Clinical Oncology News - September 2009 - Digital Edition

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McMahon Publishing

Advances in Cancer Care CLINICALONCOLOGY.COM • SEPTEMBER 2009

HEMATOLOGIC DISEASE

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Higher dose of imatinib may improve outcomes in patients with CML. SOLID TUMORS

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Genetic variations predict outcomes in patients with pancreatic cancer. FDA NEWS

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ODAC vote against yondelis dissected.

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Bevacizumab plus interferonalfa approved for the treatment of patients with metastatic renal cell carcinoma. PEOPLE AND PLACES

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Find out who is moving where in your specialty. ASTRO names honorary member. S PE C I AL O FF ERS

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Information on how to order our popular pocket guides and wall charts such as the Guide for the Administration and Use of Targeted Cancer Agents.

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Should Tamoxifen Candidates Be Tested For CYP2D6?

Gene Assay Predicts Risk for Colon Cancer Recurrence

Miami—The question of whether or not all women with hormone receptor (HR)-positive breast cancer planning to start treatment with tamoxifen should be tested for CYP2D6 polymorphisms was debated at the fifth annual conference of the Hematology/Oncology Pharmacy Association (HOPA). Slugging it out in favor of routine testing was Chad M. Barnett, PharmD, of The University of Texas M.D. Anderson Cancer Center, Houston, who argued that numerous studies have shown shorter times to recurrence and decreased overall survival in women who have specific CYP2D6 polymorphisms and that not testing for these polymorphisms could be putting them at increased risk for bad

Orlando, Fla.—A recurrence score based on a gene profile may help guide doctors in deciding when to use adjuvant therapy to reduce the risk for recurrence in patients with stage II colorectal cancer (CRC) who have undergone surgery. According to a recent study, a score based on the gene profile not only predicts recurrence risk, but disease-free survival (DFS) and overall survival (OS) as well. Genomic Health plans to launch the tool, Oncotype DX Colon Cancer Assay, based on the gene profile, in early 2010. “This is the first study of a prospectively defined recurrence score that has been validated as a predictor of recurrence in

see TAMOXIFEN, page 7

Largest Adjuvant ADT Study Generates Surprising Outcomes Orlando, Fla.—Follow-up from the largest study ever conducted in patients receiving adjuvant androgen deprivation therapy (ADT) after radical prostatectomy has generated a surprisingly low relapse rate of prostate cancer. At five years, overall survival (OS) in patients receiving ADT is 95% (90% in high-risk individuals), a rate that is higher than those seen in similar studies. It is not clear, however, whether the low relapse rate can be fully attributed to the therapy, which consisted of a combined androgen blockade of goserelin (Zoladex, AstraZeneca) and bicalutamide (Casodex, AstraZeneca), see ADT, page 5

stage II CRC following surgery. We showed that it has

independent predictive value beyond previously available measures,� said David J. Kerr, MD, professor of clinical pharmacology at Radcliffe Infirmary, Oxford University, in Oxford, United Kingdom. Presenting the study at the recent annual meeting see GENE ASSAY, page 8

POLICY & MANAGEMENT

Financial Stimulus Offered for Use of Electronic Health Records

D

espite the reported patient-care and cost-saving benefits of electronic health record (EHR) systems, most hospitals—and indeed the majority of physician practices—have refrained from making the leap into the brave new world of EHR technology. But a new government program seeks to stimulate adoption of the technology with financial incentives. The American Recovery and Reinvestment Act (ARRA) of 2009 promises to inject more than $46 billion into a decadelong drive to stimulate EHR adoption. The Obama administration sees the technology

as a key to lowering overall health care costs at the same time as it extends benefits to more Americans. The stimulus funds will be wrapped in the form of Medicare and Medicaid reimbursement incentives and delivered to hospitals and physician practices that can demonstrate “meaningful use� of their certified systems to the Department of Health and Human Services (HHS) and HHS’ Office of the National Coordinator for Health Information Technology (ONC). Medicare bonus payments are see STIMULUS, page 3

McMahonMedicalBooks.com Targeted Cancer Therapy

Product News

Razelle Kurzrock; Maurie Markman

Avastin gets an indication for mRCC.

For more information, see page 10.

See page 9.

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CLINICAL ONCOLOGY NEWS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

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Pharmacy Polly E. Kintzel, PharmD Melvin E. Liter, MS, PharmD

ADVISORY BOARD

Policy and Management

Bioethics Joseph P. DeMarco, PhD Paul J. Ford, PhD

Mary Lou Bowers, MBA Barbara Constable, RN, MBA Rhonda M. Gold, RN, MSN

Community Oncology

Solid Tumors

Michael J. Fisch, MD, MPH John W. Finnie, MD

Betty Ferrell, RN, PhD

EDITORIAL STAFF

Lung Cancer, Emesis Richard J. Gralla, MD

Infection Control

Gastrointestinal Cancer Edward Chu, MD Cathy Eng, MD Leonard Saltz, MD

Oncology Nursing

Genitourinary Cancer Ronald M. Bukowski, MD

Lung, and Head and Neck Cancers Edward S. Kim, MD

Breast Cancer Andrew Seidman, MD

Jennifer R. Brown, MD, PhD Agnes Y.Y. Lee, MSc, MD Richard Stone, MD

Russell K. Portenoy, MD Charles F. von Gunten, MD

Gynecologic Cancer Maurie Markman, MD

Bone Metastases Allan Lipton, MD

Hematologic Malignancies

Gastrointestinal Cancer and Sarcoma Ephraim Casper, MD

Kate O’Rourke, Editor korourke@mcmahonmed.com Sarah Tilyou, Senior Editor smtilyou@mcmahonmed.com James Prudden, Group Editorial Director David Bronstein, Editorial Director, Hospital Group

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Guide to Cancer Therapeutic Regimens 2009 Pocket Guide The use of cancer therapeutic agents in combination is well established. The knowledge of cell kinetics and the pharmacology of antitumor agents have allowed the clinician to use combination therapy to maximize tumor cell kill with minimal or acceptable toxicity to the patient.

Guide to Cancer Therapeutic Regimens 2009 Wall Chart—Part 1 Part 1: Solid Tumor Cancers This wall chart lists common combination regimens and doses used in solid cancers.

Guide to Cancer Therapeutic Regimens 2009 Wall Chart—Part 2 Part 2: Hematologic Cancers This wall chart lists common combination regimens and doses used in hematologic cancers.

Oral Mucositis: Causative Regimens and Pathways for Treatment Mucositis can be best described as a distinct and complex pathobiologic entity resulting in mucosal barrier injuries that is a consequence and frequent complication of chemotherapy and radiation therapy in patients with cancer.

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Cancer Support 2009 This guide outlines characteristics of hazardous drugs, detrimental effects of occupational exposure, methods of determining exposure and common routes of exposure. It also highlights the technologies available to reduce risks and national guidelines for ensuring safe compounding, transport, delivery, administration and disposal of hazardous drugs by using personal protective equipment.

