ed research that improves the cost-bene-fit 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.

Blocking Angiogenesis Throughout Cancer TreatmentsIn metastatic colorectal cancer, continuing bevacizumab benefits survival

Chicago—A single case study has shownthat vemurafenib (Zelboraf, Genentech) may be effective in treating patients with hairy cell leukemia (HCL). The drug jettisoned a chemotherapy-refrac-tory patient with HCL into remission, according to researchers who report-ed the success story at the annual meet-ing of the American Society of Clinical Oncology (abstract 6519).

Vemurafenib is currently approved for BRAF V600E metastatic melano-ma. BRAF V600E is found in virtu-ally all cases of HCL, suggesting dis-ease-specific oncogene dependence. For this reason, German research-ers led by Sascha Dietrich, MD, fromthe University Hospital Heidel-berg, decided to try vemurafenib in a

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

cytopenia (leukocytes 680/mcL; hemo-globin 10 g/dL; platelets 36,000/mcL).

After a single loading dose of vemu-rafenib 960 mg, clinicians started thepatient 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 after56 days, and at three months, remis-sion 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 virtual-ly pathognomonic of hairy cell leukemia. Therefore, it is eminently sensible to start to mount therapies in hairy cell leu-kemia using this newly available drug,” said Kanti Rai, MD, the chief of CLL Research and Treatment Programs at North Shore-Long Island Jewish Medi-cal Center in New Hyde Park, N.Y.

Vemurafenib Induces Remission in Patient With Hairy Cell LeukemiaClinical trial to test therapy in relapsed HCL patients

AT A GLANCE

Angiogenesis inhibitors in advanced cancers

Continuing bevacizumab through second-line chemotherapy improvedOS by six weeks

There were no additionaladverse events

The high cost of anti-angiogenic agents is a serious hurdle

Bevacizumab binds to vascular endothelial growth factor (VEGF) extracellularly to prevent interaction with cell surface receptors, blocking angiogenesis via the VEGF pathway.

Hairy cell leukemia.

‘I expect that there will be a label change for

bevacizumab which will be bevacizumab beyond

progression.’—Alan P. Venook, MD

HEMATOLOGIC DISEASE

‘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


The 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 theHarper Cancer Institute at Indiana University School of Medicine-SouthBend, said the study is the first time thatbreakthrough CINV has been studied ina systematic way.

American Society of Clinical Oncolo-gy (ASCO) president Sandra Swain, MD,said the drug provides oncologists witha new tool to help patients who experi-ence breakthrough CINV.

“I would definitely consider using olanzapine in a patient who had already had optimal first-line treatment withmultiple drugs, which include a 5-HT3

antagonist to prevent nausea and vomit-ing. Relatively speaking, it is very inex-pensive,” she wrote in an email to Clini-cal Oncology News.

Some community oncologists, how-ever, say the study won’t change theirpractice.

“I don’t think metoclopramide isused much in the breakthrough CINV setting—that agent is more useful forchronic nausea in cancer patients,” saidMichael Fisch, MD, MPH, an associateprofessor of general oncology at the Uni-versity of Texas MD Anderson CancerCenter in Houston.

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

Olanzapine costs around 45 cents per dose, whereas prochlorperazine is less than 10 cents per dose.

The National Comprehensive Can-cer Network guidelines currently rec-ommend a number of drugs for treating breakthrough CINV (Table) and sug-gest 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 chemothera-py-naive patients with a variety of can-cers who received highly emetogenic

chemotherapy (cisplatin, cyclophospha-mide and doxorubicin) who were receiv-ing guideline-directed prophylactic antiemetics. Roughly 80 patients were randomized to receive either olanzapine (10 mg per day for three days) or meto-clopramide (10 mg three times per day for three days).

At the annual ASCO meeting, Dr. Navari reported that during a 72-hour

period, 71% of patients taking olanzap-ine reported no emesis compared with 32% of patients on metoclopramide(P(( <0.01; abstract 9064). The percent-age of patients reporting no nausea wasalso 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-termuse in this study did not lead to any sig-nificant toxicities.

—Kate O’Rourke

Drs. Navari, Swain and Fisch have norelevant disclosures.

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

“This is a fascinating poster,” Dr. Raisaid. “One single patient with one anda half feet in the grave—multiply treat-ed, huge splenomegaly, wall-to-wallhairy 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 tohear more about.”

Richard Stone, MD, the programdirector of the Adult Leukemia Program at Dana-Farber Cancer Insti-tute 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

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 cli-nicians who learn about the soon-to-be 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 Inter-

national HCL Research Consortium has launched a clinical trial to test the Bru-ton’s tyrosine kinase inhibitor ibrutinib (Pharmacyclics) in relapsed HCL.

—Kate O’Rourke

Dr. Rai disclosed a consultant or advisory role with Genentech. Dr. Stone and

Dr. Dietrich had no relevant disclosures.

Table. NCCNRecommended Agentsfor BreakthroughChemotherapy-InducedNausea and Vomiting

Benzodiazepine

Lorazepam

Cannabinoids

Dronabinol

Nabilone

Phenothiazines

Prochlorperazine

Promethazine

5-HT3 Antagonists

Dolasetron

Granisetron

Ondansetron

Corticosteroid

Dexamethasone

Others

Haloperidol

Metoclopramide

Olanzapine

Scopolamine

‘I don’t see the Navari trial changing practice much,

other than further reducing the already infrequent

use of metoclopramide in this particular setting.’

—Michael Fisch, MD, MPH

HEMATOLOGIC DISEASE

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


Chicago—Two emerging ablativetechnologies hold promise for treat-ing tumors that are too risky to ablatewith existing technologies, experts toldattendees of the 2012 World Conferenceon Interventional Oncology (WCIO).

These new technologies—irreversibleelectroporation (IRE) and image-guid-ed high-intensity focused ultrasound(HIFU)—were discussed as potentialoptions for ablating tumors located inclose proximity to critical structuresand blood vessels, but experts notedthat their exact place in the treatmentarmamentarium remains unknownbecause of a paucity of data.

“These are very interesting technol-ogies that may have applications inselected patients,” said Eileen O’Reilly,MD, a gastrointestinal oncologist atMemorial Sloan-Kettering Cancer Cen-ter and associate professor of medicineat Weill Cornell Medical College, bothin New York City.

Dr. O’Reilly said IRE has been usedat her institution to ablate tumors closeto blood vessels and the biliary tract inselected patients and it has proven safe.However, outcomes data for both IRE andHIFU, the latter of which has not receivedFDA approval for use, are lacking.

“Given that the field of ablative tech-nologies is crowded and reported expe-rience with these two technologies isrelatively limited, further prospectivestudy is needed to determine where they might fit in,” she said.

According to Govindarajan Narayan-an, MD, the chief of vascular and inter-ventional radiology at the University of Miami’s Miller School of Medicine,the strength of IRE is that, unlike radio-frequency ablation (RFA), microwaveablation (MWA) and cryoablation, it is a non-thermal technology. Instead, it useshigh-level electrical pulses to damagecell membranes and induce apoptosis.

“Since it does not emit heat, IRE issafer than thermal ablation when usedin close proximity to critical structureslike bile ducts and blood vessels,” Dr.Narayanan said.