Guide for the Administration and Use of Targeted Cancer Agents 2009 The National Cancer Institute defines targeted therapy as “a type of treatment that uses drugs or other substances, such as monoclonal antibodies, to identify and attack specific cancer cells without harming normal cells.� Although other variations of the definition exist, collectively they define a change in the drug development process.

Prevention of Chemotherapy Mepdication Errors 2009 This pocket guide is intended to help clinicians develop practical strategies to prevent chemotherapy medication errors. It includes information on selected publicized chemotherapy errors and their outcomes; examples of potential causes of errors, such as look-alike/sound-alike drug names and the use of handwritten orders; examples of optimal requirements and prohibitions for chemotherapy orders; and how to assess the risk for medication errors at one’s own institution or practice site.

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POLICY & MANAGEMENT

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

Electronic Health Records

STIMULUS continued from page 1

slated to begin in October 2010; Medicaid incentives start in January 2011. The precise definition of “meaningful use� will not be determined until the end of this year, but ARRA’s language includes the concept of “interoperability,� the use of certified EHR technologies, the ability to submit quality measures to HHS, and—for physicians—the use of electronic prescribing. The key element may be interoperability: the capacity to communicate relevant patient data across all practice settings. (A Web site created by the Association of Medical Directors of Information Systems contains detailed discussions of “meaningful use,� as well as how the stimulus will affect various parts of the health care community.) HHS also will be working with the ONC to flesh out the details of the incentive program. The government is counting on the technology to recoup a substantial portion of the stimulus funds through improvements in hospital readmission rates; reduction in costly duplications of treatments and tests; and fewer errors and adverse events. Still, with many hospitals and physician practices reluctant to invest the substantial sums required to build and maintain complex technological systems, the big question is: How much of an impact will the federal stimulus have on EHR adoption? “We believe it will be large,� said Carla M. Smith, executive vice president of the Health Information and Management Systems Society (HIMSS). “There is now enough evidence, based on other hospitals and physicians across the United States having [successfully] implemented EHR, where the return on investment has been documented for the technology.� Ms. Smith suggested that detailed examples of successful return-on-investment analyses could be found among the submissions filed by recipients of HIMSS’s annual Nicholas E. Davies Award of Excellence on the organization’s Web site. According to the results of a major survey described in the April 16 issue of The New England Journal of Medicine (2009;

Beginning in 2015, hospitals and professional groups that do not have a system up and running will find their Medicare and Medicaid payments reduced.

360:1628-1638, PMID: 19321858), only about one in 10 U.S. hospitals have any type of EHR system at all. The implementation rate for comprehensive systems was far lower, the survey found. If successful, the stimulus program stands to make a large impact. Hospitals that have put EHR into practice often have relied on more than a strict dollar return to make a business case for their investments, which can amount to millions of dollars in startup costs and millions more in training and system maintenance expenses over

time. Factors such as improved care and safety also have been key elements in their cost–benefit calculations because they can help speed patient recovery time, reduce readmissions and avoid costly malpractice litigation. With the Medicare and Medicaid incentives set to begin in less than two years, hospitals that do not already have systems in place or on the launching pad may find it challenging to take full advantage of the bonus payments, which will be highest in the first year and then gradually diminish year by

year. Medicare incentives will continue through 2016, while Medicaid bonuses will extend through 2021. Beginning in 2015, the “stick� component of the government’s carrot-and-stick approach to EHR compliance will kick in, and hospitals and professional groups that do not have a system up and running will find their Medicare and Medicaid payments reduced. Detailed information can be found on HHS’s Recovery Web site (www.hhs.gov/recovery/reports/plans/ index.html#programs). Brent I. Fox, PharmD, PhD, assistant professor of pharmacy care systems at Auburn University Harrison School of Pharmacy, in Alabama, believes that 2015 may be a more realistic target date for hospitals that are on the fence about EHR technology investment. He said their thinking may go something like this: “Okay, we eventually have to spend the money. We may not be able to get the incentive bonuses, but what we really want to avoid is having our reimbursement decreased.� The government’s stimulus plan would seem to favor hospitals with the resources to develop and maintain costly EHR systems. In fact, The New England Journal of Medicine study found that EHR technology adoption was highest among large university hospital systems. But Ms. Smith noted that the stimulus legislation contains language that could help smaller and rural hospitals to acquire EHR technology through loans provided by states. However, the details of how much will be available in loan funds have not yet been worked out, according to Ms. Smith. A “clear and present challenge� for many hospitals, she added, will be finding the upfront money to purchase systems “in a very tight economy.� Even hospitals that are able to muster the investment dollars face challenges. They need to pay very close attention later this year when HHS releases draft regulations laying out in greater detail how the incentive amounts will be calculated and what the standards are that define “meaningful use� systems. The final HHS rule is expected in December. —Bruce Buckley

We Want Your Feedback. Dear Clinical Oncology News Reader: We want your opinions, criticisms, ideas and suggestions to help us improve this new publication. Please contact the editor at the e-mail address listed below. We would sincerely value your input. Kate O’Rourke, Editor • korourke@mcmahonmed.com • (212) 957-5300, x 265

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

Chronic Myeloid Leukemia

Higher Dose of Imatinib May Improve CML Outcomes San Francisco—New data from a series of large trials lend support to the idea that intensification of first-line imatinib in patients with chronic myeloid leukemia (CML) may improve outcomes.

Imatinib 800 mg Imatinib 400 mg

60

Need for Improvement The series of studies, all presented at the most recent annual meeting of the American Society of Hematology, address a major clinical issue. Although imatinib has been a highly effective therapy for patients with newly diagnosed CML, major studies such as IRIS (International Randomized study of Interferon and ST1571) indicate that 20% to 30% of patients do not do well on a standard 400-mg imatinib dose and require alternative therapies. Reducing this percentage is an important clinical goal. “The standard first-line therapy for newly diagnosed CML is 400 mg of imatinib daily, but 50% to 60% [of patients] will not achieve a complete cytogenetic response [CCyR] at 12 months,� said Francois Guilhot, MD, Centre Hospitalier Universitaire de Poitiers, France, lead investigator of two of the studies. The goal of both of the studies presented by Dr. Guilhot was to evaluate strategies to boost early response in order to improve late outcome.

chromosome–positive CML (CML Ph+) to 400 or 800 mg imatinib. The lack of a significant difference in such major clinical outcomes as progression-free survival and overall survival after only 31 months of follow-up (both >90%) was not surprising, but the study also failed to associate the higher dose with a significant improvement in CCyR, which was the primary end point. However, dose reductions on the higher dose were common. “Although this study did not show a statistical benefit of 800 mg imatinib over 400 mg on ITT analysis, the patients who could comply with the higher dose did have a better cytogenetic outcome,� said Michele Baccarani, MD, an oncologist in the Department of Hematology and Oncological Sciences, University of Bologna, Italy. In pointed questions that followed his presentation, Dr. Baccarani acknowledged that it might be reasonable, despite these results, to start high-risk patients with CML on

Major studies such as IRIS indicate that 20% to 30% of patients do not do well on a standard 400-mg imatinib dose and require alternative therapies.

TOPS Trial Of the two trials, TOPS (Tyrosine Kinase dose Optimization Study) may be the most important as a proof of principle (abstract 447). In this multicenter, Phase III, open-label study, more than 800 patients received either 400 or 800 mg (400 mg twice daily) imatinib, but response rates were evaluated in the context of trough plasma levels regardless of dose. When stratified into quartiles, the major molecular response rates at 12 months were more than 50% greater among patients with the highest trough concentration of imatinib compared with those with the lowest (59% vs. 38%; P=0.0338; Figure 1). Although it also was true that patients with the highest trough plasma concentrations also had the greatest frequency of adverse events, Dr. Guilhot indicated that drug exposure does appear to predict response. He suggested that some form of drug monitoring might be needed to maximize the risk–benefit ratio of imatinib therapy.

European LeukemiaNet Although another trial addressing the same topic produced a negative result, the data may support the same conclusion. Conducted specifically in patients labeled as high risk based on Sokal score, the ongoing European LeukemiaNet study (abstract 185) randomized 217 treatment-naĂŻve patients with Philadelphia

Imatinib 400 mg Imatinib 600 mg Imatinib 400 mg plus ARAC-C

100

Imatinib 400 mg plus PEG-IFN Each arm had roughly 160 patients.

80 71 65 60

66

57

40

20

0

Figure 2. Comparison of CCyR in patients with CML. ARA-C, cytarabine; CCyR, complete cytogenetic response; CML, chronic myeloid leukemia; PEG-IFN, pegylated interferon

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50

% of Patients

Of four studies designed to address this topic, three suggested that either increasing the dose or adding a second agent such as cytarabine (ARA-C) or pegylated interferon (PEG-IFN) improved response rates. Although a fourth study did not associate a higher imatinib dose with a significantly improved response on an intention-to-treat (ITT) basis, there was a higher rate of cytogenetic response in those who tolerated the higher dose.

% of Patients Achieving CCyR

4

38

40 30 20 10 0

MMR

Figure 1. Comparison of patients with CML achieving a major molecular response in the TOPS trial. CML, chronic myeloid leukemia; MMR, major molecular response; TOPS, Tyrosine Kinase dose Optimization Study

800 mg of imatinib and then reduce the dose if it is not well tolerated.

Further Evidence Although Dr. Baccarani cautioned that he could not provide hard evidence from his study to support this approach, preliminary support for higher doses of imatinib could be drawn from the other studies, including a second study presented by Dr. Guilhot (abstract 183). This was a randomized comparison of three experimental arms with a reference arm of 400 mg imatinib daily in patients with newly diagnosed chronic-phase CML. The experimental arms were 400 mg imatinib daily, 600 mg imatinib daily, 400 mg imatinib in combination with ARA-C (20 mg/m2 per day on days 15-28 of a 28-day cycle), and 400 mg imatinib in combination with PEG-IFN alfa-2a (90 mcg weekly). The four study groups were nearly equal in size with about 160 patients per arm. In this study, there was an advantage at 12 months for the higher-dose imatinib as well as for both arms that included a second agent. Specifically, CCyR climbed from 57% for imatinib 400 mg to 65% for imatinib 600 mg, 66% for imatinib plus ARA-C, and 71% for imatinib plus PEG-IFN (Figure 2). Relative to 400 mg imatinib, dose reductions due to adverse events also were more common for the alternative strategies, but the response advantages were achieved despite these dose reductions. Although longer follow-up is needed to verify that the greater cytogenetic responses translate into outcome advantages, Dr. Guilhot suggested that a more aggressive approach appears promising. The same conclusion was reached from a third multicenter study conducted in Germany (abstract 184). Again, a series of experimental arms were compared with a standard of 400 mg imatinib in patients

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HEMATOLOGIC DISEASE

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

Chronic Myeloid Leukemia

newly diagnosed with chronic-phase CML. In lowand intermediate-risk groups, the experimental arms included imatinib plus ARA-C, imatinib plus IFN, and imatinib after IFN failure. There also was an arm of 800 mg imatinib daily evaluated in highrisk patients. The study was subsequently amended to randomize low- and intermediate-risk patients to 800 mg imatinib. As in the other studies that suggested better results can be achieved with intensification of therapy, the CCyR rates have been higher with higher imatinib doses and when imatinib is combined with another agent. Although the lead author, RĂźdiger Hehlmann, MD, Medical Faculty Mannheim, University of Heidelberg, Mannheim, Germany, cautioned that the study is still randomizing patients and that data from the 800-mg imatinib arm are not yet fully evaluable, he said that the projected five-year survival from those on intensified therapy is greater than 90%, which is better than that

‘While a couple of the studies showed a higher response rate at 12 months, it may not be true that fastest is best. Previous data suggested that as long as you eventually got the response you were looking for, you did OK.’ —Richard Stone, MD

previously reported with standard doses of imatinib in such studies as IRIS. “The combination strategies and high-dose imatinib

have not been associated with major problems,� said Dr. Hehlmann. Based on the early results he said that an “optimization of outcome is expected� with the newer therapeutic approaches, although he, like others, cautioned that response rates are surrogates and none of these strategies can be declared superior until a survival advantage has been demonstrated. Richard Stone, MD, director of the Adult Leukemia Program at Dana-Farber Cancer Institute, Boston, who was not involved with the research, says that more studies are needed before drawing conclusions. “While a couple of the studies showed a higher response rate at 12 months, it may not be true that fastest is best,� he said. “Previous data has suggested that as long as you eventually got the response you were looking for, you did OK. The real question is not response but failure rates.� —Ted Bosworth

SOLID TUMORS Prostate

ADT continued from page 1

or whether other contributing variables played a role, such as the relatively high number of individuals considered to be low risk. What the study does do is contribute to data indicating that “prostate cancer patients diagnosed in 1999 through 2007 have improved survival compared with previous decades,â€? said L. Michael GlodĂŠ, MD, professor of medical oncology at the University of Colorado Health Sciences Center, Aurora. The study revealed overall relapse-free survival (RFS) at five years was 92.5%, a promising result at this milestone. Even in the high-risk patients, 87.5% remained relapse-free at the end of five years. Dr. GlodĂŠ acknowledged that longer follow-up is needed to confirm the benefits of ADT after five years. The study, run by the Southwest Oncology Group (SWOG) and presented by Dr. GlodĂŠ at the most recent meeting of the American Society of Clinical Oncology (ASCO; abstract 5009), was designed to compare the combination of goserelin and bicalutamide with the same dual-androgen blockade plus mitoxantrone (Novantrone, Serono/ OSI Pharmaceuticals) and prednisone as adjunctive treatment after radical prostatectomy. The primary end point of the trial, conceived in 1997 and launched in October 1999, was OS with several secondary end points, including disease-free survival. However, the Data and Safety Monitoring Committee (DSMC) recommended discontinuing the chemotherapy arm in January 2001 because of an increased number of cases of acute myelogenous leukemia (AML).