IRE treatment led to few bile ductcomplications, including a 5% inci-dence of mild biliary dilatation but no instances of strictures, stenoses, leaksor fistulas, in a retrospective review of 76 patients with 114 primary and meta-static liver tumors (WCIO paper 35).

Similarly low rates of complicationswere reported by Riccardo Lencioni,MD, a professor and the director of diag-nostic imaging and intervention at Pisa University School of Medicine in Pisa,Italy,yy and colleagues at several Europe-an centers.

In 26 patients with 29 early-stage, unresectable hepatocellular carcino-mas, major complications with IRE included one punctured intercostal artery and one case of transient hepat-ic decompensation that resolved with-out treatment (WCIO paper 9). Com-plete response occurred in 77% of patients and 79% of tumors.

“IRE appears to be safe and effective and could potentially be a very prom-ising new tool for image-guided abla-tion 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 poten-tial for IRE to manage unresectable, locally advanced pancreatic cancer, Dr. Lencioni said.

“Thermal ablation has been out of the question for treating pancreat-ic 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

seven tumors located in the pancre-atic 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 surround-ing IRE, Dr. Narayanan said, “There are lots of challenges with the proce-dure.” The treatment involves placing multiple needles in parallel around the tumor in order to administer suf-ficient levels of electrical pulses, and its complexity translates into a steep learning curve. Moreover, the place-ment of multiple needles means tumor access is critical.

“In the pancreatic cancer population, we’ve aborted more IRE procedures

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

“I don’t see IRE as a replacement for existing treatments, but rather as a potential treatment for previous-ly 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 ben-efit with IRE even in conventional-

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 ultra-sonic 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 oth-er ablative modality is limited by the fixed location of the delivery instru-ment, whereas with HIFU, because it is so focused, you can shape your ablation

zone,” said Dr. Orsi, who reviewed exist-ing data on HIFU at the meeting.

Cumulative data from nearly 200 HIFU-treated pancreatic cancer pa-tients, from China, showed HIFU sig-nificantly decreased pain, led to a par-tial tumor response in approximately

15% of patients and stopped tumor pro-gression 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 foradverse events and to identify what incremental benefits HIFU may add over other conventional treatments.

“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 bedetermined,” she said.

For both new technologies, Dr. O’Reilly said, “Until randomized, controlled stud-ies 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.

Ablative Technologies Promising for Risky TumorsField awaits long-term data on efficacy and safety of two modalities

Nonresectable pancreatic head tumor obstructing the common bile duct and pancre-atic duct. Tumor surrounds the superior mesen-teric vein at thejunction with the splenic vein. Para-aortic andceliac lymph nodes and a small liver metastasis.

‘I don’t see IRE as

a replacement for

existing treatments,

but rather as a

potential treatment for

previously untreatable

tumors.’

—Riccardo Lencioni, MD

‘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


Chicago—Clinicians can now overlay two or more imaging modalities,manipulate them simultaneously “onthe table” and potentially improvetumor diagnosis and treatment, anexpert told attendees of the 2012 WorldConference on Interventional Oncology.

“Medical GPS, or fusion imaging, canincrease the accuracy of image-guidedtumor biopsy and ablation and helpdirect 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 betweendiagnosis and therapy,” said BradfordWood, MD, chief of interventionalradiology and director of the Center forInterventional Oncology at the NationalCancer Institute in Bethesda, Md.

Fusion systems superimpose two ormore images from separate modalities,stretching them as necessary andmatching them in real time according tothe location of sensor coils embeddedin 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’sskin. In the case of a sensor-enabledUS transducer, the device facilitatesmultiplanar, real-time reconstructionand matching of the two three-dimensional data sets of images whilefunctioning as a standard US.

In a study comparing US/magneticresonance imaging (MRI) fusion-guidedprostate biopsy to standard “blind”sextant biopsies, fusion guidance nearly doubled the cancer detection rate for a subset of patients (J Urol(( 2011;186:1281-1285, PMID: 21849184). Fusion guidancealso is associated with more accurateneedle positioning and potentially fewer complications than using a singleimaging modality (J Vasc Interv Radiol((2011;22:515-524, PMID: 21354816).

The cost savings of conducting pro-cedures under US using fused and pre-viously obtained MRIs also are signif-icant, Dr. Wood added. Furthermore,fusion guidance leverages the advan-tages of each modality, he said.

“One can combine the spatial resolutionof CT [computed tomogramphy], themetabolic and functional data providedby real-time PET [positron emissiontomography] guidance, and the temporalresolution and real-time feedback of US,” Dr. Wood said.

According to Eileen O’Reilly, MD, a gastrointestinal oncologist at MemorialSloan-Kettering Cancer Center andan associate professor at Weill CornellMedical College, both in New York City,single-modality imaging is adequate

when lesions are clearly visible andeasily accessible. However, in the caseof smaller lesions, fusion imaging hasthe potential to affect both surgical andmedical treatment.

“We’ve entered the era of personalizedtreatments in medical oncology, andbiopsies are recommended not only fordiagnosis, but sometimes for refining the treatment plan also, so there are

potentially broad applications for thistechnology,” 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 shareintellectual property in the field. Dr. O’Reilly

has nothing to disclose.

‘Fusion Imaging’ May Improve Tumor Diagnosis, TreatmentDifferent diagnostic modalities fused to improve accuracy, particularly for smaller lesions

Fusion systems superimpose two or more

images from separate modalities, matching them

in real time.

®

Now Available...

Chair

Julie M. Vose, MD, MBA

Neumann M. and Mildred E. Harris Professor

Chief, Division of Hematology/Oncology

Professor of Medicine

Nebraska Medical Center

Omaha, Nebraska

Faculty

John P. Leonard, MD

Clinical Director, Center for Lymphoma and

Myeloma

Professor of Medicine

Weill Medical College of Cornell University

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

Learning ObjectivesReview optimal therapy for the management of

newly diagnosed and relapsed/refractory follicu-

lar lymphoma (FL) and diff use large B-cell lym-

phoma (DLBCL), taking into consideration the

heterogeneity of patient and tumor characteristics.

1 Identify the most recent data pertaining to

emerging single and combination therapies for

the treatment of relapsed/refractory NHL.

2 Explain the most signifi cant new data on con-

solidation and maintenance strategies in NHL.

3 Describe current and emerging prognostic clin-

ical and molecular markers to aid in treatment

decision making for NHL.

Intended AudiencesTh e intended audiences for this educational

activity are hematologists, community oncolo-

gists, oncology nurses, pharmacists, and other

hematology/oncology health care profession-

als. Th ese professionals constitute the core audi-

ence for this initiative as they direct treatment for

patients with NHL.

Statement of NeedTh e 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. Th e

abundance of ongoing research into therapeu-

tic strategies for these conditions presents oppor-

tunities for improved patient outcomes as well as

challenges for clinicians, who must stay abreast

of the new data and be prepared to incorporate

emerging therapeutic strategies into their practice.

Course FormatInteractive Web-based monograph

Estimated Time for Completion: 60 minutes

Accreditation StatementTh is activity has been planned and implemented

in accordance with the Essential Areas and Poli-

cies 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 continu-

ing medical education for physicians.