The study revealed overall relapse-free survival at five years was 92.5%, a promising result at this milestone.

Syringe of goserelin

By the time the data were presented at ASCO, there had been five cases of AML among the 487 patients randomized to chemotherapy and no cases in the arm that received ADT alone. The data presented at ASCO were limited to the 376 patients who were randomized to the ADT-alone arm and had completed at least two years on the protocol. Although all patients might be considered high risk because of adverse pathologic risk factors after surgery, the outcomes were stratified by low-, intermediate- and high-risk categories. Although Dr. GlodĂŠ acknowledged these distinctions were “somewhat arbitraryâ€?

in the absence of accepted definitions, low risk was defined as positive margins or extraprostatic extension only. Intermediate risk was defined as seminal vesicle invasion of Gleason score of 8 or greater but no positive nodes. High risk was defined by positive nodes. When these risk groups were compared, survival (95%, 96% and 90%, respectively) was appreciably lower only in the highrisk group. For RFS (98%, 91.6% and 87%, respectively), each increase in risk category was associated with about a 5% reduction in the end point. Of the 17 deaths in the study overall, seven were from prostate cancer, four were from another type of cancer, and the remaining six deaths were from noncancer causes of which only one death was cardiovascular, which was considered low for this study group. In the 189 patients for whom there was sufficient follow-up and data on testosterone recovery, the median time for patients to achieve levels at the lower limit of normal was 9.5 months with 28% achieving this outcome by six months, 75% by 12 months and 90% by 18 months. One of the reasons for the high rates of survival may be that 25% of patients were in the low-risk category (approximately 60% were intermediate risk). In reviewing other studies evaluating ADT, Dr. GlodĂŠ said that definitions of risk may have varied, but results from previous studies are not inconsistent with results from the new study. For

example, a study that compared immediate with delayed adjuvant androgen deprivation associated immediate treatment with significant improvements in OS (hazard ratio [HR], 1.84; 95% confidence interval [CI], 1.01-3.35; P=0.04), prostate cancer-specific survival (HR, 4.09; 95% CI, 1.76-9.49; P=0.0004) and progression-free survival (HR, 3.42; 95% CI, 1.96-5.98; P<0.0001) at median follow-up of 11.9 years. That study also associated immediate androgen deprivation with statistically significant improvements in progression-free survival (P<0.0001) and prostate cancerspecific survival (P=0.0004). Asked to comment on the study, Joel Nelson, MD, chairman of the Department of Urology at the University of Pittsburgh, suggested that patients with positive margins but no positive nodes might be in a marginal zone of high risk. He offered the term “low high-risk patients,� agreeing that the substantial representation of such patients in the SWOG study may explain the high rates of survival. Overall, these results verify a benefit from androgen deprivation, but Dr. Nelson expressed more interest in the original study objective, which was to compare androgen deprivation with or without chemotherapy. He suggested that he is “very much in favor� of providing adjuvant chemotherapy in high-risk patients based on the available data, but indicated the practice needs validation with controlled evidence. Unfortunately, the data to assess the activity of the chemotherapy arm may be years away, and they will have to clear “an extremely high bar� with high rates of RFS achieved with androgen blockade alone. —Ted Bosworth

5

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

Pancreatic

Genetic Variations Predict Outcomes in Pancreatic Ca Number of Adverse Genotypes

Median Survival (mo)

0-1

Not reached

2

36

3

24

4

16

5

13

6-7

8

‘We hope to identify a panel of mutations, like Dr. Li has done, that indicate poor response to chemotherapy and poor survival. If we can do this, we can avoid aggressive therapies in those unlikely to benefit.’ —Jennifer Obel, MD

According to Jennifer Obel, MD, a gastrointestinal cancer specialist from NorthShore University HealthSystem, Chicago, Dr. Li’s research exemplifies goals for the future of gastrointestinal treatment. “We know that the majority of pancreatic patients will [have recurrent cancer] and die of disease within five years,� she said. “We hope to identify a panel of mutations, like Dr. Li has done, that indicate poor response to chemotherapy and poor survival. If we can do this we can avoid aggressive therapies in those unlikely to benefit.� —Caroline Helwick

100

26.4

25.5

25 21.6 20 15.5

7.4 TP73 Ex2+ 4G>A AA

TP73 Ex2+4G>A GG/GA

TREX1 Ex14-460C>T CC

EXO1 R354H GG/AA

EXO1 R354H GG

10

TREX1 Ex14-460C>T TT/CT

15

0

80

75.6

72.2

60

40

20

TREX1 Ex14-460C>T CC

30

94.3 88.5

TREX1 Ex14-460C>T TT/CT

31.0

% of Patients With Partial Response/Stable Disease

35

5

Table. Combined Effect of Adverse Genotypes on Survival

TP73 Ex2+4G>A GA/AA

The findings may explain why the disease is deadly in some patients, but indolent in others, said Donghui Li, PhD, professor of gastrointestinal medical oncology at The University of Texas M.D. Anderson Cancer Center, Houston. She presented her findings at the 2009 Gastrointestinal Cancers Symposium (abstract 118). Approximately 30% of patients with resectable pancreatic cancer do not benefit from tumor resection because of rapidly progressive disease. Clinicians, however, have had difficulty identifying which patients will benefit. Factors that influence a patient’s response to gemcitabine (Gemzar, Eli Lilly), which is standard therapy, also are not well defined. Pharmacogenetic studies have shown that genetic variations in drug metabolism and DNA repair affect individual response to therapy. DNA mismatch repair is a critical genome caretaker that guards genomic stability by correcting mismatches generated during DNA replication and recombination. It also triggers apoptosis in cells with severe DNA damage. In vitro studies have shown that cells deficient in DNA mismatch repair are more sensitive to gemcitabine-mediated radiosensitization, Dr. Li explained. “Based on this information, our goal was to determine whether there is an association between genetic variation in DNA mismatch repair and the clinical outcomes of patients and to see if genetic markers can be used for prognosis, or for prediction of therapeutic outcome,� she said. The study included 154 patients with potentially resectable pancreatic adenocarcinomas enrolled in two Phase II trials of neoadjuvant gemcitabine-