Credit DesignationGlobal Education Group designates this endur-

ing activity for a maximum of 1.0 AMA PRA Category 1 Credit™. Physicians should claim only tthe credit commensurate with the extent of their

participation in the activity.

Method of PreparationTo receive CME credit, participants should read

the preamble, complete the pre-test, read the

monograph, and complete the post-test and eval-

uation. A score of at least 75% (in 3 attempts)

is required to complete this activity successfully.

CME certifi cates will be issued immediately

upon successful completion.

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

This activity is jointly sponsored by Global Education Group and Applied Clinical Education. This activity is supported by educational grants from Genentec

in Non-Hodgkin’s LymphomaEvolving 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


with anticancer drugs,” said Ian Tan-nock, MD, PhD, a professor of medical oncology at Princess Margaret Hospital in Toronto, Canada. He discussed the cost of cancer drugs at the recent annu-al meeting of the American Society of Clinical Oncology (ASCO).

A study published in 2004 showed that the near doubling of median sur-vival 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;351:3PMID: 15269308). Drug prices hen sharply since 2004.

“Some of the workhorses thvide real value are priced relaly inexpensively. Paclitaxel atrastuzumab (Herceptin, Genetech) are under $5,000 a monthwhereas the new drugs are coming in at $10,000 a month,” saiThomas Smith, MD, pointing tvemurafenib (Zelboraf, Genentech) and crizotinib (Xalkori, Pfizer) as examples. “Somdrugs are over $100,000 for aone-time administration.” Dr.

Smith, the director of palliative medi-cine at Johns Hopkins Sidney Kimmel Comprehensive Cancer Center in Balti-more, also spoke at the ASCO meeting.

Cost-EffectivenessAlthough drug costs have risen, cost-

effectiveness has declined. In many countries, cost-effectiveness is mea-sured in cost per life-year gained.

“If you live in Paris, Chicago or Toron-to, it’s been suggested that the public-ly funded health care system can gener-ally 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, metho-trexate and fluorouracil), and $15,000 to $45,00 for adjuvant trastuzumab.

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

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 ther-apy costs $120,000. Vismodegib (Eri-vedge, 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, respec-tively, with a full course of therapy cost-ing $75,000. Pemetrexed (Alimta, Eli Lilly) was approved for maintenance therapy of nonsquamous non-small cell

ed on a three-month in median overall sur-d the cost of therapy

runs between $20,000and $30,000.

So, how are drug pric-es determined? A recentstudy found no corre-ation between marketricing of new antican-r drugs and the magni-e of clinical benefit. The ooked at three groups of roved by the FDA since that new agents with ar targets are clinical-

ly the most beneficial, but their month-ly market prices are not significantly dif-ferent from the price of other anticancer agents (J Clin Oncol(( 2011;29:2543-2549, lPMID: 21606435). For example, the over-all survival hazard ratio (HR) was 0.69 for a group of targeted agents with a month-ly 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 rela-tively small benefits that translate usually into absolute benefits of a few months, at most, in survival,” said Dr. Tannock, who

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 andbill” approach for reimbursement pro-vides incentives for medical oncolo-gists to use expensive medications when less costly alternatives that deliver sim-ilar results are available (Health Aff((2012;31:780-785, PMID: 22492895). “Weas oncologists are encouraged constant-ly and sometimes directly to prescribe more expensive drugs. Some people getdirect 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

2010 and estimated the cost per life-year 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 com-panies aim to maximize profit. When Clinical Oncology News asked vari-ous 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 invest-ment in future research.

“At Genentech, we choose prices for our medicines that allow us to contin-ue discovering new medicines for peo-ple with serious diseases such as cancer and Alzheimer’s disease,” said Char-lotte Arnold, a spokesperson for Genen-tech, in an email. “Things we consid-er when choosing a price [include] how well the medicine works; what oth-er medicines are used to treat the same disease; the amount of money we will

Western 317-319,

have ris-

at pro-ative-andn-h,

m-d

to n-o-mea

$45,00 for adjuvant trastuzumab. therapy of nonsqlung cancer bas

improvement vival and

es

lapr

certude

study loagents appr

2000 and foundspecific moleculaly the most benef

DRUG COSTScontinued from page 1 ��

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

Not receiving Clinical Oncology News? ss Like to?Clinical Oncology News is distributed free of charge to selected oncology and shematology/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 whetheryou prefer to have Clinical Oncology News mailed to you at your offi ce or home.s

You can also visit www.clinicaloncology.com/Subscription.aspxfax to subscribe directly.

Independent News for the Oncologist and Hematologist/Oncologist


need to continue discovering new medi-cines 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 HER2-targeted 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 Per-jeta (as a single agent) less than many other recently approved cancer med-icines,” said Ms. Arnold. “The month-ly cost of Herceptin is $4,500. Most patients will take the combination of Perjeta and Herceptin until their dis-ease worsens, which is about 18 months. The estimated cost for a course of treat-ment with Perjeta and Herceptin for 18 months is approximately $188,000.” The combination of pertuzumab, trastuzumab and docetaxel improvedprogression-free survival by roughly six months compared with trastuzum-ab and docetaxel.

Amy Sousa, a spokesperson for Eli Lil-ly, said Lilly priced “medicines based on the value they bring to patients” and that “pricing also ensures that Lilly is ableto invest in research and development of new medicines to meet the medical needs of patients in the future.”

Sarah Koenig, a spokesperson for Bris-tol 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 physi-cian behavior are each a part of the sky-rocketing drug cost problem, the pro-cess by which drugs are approved in the United States can also be seen as playing a role. Historically, the FDA and the European Medicines Agen-cy (EMA), the European equivalent of the FDA, have approved drugs based on any significant difference in sur-vival. This has encouraged larger andlarger trials to demonstrate what some would say are clinically meaningless, but statistically significant differenc-es (J Natl Cancer Inst(( 2010;103:1-5). Erlotinib was approved in combina-tion with gemcitabine for patients with advanced pancreatic cancer after a clin-ical 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 safe-ty and efficacy compared with placebo, and it considers neither cost nor com-parative efficacy against other treat-ments in determining what drugs get the green light. In England, after the EMA has approved a drug, the National

Institute for Health and Clinical Excel-lence (NICE) considers all these factorsin calculating what it will cover. Afterconcluding patients would derive mini-mal benefits at an excessive cost, NICEhas rejected a number of cancer drugsthat are regularly prescribed in the Unit-ed States. The rejection list includeserlotinib (Tarceva, OSI/Genentech)for maintenance therapy of non-smallcell lung cancer and lapatinib (Tykerb,GlaxoSmithKline) in combination withcapecitabine (Xeloda, Roche) for womenwith advanced or metastatic HER2-posi-tive 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 antican-cer drugs in Western countries.”

He pointed out, however, that obvious-ly the profit motive is a powerful incen-tive for developing new treatments and that prices go down as drugs go off pat-ent, 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 researchfunding from Bayer, Exelixis, Genentech,Johnson & Johnson, Eli Lilly and Sanofi.

Dr. Smith has no relevant disclosures.

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Combo Therapy Trumps Monotherapy for Metastatic Breast Cancer

The concept of complete estro-gen receptor (ER) blockade has

regained significant interest since the report of the SWOG 0226 trial demon-strating 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 reg-imen to the clinic because of conflict-ing 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 andOS favoring the combination therapy, the clinical benefit rate and response rate were similar between the two

treatment arms. This result is remi-niscent of what was observed in the FIRST (Fulvestrant First-Line Study) trial, a randomized Phase II tri-al of fulvestrant high dose (500 mg) with anastrozole as first-line treat-ment for advanced breast cancer, in which the time to progression was improved in the fulvestrant arm com-pared with the anastrozole arm (23.4 vs 13.1 months), but the response rate and clinical benefit rate were sim-ilar.3 Because ER function is criti-cal for the development of acquired endocrine resistance,4 one could pos-tulate that more effective ER block-ade could have delayed the onset of acquired endocrine resistance, rath-er than affecting the de novo endo-crine-resistant tumors. Therefore,

tumors resistant to endocrine thera-py would not derive benefit from suchtreatment. This is supported by theunplanned subgroup analysis in theSWOG 0226 trial, showing that thebenefit of the combination therapy was restricted to those who had notreceived adjuvant tamoxifen, a popu-lation enriched for endocrine-sensi-tive disease. If the hypothesis is cor-rect, the approach of complete ER blockade should be tested in an endo-crine-sensitive population.

How do we achieve the most effec-tive ER blockade? In collaborationwith the National Cancer Institute,the Alliance for Clinical Oncology Cooperative Group is planning a neo-adjuvant trial that compares anastro-zole with fulvestrant (500 mg), eitheralone or in combination with anastro-zole, in the neoadjuvant setting. Endo-crine-resistant tumors are identifiedearly in treatment by a high Ki-67 lev-el for alternative treatment strategies.5

Results of this trial will provide essen-tial information on whether fulves-trant (500 mg) alone or in combinationwith anastrozole should be broughtforward in the adjuvant setting.

References

1. Mehta RS, et al. A Phase III randomized trial of anastrozole versus anastrozole andfulvestrant as first-line therapy for post-menopausal women with metastatic breastcancer: SWOG S0226 in CTRC-AACR. SanAntonio Breast Cancer Symposium. 2011.San Antonio, TX.

2. Bergh J, Jonsson PE, Lidbrink EK, et al.FACT: an open-label randomized phaseIII study of fulvestrant and anastrozole incombination compared with anastrozolealone as first-line therapy for patients withreceptor-positive postmenopausal breastcancer. J Clin Oncol. 2012;30:1919-1925,PMID: 22370325.

3. Robertson JFR, et al. A comparison of ful-vestrant 500 mg with anastrozole as first-line treatment for advanced breast can-cer: follow-up analysis from the “FIRST”study. San Antonio Breast Cancer Sympo-sium. 2010. San Antonio, TX.

4. Roop RP, Ma CX. Endocrine resistance in breast cancer: molecular pathways andrational development of targeted thera-pies. Future Oncol. 2012;8:273-292, PMID:22409464.

5. Goncalves R, Ma CX, Luo J, et al. Use of neo-adjuvant 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.

From The New England Journal of Medicine

The combination of a selective aro-matase inhibitor (AI) and estradiol

analogue appears to be superior to an inhibitor alone as a first-line strategy to fight hormone receptor (HR)-posi-tive metastatic breast cancer.

Researchers reported significant improvements in progression-free sur-vival (PFS) and overall survival (OS) for women receiving a combination of anastrozole and fulvestrant com-pared with those receiving anastro-zole 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 medi-an progression-free survival than had been projected in the design of the tri-al,” 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

our study has not been seen in oth-er trials of first-line hormonal thera-py for HR-positive metastatic breast cancer,” noted the Southwest Oncolo-gy 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 ver-sus 89% in the monotherapy group; at two years, 79% and 75%; and at three years, 62% and 57%, respectively.

The 350 women randomized to com-bination therapy and the 345 random-ized to anastrozole alone each received 1 mg oral anastrozole daily. The combina-tion-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 amend-ed during the study to increase subse-quent fulvestrant dosages to 500 mg after other investigators reported itssuperiority over the low-dose formula-tion and following FDA approval of thehigher-dose formulation.

The researchers also assessed wom-en previously treated versus womennot treated with tamoxifen. Overall,the advantages of combination ther-apy remained regardless of this clas-sification. In other words, the inter-action between treatment and use of prior adjuvant tamoxifen therapy wasnot significant.

Only 15 women discontinued treat-ment due to toxic effects (11 in the com-bination group and four in the anas-trozole-alone group). “In general, thetoxic effects were mild and did not dif-fer significantly in grade between thetwo groups,” the authors wrote.

Cynthia X. Ma, MD, PhDStaff Physician,Siteman Cancer Center at Barnes-Jewish Hospital andWashington University School of Medicine in St. LouisAssociate Professor of Medicine, Washington University School of Medicine in St. Louis

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Limited radiotherapy resulted in a high rate of two-year event-free sur-

vival (EFS) in pediatric patients withfavorable-risk Hodgkin lymphoma whohad a complete early response to chemo-therapy, according to a study in JAMA(2012;307:2609-2616, PMID: 22735430).The findings suggest that a risk-adapted,response-based approach may be effec-tive and well tolerated in selected patientswith favorable-risk Hodgkin lymphoma.

More than 90% of children withfavorable-risk Hodgkin lymphoma will achieve long-term survival, theresearchers reported, yet many developtoxic effects from radiotherapy. In thePhase II, multi-institutional, unblind-ed, nonrandomized clinical trial, theresearchers identified 88 patientswith Hodgkin lymphoma stage IA orIIA, fewer than three involved nodalregions, no extranodal extension andno mediastinal bulk. Patients receivedfour cycles of vinblastine, adriamycin(doxorubicin), methotrexate and pred-nisone (VAMP) chemotherapy. Aftertwo cycles, the patients were evaluat-ed for early response using computed

tomography scan and functional imag-ing. 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 pri-mary outcome measure, was 90.8% (95% confidence interval [CI], 84.7%-96.9%). Among patients who did not require radiotherapy, the primary outcome mea-sure 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 recur-rence were retrieved with chemotherapy and radiotherapy without stem cell trans-plant. Therapy was well tolerated and no

major complications occurred.Commenting by email, Frederick

Goldman, MD, a professor of pediat-rics and director of the Blood and Mar-row 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 crite-ria 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 Hospi-tal in Memphis, Tenn., said in an inter-view. 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 com-plete 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 conclu-sions but it seems quite reasonable that we may be able to eliminate radiation ina select group of low-risk Hodgkin dis-ease patients,” said Dr. Goldman.

Limitations of the study, he said, included small size and relatively short median follow-up. “It is only for a spe-cific group of favorable-risk patients. It needs to be clear that the patient meetsthe criteria.”

—George Ochoa

Drs. Goldman and Metzger reported norelevant financial conflicts of interest.