based chemoradiation at M.D. Anderson. Investigators looked for the presence of 15 single-nucleotide polymorphisms (SNPs) of eight DNA mismatch repair genes; the genes encode proteins that repair chemotherapy-induced DNA damage and enable cancer cells to become resistant to treatment. Five DNA mismatch repair genes were found to be significantly associated with tumor response, six were associated with resectability, and 10 were associated with overall survival in a univariate analysis, Dr. Li reported. Patients were divided into groups based on the number of unfavorable genotypes (defined by their association with poor response, lower likelihood of resection and shorter survival time). In particular, EXO1, MLH1, TREX1 and TP73 genotypes were significantly associated with clinical outcomes after adjusting for other factors. At a median follow-up of 50 months, median survival for the whole cohort was 21.7 months, but favorable genotypes were associated with longer median survival. For example, median survival for patients with the “good� TP73 GG/GA genotype was 25.5 months, compared with only 7.4 months for those with the “bad� TP73 AA genotype. Similarly, response and resectability rates also were higher for patients with favorable genotypes (Figures 1 and 2). Dr. Li speculated that the observed effects may be related to interference with the ATR/Chk1 signal pathway and failed apoptosis in response to gemcitabineinduced DNA damage. “For example, after neoadjuvant treatment, tumors actually became larger in 27.3% of the TP73 GA/AA genotype carriers, versus 5.7% of the TP73 GG carriers,� she noted. The GG carriers had an 83% R0 resection rate, compared with 51.5% of the GG/AA carriers. “We observed that some genotypes had weak effects, but when we combined the genotypes together, we saw a strong effect on each clinical end point,� she continued. “Median survival time diminished as the number of variants increased.� (See table.) “Identifying a panel of genes that are working on the same pathway may help predict treatment response, and identify patients who will benefit from tumor resection,� Dr. Li concluded.

TP73 Ex2+4G>A GG

San Francisco—Certain genetic variations may enable clinicians to predict response to treatment, resectability of tumor and survival in patients with pancreatic cancer, according to a new study.

Survival, mo

6

0

P=0.032

P=0.003

P=0.010

Figure 1. Association of genotypes with overall survival.

Figure 2. Association of genotype with tumor response to neoadjuvant gemcitabine-based chemoradiation.

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PRN

CLINICAL ONCOLOGY NEWS • SEPTEMBER/OCTOBER 2009

Research

Government-Funded Initiative Meets With Skepticism Recently, the Obama administration committed to spending $1.1 billion on comparative effectiveness research (CER). The funds should start flowing next spring, which is good news, but the medical community has expressed mixed feelings about the initiative. The funds will be allocated in the form of grants from the Department of Health and Human Services (HHS), the National Institutes of Health (NIH) and the Agency for Healthcare Research and Quality (AHRQ). Everyone agrees that, in the age of budget constraints, health care spending must be kept in check. But they also worry that it may be impossible to sort through the huge volume of evidence to arrive at a completely accurate and impartial conclusion on any topic—with the task made even more difficult by the ambitious array of therapeutic areas to be tackled under very tight timelines—and that any conclusion favoring one treatment may well lead to other treatments being barred.

‘[Comparative effectiveness research] isn’t about denying treatments; it’s about making sure all types of patients are appropriately treated.’ —Sheldon Greenfield, MD

John I. Allen, MD, clinical associate professor of medicine, University of Minnesota, Minneapolis, noted that most people are “on board� with the concept of evidence-based medicine. “But I think skepticism comes from the fact that it’s an extraordinarily complicated and costly proposition to arrive at evidencebased medicine in general, and to arrive at decisions about every area of medicine at once will compound the complexity and cost to an unobtainable level,� Dr. Allen said. “We’re concerned that this is going to be superficial and not reflect the complexity of realworld patient care. We’re also concerned that comparative effectiveness analysis will lead to decisions that might restrict choices for patient care and development of new technologies and treatments.� Douglas Blayney, MD, president of the American Society of Clinical Oncology (ASCO), in Alexandria, Va., expressed a similar view. “I think that it is valuable to call attention to the fact that comparative effectiveness research is important for doctors’ and patients’ decision making,� Dr. Blayney said. “But, in general, ASCO also wants to have the decision making remain in the hands of physicians and patients.�

The Top 100 The initiative is part of the rolling out of the American Recovery and Reinvestment Act of 2009. The legislation, signed into law on Feb. 17 by President Barack Obama, allocated $400 million to the Office of the Secretary of the HHS, $400 million to the NIH and $300 million to the AHRQ for CER.

Reinvestment Act of 2009 called for the Institute of Medicine (IOM) to form a committee to recommend priorities for the funding of CER. The IOM solicited input from the public, health care professionals and medical organizations before voting on the results and recommending 100 priorities, which can be found at www.iom.edu/CMS/3809/63608/71025.aspx.

‘Let’s make sure there’s no hidden issues here. Let’s make sure there’s no subterfuge for rationing drugs, or for funding your research.’ —Gary Lyman, MD, MPH

The law also called for the creation of the Federal Coordinating Council for Comparative Effectiveness Research, whose objectives are outlined in a June 30 report to the president and Congress, available at www. hhs.gov/recovery/programs/cer/cerannualrpt.pdf. The council’s report sketched out a framework for arriving at priorities for research, investment of human and scientific capital, assembly of data and infrastructure, and dissemination and translation of CER. Additionally, the American Recovery and

Table. Oncology Priorities Recommended To Receive Funding for Comparative Effectiveness Research Oncology Effectiveness of imaging technologies in diagnosing, staging and monitoring patients with cancer, including positron emission tomography, magnetic resonance imaging (MRI) and CT Effectiveness of film-screen or digital mammography alone and mammography plus MRI in community practice–based screening for breast cancer in high-risk women of different ages, risk factors, and race or ethnicity Effectiveness of management strategies for localized prostate cancer (e.g., active surveillance, radical prostatectomy [conventional, robotic and laparoscopic], and radiotherapy [conformal, brachytherapy, proton-beam and intensity-modulated radiotherapy]) on survival, recurrence, side effects, quality of life and costs Effectiveness of surgical resection, observation or ablative techniques on disease-free and overall survival, tumor recurrence, quality of life and toxicity in patients with liver metastases Effectiveness of genetic and biomarker testing and usual care in preventing and treating breast, colorectal, prostate, lung, and ovarian cancers, and possibly other clinical conditions for which promising biomarkers exist.

Cancer was one of the 14 priority conditions set out by the HHS Secretary in 2008. Hence it is emphasized in the IOM report (Table), as well as in the Council report. “The report is meant to address the fear that if one treatment comes out ahead, the other treatments will be denied,� remarked Sheldon Greenfield, MD, professor of medicine at University of California, Irvine, and co-chair of the IOM committee that produced the report. “If one treatment is found to work well, and another treatment works only somewhat better, then both treatments will be available. CER isn’t about denying treatments, it’s about making sure all types of patients are appropriately treated.� AHRQ is expected to publish solicitations for research projects in fall 2009, and funding will commence in spring 2010. The agency announced that it is suspending the appeals procedure for investigators applying for grants “due to the time sensitivity of the Recovery Act granting process.� At press time, neither the HHS nor the NIH had revealed when grant solicitations would be made or when funding will start to flow.