Tailoring Radiotherapy for Pediatric Hodgkin Lymphoma

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Trastuzumab Injection ‘Noninferior’ to IV in Breast Cancer

The HannaH studydemonstrates 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 trastu-zumab. Subcutaneous trastuzumab was administered at a fixed dose (600 mg) in combination with hyaluroni-dase 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 aid-ing absorption of trastuzumab. This study was an international trial with the majority of patients treated in East-ern 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 trastuzum-ab gave a slightly higher pCR rate than IV trastuzumab (45.4% vs. 40.7%), although this difference is not signifi-cant. Virtually all (97%) of the subcu-taneous trastuzumab patients achieved a therapeutic serum target level of trastuzumab. Local adverse reactions were low, with only 1% of patients developing a local cellulitis. System-ic adverse effects were comparable between subcutaneous and IV trastu-zumab, although three deaths occurred on the subcutaneous arm compared

with one death with IV trastuzum-ab. All of these deaths were attribut-ed to comorbidities preexisting in thepatients and were not related to theroute of administration of tras tuzum-ab. No cases of symptomatic congestiveheart failure occurred in either arm.Clinical follow-up on this trial wasshort (12.4 months), but this is in keep-ing with the neoadjuvant trial design.

This trial demonstrates the noninfe-riority of subcutaneous trastuzumab inthe neoadjuvant setting. Although theseresults will likely translate into the adju-vant setting, formal demonstration of that is needed. In fact, a trial is currently being performed in Canada and Europecomparing subcutaneous with IV trastu-zumab in early-stage HER2-positivebreast cancer.1 Subcutaneous trastu-zumab has several advantages, including requiring less time to administer thanthe IV drug and the possibility of self-administration by patients. A trial com-paring self-injection of subcutaneoustrastuzumab through a single-use injec-tion device with more standard adminis-tration of subcutaneous drug via medical

staff is being conducted internationally.2

The success of subcutaneous trastu-zumab on the HannaH trial expandsthe availability of trastuzumab to coun-tries or patients where long-term cen-tral venous access is difficult. Further-more, it opens the possibility that other antibody drugs (both for cancer or oth-er types of diseases) can be administeredsubcutaneously. Although the usage of subcutaneous trastuzumab in the UnitedStates is likely to be low, at least initial-ly, this trial provides a very interesting alternative for patients who have prob-lems 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 disclosuresrelevant to this study.

From Lancet Oncology

It makes sense that a five-minute subcutaneous injection of trastu-

zumab 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 new-ly diagnosed, non-metastatic prima-ry cancer. Hoffmann-La Roche fund-ed the study.

The two primary end points of the

HannaH (enHANced treatment with NeoAdjuvant Herceptin) study were serum trough concentration (Ctrough) h

of the study drug, recorded before sur-gery (predose cycle 8), and patholog-ic complete response (pCR). Women were enrolled in the study from Octo-ber 2009 to December 2010 at 81 cen-ters worldwide. Median duration of fol-low-up was 12 months.

The pharmacokinetic profile, total pCR and overall response were second-ary end points. Other secondary mea-sures included time to response, event-free 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 wom-en. A nurse used a handheld syringe to deliver the subcutaneous injection to

the thigh every three weeks. Adminis-tration took about five minutes.

Another 299 women were random-ized 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 treat-ment cycles), suggesting that the lack of a loading dose in the subcutaneous regimen does not compromise effica-cy,” 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 find-ings support the noninferiority of

subcutaneous trastuzumab comparedwith the IV formulation.

Median relative dose intensity wasgreater than 96% in both groups, “sug-gesting good tolerability of subcutane-ous trastuzumab,” the authors noted.

The incidence of grade 3 to 5 adverseevents was similar. Neutropenia occurred in 29.0% of the subcutaneousgroup versus 33.2% of the IV group;leukopenia developed in 4.0% versus5.7%; and febrile neutropenia devel-oped in 5.7% versus 3.4%.

At 21%, the serious adverse eventrate was higher in the subcutaneousgroup than in the IV group, at 12%,driven in part by infections and infes-tations (8.1% vs. 4.1%, respectively).None of the reported infections wasassociated with the site of subcutane-ous injection.

Ron Bose, MD, PhDStaff Physician,Siteman Cancer Center at Barnes-Jewish Hospital andWashington University School of Medicine in St. LouisAssistant Professor,Washington University School of Medicine in St. Louis

EXPERT INSIGHT

LymphomasJohn Sweetenham,

Jame Abraham (Editor)

See page 27


Regimen With Bortezomib Effective in Multiple Myeloma

Anumber 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, tha-lidomide was found to improve event-free survival (EFS) in several trials and OS in one.1 Maintenance with thalido-mide has been hampered by significant toxicities, most importantly problems with peripheral neuropathy that pre-vent long-term use of this agent. More recently, the use of lenalidomide main-tenance following autologous stem cell transplant was reported in two pro-spective randomized trials.2,3 These studies both demonstrated an improve-ment in EFS and one trial also showed improved OS for patients randomized to

lenalidomide maintenance.The Phase III HOVON-65/GMMG-

HD4 trial by Sonneveld and colleagues examines the efficacy of bortezomib induction and post-transplant mainte-nance compared with alkylator-based induction and thalidomide mainte-nance. There are a number of impor-tant findings from this trial, howev-er it does not answer the question of whether bortezomib maintenance is superior to thalidomide mainte-nance 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, main-tenance or a combination of the two.

Of patients in the bortezomib arm,13% did not start maintenance therapy primarily due to treatment-emergentperipheral neuropathy.

One of the findings of the lenalid-omide maintenance trials was anincrease in second primary malignan-cies (SPMs) in the patients randomizedto lenalidomide maintenance. In thesetwo lenalidomide trials the incidenceof SPMs was approximately 8% in thelenalidomide patients and 3% to 4% in the placebo arms. Including SPMs inthe EFS calculations still shows a ben-efit for lenalidomide maintenance, andadditional studies are ongoing trying todetermine the mechanism of this riskand whether it is a reproducible sig-nal. Although not reported in the cur-rent paper by Sonneveld, there was noincreased risk for SPMs associated withthe bortezomib arm in data presentedat ASH in December 2011.4

There is adequate data to supportmaintenance therapy following autol-ogous transplantation but what is theoptimal induction before autologoustransplant and what is the appropriatemaintenance therapy? Should a differ-ent 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 impor-tant questions, which should lead to longer remissions and survival forpatients with myeloma.

References

1. Attal M, et al. Maintenance therapy with thalidomide improves survival inpatients with multiple myeloma. Blood.2006;108:3289-3294, PMID: 16873668.

2. Attal M, et al. Lenalidomide maintenanceafter stem-cell transplantation for multiplemyeloma. N Engl J Med. 2012;366:1782-1791, PMID: 22571202.

3. McCarthy PL, et al. Lenalidomide afterstem-cell transplantation for multiplemyeloma. N Engl J Med. 2012;366:1770-1781, PMID: 22571201.

4. Miguel JFS, et al. Risk of second primary malignancies (SPMs) following bortezo-mib (Btz)-based therapy: analysis of fourPhase III randomized controlled trials inpreviously untreated or relapsed multi-ple myeloma (MM). ASH Annual Meeting Abstracts 118:2933, 2011.

Dr. Stockerl-Goldstein discloses that heis a member of the speakers’ bureaus for

Celgene, Millennium and Onyx.

From the Journal of Clinical Oncology

Bortezomib (Velcade, Takeda/Mil-lennium) achieved promising

results during an open-label, Phase III clinical trial designed to assess its util-ity both at induction, as part of a com-bination regimen, and as maintenance therapy in patients with newly diag-nosed m ultiple myeloma. A summary of the trial’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 Multi-center 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 main-tenance therapy of thalidomide (50 mg per day) for two years, whereas those in the PAD arm received main-tenance 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

induction and bortezomib mainte-nance (49%) than it was with VAD induction and thalidomide mainte-nance (31%; P<0.001). Similarly, pro-gression-free survival (PFS) was also higher in the PAD-bortezomib main-tenance 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-bortezo-mib regimen significantly improved PFS from a median of 13 to 30 months (P=(( 0.004) and overall survival (OS) from a median of 21 to 54 months (P(( <0.001).

There was a significant difference with regard to treatment adherence between the two study groups, how-ever. Of those in the VAD-thalidomide

group who remained in the trial follow-ing induction therapy, 22% (77 of 347)went off protocol following high-dosemelphalan because of allogeneic stemcell transplantation (21%), persistenttoxicity (3%) or other reasons (13%),which in some cases included deathand/or noncompliance. In the PAD-bortezomib group, 35% (123 of 352) of the remaining patients went off pro-tocol because of allogeneic stem celltransplantation (8%), persistent toxic-ity (13%) or other reasons (14%), whichincluded death and/or noncompliance.Most instances of persistent toxicity reported in the PAD-bortezomib arminvolved polyneuropathy. According to the study design, persistent toxicity was an exclusion criterion for starting maintenance therapy.

Keith Stockerl-Goldstein, MDStaff Physician,Siteman Cancer Center at Barnes-Jewish Hospital andWashington University School of Medicine in St. Louis Associate Professor of Medicine,Washington University School of Medicine in St. Louis

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More Evidence ACE Inhibitors Protect Against Radiation Pneumonitis

Kharofa et al from the Medical College of Wisconsin report on

a population of lung cancer patients receiving curative radiation ther-apy at the Zablocki VA Medical Cen-ter in Milwaukee, and suggest that the incidental use of ACE inhibitors may decrease the risk for developing radia-tion 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 oth-er 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 provoca-tive article suggesting that elevated lev-els of exhaled nitric oxide (NO) also are predictive of radiation pneumonitis.1

They used a simple, cheap, commercial-ly available device, tested it prospec-tively, and provided a strong indica-tion that exhaled NO is predictive of this toxicity. Regardless, the only treat-ment intervention for patients with increased exhaled NO is to reduce the volume of normal lung receiving radia-tion. Like these ACE inhibitor data, the

exhaled NO data needs to be verified.Plans are under way to test this prog-nostic marker in clinical trials.

I was peripherally involved withRTOG (Radiation Therapy Oncolo-gy Group) 0123, a prospective Phase IIstudy that administered captopril in aneffort to provide clinical evidence thatACE inhibitors reduced risk for radia-tion pneumonitis. The idea was a resultof the preclinical laboratory work of Dr.Bill Ward at Northwestern University.The trial’s PI was Dr. Bill Small, a men-tee of Dr. Ward’s who was committed totesting this hypothesis clinically. Unfor-tunately, RTOG 0123 was closed prema-turely due to lack of accrual. It was very difficult to enroll lung cancer patients in this trial. The list of contraindica-tions to ACE inhibitor therapy includecommon problems in elderly lung can-cer patients, including hypertrophiccardiomyopathy, valvular heart dis-ease, renal artery stenosis, abnormal-ly low blood pressure, liver problems,

kidney disease, connective tissue disor-ders, hyponatremia, hyperkalemia and/or low neutrophil counts.

The Kharofa et al study carries all the major problems associated with retro-spective studies. Retrospective findings should really only serve as ideas for pro-spective testing. However, in this caseI don’t think a prospective clinical tri-al testing the value of ACE inhibitors inreducing radiation pneumonitis risk willbe attempted again. Research dollars arein short supply and are prioritized forinterventions that may improve surviv-al in this frustrating disease.

Reference

1. Guerrero T, Martinez J, McCurdy MR, etal. Elevation in exhaled nitric oxide pre-dicts for radiation pneumonitis. Int J Radi-at Oncol Biol Phys. 2012;82:981-988, PMID: 21377296.

Dr. Bradley reported no relevant financial disclosures.

From the International Journal of Radiation Oncology, Biology, Physics

The 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 labora-tory finding, has now been confirmed in the clinical setting.

In a retrospective study report-ed 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 concur-rent use of ACE inhibitors reduces the risk for radiation pneumonitis in subjects undergoing radiation therapy for lung cancer,” the researchers con-cluded. Jordan Kharofa, MD, was first author of the study.

In contrast, the researchers found that nonsteroidal anti-inflammato-ry drugs, statins, angiotensin recep-tor antagonists and inhaled glucocor-ticoids imparte d no such significant protective effect.

Age appears to play a role as well. A significantly higher proportion of patients 70 years and older experi-enced grade 2 or greater pneumoni-tis (16%) versus younger patients (2%;

P=0.005). In fact, 11 of the 12 pneu-monitis events in the study occurred in this older age group. Again, ACE inhibitors ameliorated this risk; symp-tomatic 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 asso-ciated with grade 2 or greater pneu-monitis for all patients. Specifical-ly, a V5 (volume of lung receiving at least 5 Gy irradiation) of 50% or great-er significantly predicted this adverse effect (13% versus 4%; P=0.04). Medi-an survival did not differ significant-ly 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 exper-imental evidence, but the precise mech-anism remains a mystery. Changes inblood flow or reduction of pulmonary hypertension are other possibilities.

All patients were men treated at theClement J. Zablocki Veterans AffairsMedical Center in Milwaukee from2004 to 2009. Median age was 65 years.Nearly two-thirds of patients had stageIII lung cancer (64%) and receivedconcurrent chemotherapy (61%).

Despite encouraging preclinicalfindings, the current study is only thefourth published clinical study to eval-uate ACE inhibitors’ mitigation of radi-ation pneumonitis. The other threeclinical reports also were retrospective.Prospective evaluation is warranted inthe future, the authors noted.

Jeffrey D. Bradley, MDStaff Physician,Siteman Cancer Center and Barnes-Jewish HospitalS. Lee Kling Professor of Radiation Oncology,Washington University School of Medicine in St. Louis

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1 Diagnostic Imaging: Musculoskeletal: Non-Traumatic Disease

B.J. Manaster; Cheryl A. Petersilge; Catherine C. Roberts; Christopher J. Hanrahan; Sandra MooreMarch 26, 2012 This reference guides practicing radiologists through the intricacies of musculoskeletal diseases. Richly colored graphics pop off the page, and all images are fully annotated to highlight the most important diagnos-tic possibilities.

2 Gynecologic Oncology: Clinical Practice and Surgical Atlas

Beth Karlan; Robert Bristow; Andrew LiJune 22, 2012This book brings together a skill-sharpening reference and full-color atlas to deliver an unmatched introduction to the field. As the most compre-hensive, evidence-based gynecologic oncology resource available, this all-in-one resource offers high-yield coverage of the discipline’s underly-ing principles and proven management strategies.