What Does This Mean for You? While the particulars of the grant solicitations are being worked out, there is little for clinicians across the country to do but wait. Gary Lyman, MD, MPH, examined oncology CER in the July issue of Cancer Investigation (2009;27:593-597). In the article, Dr. Lyman, editor-in-chief of the journal, chair of four ASCO guidelines committees and a member of the FDA’s Oncology Drug Advisory Committee, lays out how systematic reviews, prospective clinical trials, longitudinal registries, comparative effectiveness simulations and clinical practice guidelines can deliver the apparent intent of the Obama initiative, which is to optimally inform clinical decisions. “But first, we have to carefully define what comparative effectiveness research is,� said Dr. Lyman, who is also professor of medicine and director of Health Services, Effectiveness and Outcome Research at Duke University School of Medicine and Duke Comprehensive Cancer Center, in Durham, N.C. “And No. 2, let’s make sure there’s no hidden issues here,� he said. “Let’s make sure there’s no subterfuge for rationing drugs, or for funding your research.� —Rosemary Frei, MSc

A

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SOLID TUMORS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

Breast

TAMOXIFEN continued from page 1

outcomes. “It is my position that clinical testing for CYP2D6 is indicated for all women with hormone receptor-positive breast cancer who are planning to take tamoxifen,� Dr. Barnett said. Taking the opposing view, Janet L. Espirito, PharmD, of US Oncology, Inc., The Woodlands, Texas, countered that all but one of these studies were retrospective, with small numbers of patients, conflicting results and variable methodology. Dr. Espirito added that without prospectively validated data from large, randomized controlled trials, recommendations for routine testing for CYP2D6 are premature. “I take the con view, that clinical testing for CYP2D6 is not indicated for all patients with HR-positive breast cancer who are planning to take tamoxifen,� she said. Dr. Barnett told HOPA delegates that CYP2D6 testing can categorize patients into one of four phenotypic groups: poor, intermediate, extensive or ultra-rapid metabolizers. The majority of patients fall into the extensive metabolizer category, closely followed by intermediate metabolizers. Poor metabolizers—women with the *4 variant of the CYP2D6 gene—are the ones who have the worst outcomes with tamoxifen therapy. “Polymorphism frequencies vary by race and ethnicity,� Dr. Barnett said. “The most common nonfunctional allele is the *4 allele in the Caucasian population; in the African population, it is the *17 allele; and in the Asian population, it is the *10 allele.� To support his argument, Dr. Barnett detailed several studies that evaluated the importance of the *4 variant and clinical outcome in white and Asian women. “Two studies by Matthew P. Goetz and colleagues at Mayo Clinic in Rochester, Minn., have contributed a great deal of clinical information in this area,� he said. The first (J Clin Oncol 2005;23:93129318, PMID: 16361630), a retrospective analysis of a prospective clinical trial of 223 estrogen receptor-positive postmenopausal patients receiving five years of adjuvant tamoxifen therapy with or without an aromatase inhibitor, found that poor metabolizers who were homozygous for *4 had reduced relapse-free time (P=0.023) and disease-free survival (P=0.012) compared with extensive metabolizers who were homozygous for the wild-type allele (wt/wt) and intermediate metabolizers who were heterozygous (wt/*4). A second study by Goetz et al (Breast Cancer Res Treat 2007;101:113-121, PMID: 17115111) re-analyzed 180 of these patients, incorporating concomitant use of CYP2D6 inhibitors and found that patients who were poor metabolizers, either as a result

of concomitant medication or polymorphism or both, had significantly reduced times to recurrence (P=0.034) and relapse-free survival (P=0.017) compared with patients who were deemed extensive metabolizers. A third trial, a cohort study of 85 tamoxifen users in the Netherlands (Breast Cancer Res Treat 2009 Feb 3 [Epub ahead of print], PMID: 19189212) found that patients who were deemed to be poor metabolizers had significantly worse breast cancer mortality compared with patients who were extensive metabolizers. Several studies have also evaluated the importance of the *10 allele in the

“I hope I’ve convinced you with these data that there are many trials that have shown and identified patient populations that have poor outcomes due to specific polymorphisms in CYP2D6,� Dr. Barnett concluded. “In my opinion, we should be testing anyone who receives tamoxifen. There are many studies to back up these recommendations.�

Supportive Studies Lack Weight “While the data that were presented are definitely thought-provoking and compelling, the majority of the studies were retrospective and included small numbers of patients,� Dr. Espirito said

‘Many trials ‌ have identified patient populations that have poor outcomes due to specific polymorphisms in CYP2D6.’ —Chad M. Barnett, PharmD

Asian population and found similar results in poor metabolizers. Investigators in China (Ann Oncol 2008;19:1423-1429, PMID: 18407954) analyzed the records of 152 patients who received tamoxifen in the adjuvant setting and found that patients who were poor metabolizers due to

in her argument against routine CYP2D6 testing. “The patient population was also varied and included pre- and postmenopausal women, and we know that age and menopausal status can influence outcomes.� She pointed out that the majority of the studies had been carried

‘Drugs such as SSRIs, if used with tamoxifen for depression or hot flashes, can reduce tamoxifen’s efficacy, and the studies cited by Dr. Barnett did not adequately account for such concurrent therapy.’ —Janet L. Espirito, PharmD

the CYP2D6 *10 allele had significantly reduced disease-free survival compared with patients who were extensive or intermediate metabolizers (P=0.04). A Japanese study of 67 HR-positive women (Cancer Sci 2008;99:995-999, PMID: 18294285) found significantly shorter recurrence-free survival in the poor metabolizers compared with the extensive metabolizers (P=0.036). In the one prospective study that has been done (J Clin Oncol 2007;25:38373845, PMID: 17761971), 21 HR-positive patients with metastatic breast cancer who were poor responders had a time to progression that was five months, versus 22 months for extensive responders (P=0.0032).