3 Lung CancerAthanassios Argiris

May 18, 2012 This book details the current management of lung cancer and reviews new therapies in development, with an emphasis on therapeutic exploi-tation of the heterogeneous nature of lung tumors at the molecular level.

4 LymphomasJohn Sweetenham, Jame Abraham

September 1, 2012 This book explores the evolving role of established therapies such as stem cell transplantation with other disease-oriented chapters describ-ing pathway-directed agents and the evolving paradigm of “personal-ized” lymphoma treatment. Coverage includes discussion of molecular characterization for different disease-specific lymphoma subtypes and t e pote t a o de e op g pe so a ed t eat e tthe potential for developing “personalized” treatment.

5 Malignant Gliomas (Radiation Medicine Rounds Volume 3 Issue 2)

Demos Medical PublishingOctober 15, 2012

This book provides a multidisciplinary update on the treatment of the complex area of malignant gliomas. Authoritative reviews and updates discuss recent advances in radiation therapy including coverage of

emerging areas.

6 Non-CML Myeloproliferative Diseases, An Issue of Hematology/Oncology Clinics of North America

Ross LevineNovember 11, 2012

Topics in this volume include: clinical predictors of outcome in MPNs, molecular pathogenesis of MPNs, disordered signaling in MPNs, role of TET2/ASXL1 in MPN pathogenesis, pathogenesis and treatment of sys-temic mastocytosis, role of additional novel therapies in MPNs, role of novel mutations in MPN pathogenesis and outcome, role of JAK inhibi-tors in MPN treatment and animal models of MPNs.

7 Outcomes Research in Surgical Oncology: An Issue of Surgical Oncology Clinics

Clifford KoJune 20, 2012 In this issue of Surgical Oncology Clinics of North America, guest editor

Clifford Ko, MD, has assembled the top experts concerning “OutcomesResearch in Oncology.“

8 Why Millions Survive Cancer: The Successes of ScienceLauren Pecorino

Oxford University Press, September 7, 2012 In Why Millions Survive Cancer, Lauren Pecorino illuminates the enorrr -rrmous and recent progress in fighting cancer, painting an intriguing por-rr

trait of scientific breakthroughs, the leading scientists behind these keydiscoveries and the steps that we can all take to reduce our exposure to cancer.

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In late July, the FDA approved carfil-zomib as a monotherapy for patients

with relapsed and refractory multi-ple myeloma. Interviews with several hematology/oncology experts suggest that the drug will have a significant impact on the treatment of this chal-lenging 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 treat-ment and who had received at least two prior lines of therapy that included the proteasome inhibitor bortezomib (Vel-cade, Millennium) and an immunomod-ulatory 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 refrac-tory multiple myeloma was the central trial in carfilzomib’s new drug applica-tion. 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 demograph-ics, disease-related or treatment-relat-ed characteristics, including wheth-er 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 sug-gesting the drug’s benefit might not outweigh the risks, especially cardi-ac risks. In the 0031A1 study, according to the briefing document, seven deaths that occurred in the carfilzomib arm most likely were caused by cardiac tox-icities. At the ODAC meeting, however, a non-voting participant from the FDA downplayed this data, saying the life-threatening heart-, lung- and liver-relat-ed adverse events (AEs) documented in the clinical trial were seen in only 4% of patients. The FDA participant point-ed 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

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 lym-phoma therapeutics at the National Cancer Institute. He said he had no hes-itation voting yes.

Option for Refractory Patients

Shaji Kumar, MD, an MM expert atMayo Clinic in Rochester, Minn., said that carfilzomib “adds one more option for patients who have exhausted cur-rently available therapies” and carries an added benefit: “It causes very lit-tle neuropathy,” he stressed. This AE can range from tingling and numbness in the fingers and toes, to painful neu-ropathy and autonomic neuropathy. The condition is a common dose-lim-iting toxicity of several MM therapies,including bortezomib, thalidomide and vincristine. In the case of IV bortezo-mib, 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 neurop-athy was nonexistent. No patients

discontinued treatment because of neu-ropathy. (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 associ-ate professor of medicine in the Divi-sion of Oncology at Washington Uni-versity School of Medicine, in St. Lou-is, who was heavily involved with the

carfilzomib trials. Lenalidomide, in con-trast, is rarely associated with mild neu-ropathy, he added. If neuropathy doesset in, Dr. Vij said, it often takes weeksor months to resolve and good support-ive-care treatments do not exist.

Dr. Vij added that physicians alsoshould keep an eye out for dyspnea asa possible side effect associated withcarfilzomib therapy. He said that 33.8%of patients in the 003A1 study experi-enced dyspnea of any grade; 3% experi-enced grade 3 and 0.04% experiencedgrade 4. “When people use carfilzomib inthe community, they will need to be a lit-tle vigilant about dyspnea,” he stressed.

Prior to the drug’s approval, someanalysts speculated that the FDA mightimpose a postmarketing program tohelp ensure the safe and effective useof carfilzomib. Something of the sortdid occur; as a condition of carfilzo-mib’s accelerated FDA approval, OnyxPharmaceuticals is required to provideadditional clinical data about the drug.According to the manufacturer, suchstudies are now under way.

Strength in Numbers

Both Drs. Kumar and Vij said thatcarfilzomib is likely to be used in com-bination with at least dexamethasoneor even with lenalidomide and dexa-methasone. Two- and three-drug com-binations are common in MM, they noted. Their views, stated just prior tothe drug’s approval, proved to be part-ly prescient; the FDA-approved drug label recommends that patients shouldbe premedicated with dexamethasonebefore each infusion to lower the riskfor infusion reactions.

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

Table. Discontinuations in Multiple MyelomaPatients 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)

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

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

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

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

28 CLINICAL ONCOLOGY NEWS • OCTOBER 2012HEMATOLOGIC DISEASE

Dr. Kumar added that he also sees a rolefor carfilzomib in up-front therapy, “butobviously there are no Phase III trialsthat have been done, so there is not going

to be an approval in that setting,” he said.“It is something that needs to be studied.”

A recent Phase I/II study suggest-ed that up-front combination therapy might indeed be a viable option. Thestudy evaluated carfilzomib in tan-dem with low-dose dexamethasoneand lenalidomide. Of 36 patients new-ly diagnosed with MM completing eight or more cycles of therapy, 42%reached stringent complete respons-es. The 24-month progression-free sur-vival estimate was 92%, the investiga-tors reported (Blood(( 2012 June 4 [Epubdahead of print]. The results were firstpresented at the 2011 annual meeting of the American Society of Hematology, inSan Diego; abstract 631.)

How the drug will be used also willdepend on whether insurers will pay forit, which is dependent on the FDA labeland compendia listing, Dr. Kumar not-ed. The cost of the drug and schedulealso will influence use.

Convenience also may play into treat-ment decisions. “With carfilzomib you

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.

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 Univer-sity 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 poten-tial 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 bortezo-mib?” All of these various clinical sce-narios “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 giv-en 20 mg/m2 of the drug for all treat-ment 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 mini-mal 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 co-investigator. Consistent with the FDA trial data, carfilzomib elicited a relative-ly low incidence of peripheral neuropa-thy (17.1% overall, with one grade 3 and no grade 4), the investigators reported.

The lower rate of peripheral neurop-athy seen in clinical trials of carfilzo-mib is significant, Dr. McBride stressed. “It may prove to be one of the guiding points in choosing this drug over bort-ezomib,” he said. He noted, howev-er, 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% treat-ed 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-driv-en decision,” he said. “The big issue, at least initially, is to remember that you will only be able to use the drug in therelapsed/refractory setting. Payers willmost 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 pro-longs patients’ lives or increases pro-gression-free survival, both of which are considered to be important mark-ers of clinical response. Still, carfilzo-mib’s approval “is an important addi-tion to our armamentarium for multi-ple myeloma—especially given its role in patients who are running out of oth-er 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.

Chicago—High-dose vitamin D iseffective at combating joint pain, a com-mon side effect of aromatase inhibitor(AI) therapy, according to a randomizedclinical trial presented at the recentannual meeting of the American Society of Clinical Oncology (abstract 9000).

“Six months of vitamin D3 at a doseof 30,000 IU per week is safe in wom-en starting an AI for adjuvant treatmentof breast cancer, is associated with lessworsening of AI-related musculoskeletalsymptoms, and is associated with feweroverall adverse quality-of-life events,”said Qamar Khan, MD, an associate pro-fessor at the University of Kansas Medi-cal Center in Wichita, who led the study.

According to Dr. Khan, approximate-ly 50% of breast cancer patients taking adjuvant AIs for breast cancer reportnew or worsening musculoskeletalpain (J Clin Oncol(( 2010;28:4120-4128,PMID: 20585090). These symptomsfrequently cause women to discontin-ue therapy prematurely.

The exact mechanism by which AIscan induce musculoskeletal symptomsis unclear, but estrogen deprivation has

been shown to cause inflammation and increase pain sensitivity. “Some of the women on AIs have MRI [magnetic res-onance imaging] findings of tenosyno-vitis suggestive of local inflammation,” said Dr. Khan.

The double-blind, randomized VITALtrial (VITamin D for Arthralgias fromLetrozole) was conducted at Kansas Medical Center and the Cancer Cen-ter of Kansas, Wichita, a large commu-nity practice. The study enrolled 160 patients with postmenopausal stage I toIII breast cancer who were starting on adjuvant letrozole and had deficient lev-els 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 vitaminsand supplements. Patients were exclud-ed from the study if they had severe or debilitating musculoskeletal pain,

Vitamin D Reduces Aromatase Inhibitor–Induced Joint Pain

‘I don’t think there is going to be one answer that

fits all in how this drug will be used.’

—Shaji Kumar, MD

see VITAMIN D, page 30D �


Chicago—A growing body of evidence shows that neoadjuvant dual HER2-tar-geted 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 com-bination of neoadjuvant lapatinib and trastuzumab to either agent alone in patients with HER2-positive tumors.

“Combined HER2-targeted therapy produced a numerically higher pCR per-centage than single-agent HER2-direct-ed therapy, but the difference was not statistically significant,” said Andre Rob-idoux, MD, an oncologist at the Universi-ty of Montreal Hospital Center, in Cana-da. He presented the study at the annual meeting of the American Society of Clin-ical 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 (Her-ceptin, 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 trastuzum-ab and lapatinib therapy. All three arms then received surgery and one year of trastuzumab.

Rate of pCR, defined as the absence

of invasive tumor in resected breast specimens, was higher in the com-bination arm (62%) than the trastu-zumab arm (52.5%), but the differ-ence was not statistically significant (P(( =0.095). No difference was seen in the pCR rate between the trastuzumab alone (52.5%) and lapatinib alone arms (53.2%; P=0.99).

Rates of grade 3/4 toxicities, includ-ing diarrhea, were higher in the lapa-tinib arms (Table), but febrile neutrope-nia and hepatic toxicity were similar in the three treatment groups. Combina-tion therapy did not increase the rate of congestive heart failure compared with single-agent therapies.

“These results are similar to oth-er neoadjuvant studies of dual HER2-directed therapies,” said Anne Schott, MD, an associate professor of Internal Medicine at the University of Michi-gan Health System in Ann Arbor, who was not involved with the study. “Neo-ALTTO [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 Pertuzum-ab and Herceptin in an Early Regimen Evaluation] also showed an increase in pCR with trastuzumab and pertu-zumab [Perjeta, Genentech] compared to either treatment alone, and also showed a decent pCR rate of dual com-bined therapy without chemotherapy.” In the CHER-LOB trial, pCR was near-ly doubled when lapatinib and trastu-zumab were combined compared with either treatment alone (J Clin Oncol((

2012;30:1989-1995, PMID: 22493419).“Although these reports are interest-

ing, 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 random-ized clinical trials showed that pCR is a suitable surrogate end point for patients with luminal B/ER2-negative, HER2-positive (nonluminal) and triple-negative disease, but not for those with luminal B/HER2-positive or luminal A tumors (J Clin Oncol(( 2012;30:1796-1804, PMID: l22508812).

In the NSABP B-41 trial, she said, 63% of patients were hormone re-

ceptor–positive and it is therefore unclear if the pCR benefits will trans-late to disease-free survival. For a defin-itive answer, clinicians need to wait for results from the ALTTO trial (testing combination lapatinib and trastuzum-ab), and APHINITY (Adjuvant Pertu-zumab and Herceptin in Initial Thera-py 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 fromGlaxoSmithKline and Roche.

Dr. Schott disclosed research fundingfrom Dompe, GlaxoSmithKline and Merck.

a history of renal stones or a history of hypercalcemia or hyperparathyroidism. The study arms were well balanced.

In patients who received extra vita-min 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 Invento-ry (Short Form) measured pain inten-sity and how much it interfered with items such as mood, general activi-ty and sleep. The Health Assessment

Questionnaire II (HAQ II) measured the degree of difficulty that an individ-ual had performing common activities of daily living. The Brief Fatigue Inven-tory asked questions related to intensity of fatigue and impact of fatigue on com-mon activities.

The first primary end point was the incidence at six months of a musculo-skeletal 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 letro-zole. There was a statistically signifi-cant improvement in patients taking vitamin D for this end point (38% vs. 61%; P=0.008).

The incidence of an adverse quali-ty-of-life event, a secondary end point, also was improved for patients taking

extra vitamin D (42% vs. 72%; P≤0.001). This secondary end point was defined as a musculoskeletal event or worsen-ing 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 radia-tion oncology at the University of Roch-ester Medical Center in Rochester, N.Y. “Vitamin D3 may be a promising inter-vention 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.

Evidence Grows for Dual HER2 Blockade in Breast CancerComplete response higher with combo treatment, but not statistically significant

Table. Comparison of Grade 3/4 Toxicities inNSABP B-41 Trial

Trastuzumab LapatinibTrastuzumab and Lapatinib

Overall grade 3, % 46 53 51

Overall grade 4, % 4 9 9

Grade 3 diarrhea, % 2 20 27

‘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

‘Vitamin D3 may be a promising intervention for musculoskeletal symptoms and possibly cancer-related fatigue.’

—Karen Michelle Mustian, PhD, MPH

VITAMIN Dcontinued from page 29 ��


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