out in the adjuvant setting, thus making it difficult to control for the variability of the treatment the patients received. “In some of the trials, patients were randomized to chemotherapy versus no chemotherapy, radiation versus no radiation, tamoxifen versus no tamoxifen, so there was a great deal of variability there.� Two of the trials actually showed improved recurrence-free survival in patients who were poor metabolizers, she said. “And so we all know the challenges of retrospective studies, with small numbers of patients, and the challenge of controlling for confounding variables. Although some of the studies controlled for various factors, not all controlled for variability in patient and tumor characteristics that

might place a patient at higher risk. Nor did they control for the diversity of the treatments that were received.� Compliance with drug therapy and potential drug interactions were not mentioned in these studies—a lapse that makes recommending routine testing problematic, Dr. Espirito said. “Tamoxifen is an oral therapy. It obviously is not going to work in patients who don’t take it. Compliance and drug interactions are two [variables] that are very difficult to assess retrospectively.� She added that the use of concomitant medications also can influence results— especially those that decrease the activity of CYP2D6. “Drugs such as SSRIs [selective serotonin reuptake inhibitors], if used with tamoxifen for depression or hot flashes, can reduce tamoxifen’s efficacy, and the studies cited by Dr. Barnett did not adequately account for such concurrent therapy.� Other enzymes are involved in the metabolism of tamoxifen, not just CYP2D6. Additionally, the strength of estrogen or progesterone positivity, and the potential for crosstalk with other receptors make it unlikely that the acquired resistance to tamoxifen that occurs over time is a result of a single polymorphism, she said. There also are practical aspects to consider, Dr. Espirito argued. “Just because a test is available, does that mean we should use it?� It is important to ask whether knowing the results of the test will change treatment decisions. In the case of tamoxifen and HR-positive breast cancer, this is unlikely, she said. “Specifically in the adjuvant setting for premenopausal women, tamoxifen is the standard of care and there is no proven treatment alternative.� As for postmenopausal women, “most people are prescribing aromatase inhibitor therapy. If we are using aromatase inhibitors up front anyway in these patients, we may not need to do testing. Tamoxifen metabolism is not simple. CYP2D6 testing holds a lot of promise, but we need more prospective, validated data before it goes prime time.� —Fran Lowry

What’s Your View? =?6;A

@5.?2

?20<::2;1

2 :.69

0<::2;A

Do you think patients should be tested for CYP2D6 before taking tamoxifen? Have you gotten questions from patients and how do you handle them? We’d like to hear from you. Please send letters to the editor to

korourke@mcmahonmed.com

7

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FDA NEWS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

ODAC Vote Against Yondelis Dissected T he FDA’s Oncologic Drugs Advisory Committee (ODAC) panel has voted 14 to 1 against approval for trabectedin (Yondelis, Centocor Ortho Biotech) in combination with doxorubicin hydrochloride liposome injection (DOXIL, Centocor Ortho Biotech) for the treatment of patients with relapsed ovarian cancer. At the ODAC meeting, representatives of Ortho Biotech stated that the drug in combination with DOXIL increased

progression-free survival (PFS) to six Institute in Rockville, Md., summed up I have no doubt that there is a benefit weeks. Citing concerns about toxicity and concerns about the drug. “My ‘no’ vote is there—the real question is do we really the methodology used in the registration not a no for this drug, but as other peo- have a significant benefit.� Centocor Ortho Biotech Oncology trial, however, a vast majority of ODAC ple have said, it is a no for the timing of panelists voted against approval. The this application,� Dr. Wilson said. “We Research & Development approached sole vote in favor of the combined thera- are being asked to look at progression- the FDA to open a new drug applicapy came from patient representative Mar- free survival after the study was origi- tion for trabectedin in April 1996. In Sepnally written to look for overall survival. tember 2004, the agency and applicant tha Holland, of Southport, N.C. At the meeting, Wyndham Wilson, MD, And we’re being asked to accept a P val- agreed to use overall survival as the end head of the Lymphoma Therapeutics Sec- ue as predictive of a benefit. And I think point for benefit analysis. However, in tion of the Metabolism Branch, Center for that we’ve learned over the years that just 2006, after 68% of the patients in the Cancer Research at the National Cancer because we have a small benefit—and study were randomized, the applicant

SOLID TUMORS Colon High-risk patientsa Intermediate-risk patientsa

GENE ASSAY

Low-risk patientsa a

continued from page 1

of the American Society of Clinical Oncology (ASCO; abstract 4000), Dr. Kerr said that the multivariate analysis in which the recurrence score retained significance included mismatch repair, T stage, nodes examined, tumor grade and lymphovascular invasion.

Need for Improvement Because only 70% to 80% of patients with stage II CRC are cured by resection, clinicians have long been interested in trying to identify which patients may benefit from adjuvant chemotherapy. In 2007, investigators published results from the QUASAR study that randomized 3,329 patients, after apparently curative resection of colorectal cancer, to treatment with 5-fluorouracil and leucovorin (5-FU/LV) or observation (Lancet 2007;370:2020-2029, PMID: 18083404). Assuming that the five-year mortality rate without chemotherapy is 20%, the relative risk of death translated into an absolute improvement in survival of 3.6% (95% confidence interval [CI], 1.0%-6.0%). Because of the small improvement in survival, treatment cost and significant toxicities associated with 5-FU/LV, use of this therapy has not become standard practice. The concept that recurrence risk is at least partly mediated by genetic vulnerability led investigators to attempt to identify a gene profile that might be useful in predicting recurrence and identifying patients who could benefit from adjuvant chemotherapy. From a multicenter collaborative effort, 48 genes were identified that had a significant association with increased risk for recurrence of CRC. Another 66 genes were found to predict response to 5-FU/LV. For the current validation study, these were subsequently whittled down to seven prognostic genes and six genes predicting therapeutic response. The validation study used tumor blocks collected during the course of the QUASAR study (from 68% of the participants). Gene expression was evaluated by reverse transcriptase-polymerase chain reaction (RT-PCR) on paraffin-embedded primary colon cancer tissue. Based on a gene profile for recurrence that emerged from analysis of the tissue samples from previously conducted studies, the investigators tested the prognostic value of a prospectively defined recurrence score in an independent set of patients from QUASAR. Similarly, they tested whether a prespecified gene profile that assessed response to 5-FU/LV could predict

25

Risk for Recurrence, %

8

Risk categories are determined according to gene profile.

22

20

18

15

12 10 5 0

Figure. Comparison of risk for recurrence using gene profile.

‘This is the first study of a prospectively defined recurrence score that has been validated as a predictor of recurrence in stage II CRC following surgery. We showed that it has independent predictive value beyond previously available measures.’ —David J. Kerr, MD

protection from recurrence.

A Tool Emerges Of 1,490 tumor blocks collected from stage II colon cancer patients in QUASAR, 1,436 met all inclusion and exclusion criteria for the study and were subsequently analyzed by quantitative RT-PCR. When the prespecified range of recurrence scores was stratified into low, intermediate and high risk, the recurrence rate at three years was approximately twice as high in the high- versus low-risk groups (22% vs. 12%) at three years. The intermediate-risk group had a recurrence rate of 18%. In contrast, gene expression predicting response to

5-FU/LV was not validated as a useful tool for identifying patients likely to benefit from this therapy. The investigators analyzed other predictors of recurrence in the context of the gene signatures and found independent predictive value from mismatch repair deficiency, which was associated with a 69% reduction in the risk for recurrence (hazard ratio [HR], 0.31; 95% CI, 0.15-0.63; P<0.001), and stage T4 tumors, which were associated with a 94% increased risk for recurrence (HR, 1.94; 95% CI, 1.35-2.79; P=0.005). Going forward, Dr. Kerr suggested that these two factors might improve the clinical utility of the gene profile in identifying patients who might benefit from adjuvant chemotherapy. According to Ed Chu, MD, who was not involved with the study, the study is the first to show that a prospectively defined gene assay can independently predict disease recurrence following surgery in patients with stage II colon cancer. “This multi-gene assay may help patients at increased risk for disease recurrence and may be most useful in patients for whom conventional risk assessment parameters, such as T stage or microsatellite instability, are uninformative,� commented Dr. Chu. He is chief of the Section of Medical Oncology and deputy director of clinical research at the Yale Cancer Center, Yale University School of Medicine, New Haven, Conn. Although the results from this study are encouraging, other researchers are more cautious in what they actually mean for patients. Charles S. Fuchs, MD, director of the gastrointestinal malignancy program at Dana-Farber Cancer Institute, in Boston, cautioned that “it is too early to know whether this gene profile should be part of routine management.� In particular, although a high recurrence score was able to identify a patient population that had an increased likelihood of a recurrence, no prospective evidence exists that adjuvant treatment with 5-FU/LV or another therapy would have reduced this risk. Studies demonstrating that acting on prognostic information can change the course of disease are needed, he said. Although Dr. Fuchs agreed with the premise that individualized care is likely to improve outcomes in CRC, he noted that few of the “ever increasing number of candidate biomarkers� have been validated in their ability to guide management so that patient outcomes improve. It’s possible, however, that gene profiling could provide greater prognostic value than biomarkers and thus improve patient care. Despite the promise of this gene validation study, Dr. Fuchs said that the benefit of offering adjuvant chemotherapy in high-risk patients still must be proven in a prospective study. —Ted Bosworth

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FDA NEWS

CLINICAL ONCOLOGY NEWS DIGITAL EXCLUSIVE • SEPTEMBER 2009

asked the FDA to switch the end point Manufacturers of America will be held on to PFS. John Seaman, PharmD, senior Oct. 7-9, in Bethesda, Md. Panelist Gary H. Lyman, MD, MPH, a director of Regulatory Affairs at Centocor Ortho Biotech Oncology Research & medical oncologist at Duke University Development, said the request to change in Durham, N.C., said he was concerned the end point was made based on the about toxicities reported in the trabectFDA/ASCO/AACR end points workshop edin arm of the trial. “There was a fairfor ovarian cancer and subsequent to an ly dramatic increase in grade 4 toxiciapproval of gemcitabine (Gemzar, Eli ties, and we were very concerned that Lilly) and carboplatin for relapsed ovar- the data was premature to recommend ian cancer patients after a trial demon- approval,� he said. The FDA review of the trial revealed strating improvement in PFS. Panelist David P. Harrington, PhD, pro- that grade 3 to 4 neutropenia was three fessor of biostatistics at Harvard School times more frequent, febrile neutropeof Public Health, in Boston, called an nia was four times more frequent, and end point shift after a trial starts “very grade 3 to 4 thrombocytopenia was six rare.� He said that doing so creates times more frequent in the combination “issues that don’t indicate that the spon- therapy arm. Among patients receiving sor did anything wrong, but that the data trabectedin, six cases met Hy’s law crihad a lot of weaknesses.� Dr. Harrington teria for hepatic toxicity; no cases were said that using PFS as a surrogate end seen in patients receiving the monotherpoint in cancer evaluation is complicat- apy. Cardiac events were three times as ed, because of the difficulties in measur- common in patients receiving trabectedin, and included six patients who had ing disease progression. “If a sponsor is trying to get a sense congestive heart failure. Dr. Lyman said of whether an agent works or a combi- that these potential risks, when paired nation therapy works, progression-free with the questionable benefit offered by survival can be a marker for whether or a trial with a shifting end point, left him not a drug is active, but registration is a with too many questions. Now, the FDA must make a decision— different sort of thing,� he said. “You’d like to put something on the label that is it usually, but not always, follows the a reliable number that has been tested.� recommendations from ODAC. “We Dr. Harrington noted that a Progres- make a recommendation to the FDA, sion-Free Survival Workshop organized and they can take it or leave it,� Dr. by the Drug Information Associa- Lyman said, “although with a 14-1 vote, tion, FDA, National Cancer Institute, it would be unusual for the FDA to and Pharmaceutical Research and move forward with a routine approval

with the current information.� Lisa Vaga, director of Oncology/Hematology Communications at Centocor Ortho Biotech, said the company still has hope for the drug. “Ovarian cancer is difficult to treat and the disease often recurs in patients who previously have been treated with platinum-based therapy, underscoring the need for non-platinum treatment options,� she said. “We continue to believe that trabectedin has an important role in the treatment of relapsed ovarian cancer. The company remains committed to working with the FDA to address the advisory committee’s concerns.� —David Jakubiak

bevacizumab plus interferon-alfa compared with 5.4 months in patients who received interferon-alfa alone (hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.49-0.72; P<0.0001). The independent review committee analysis of 569 patients with radiographs available for review yielded similar results (median PFS of 10.4 compared with 5.5 months; HR, 0.57; 95% CI, 0.45-0.72). The study was originally designed to measure an improvement in overall survival (OS). However, in earlier consultation with the FDA and European regulatory authorities, the primary end point was changed to assess improvement in PFS. Secondary end points included objective response rate and OS. In this study, tumor size decreased in 30% of patients in the bevacizumab plus interferon-alfa group, compared with 12% of he FDA has approved bevacizumab patients who received interferon-alfa (Avastin, Genentech) plus interfer- alone. There was no statistically significant improvement in OS on-alfa for the treatbased on the final analysis ment of patients with after 444 deaths. metastatic renal cell The most common severe carcinoma (mRCC). adverse events (grade 3 to The approval is based 5) that occurred at a highon data from a randomer rate (at least 2% more ized, double-blind, plaoften) in patients who cebo-controlled Phase received bevacizumab plus III study (AVOREN) of 649 patients with previously untreated interferon-alfa than in the interferonalfa only group included fatigue (13% vs. mRCC. The study showed that median pro- 8%), weakness (10% vs. 7%), protein in gression-free survival (PFS) was 10.2 the urine (7% vs. 0), hypertension (6% vs. months in patients who received 1%) and bleeding (3% vs. 0.3%).

Bevacizumab Approved for mRCC

T

PEOPLE AND PLACES

Around the Water Cooler People on the Move Nicholas Vogelzang, MD, has moved from his position as director of the Nevada Cancer Institute (NVCI) to the Comprehensive Cancer Centers of Nevada, both in Las Vegas, where he will serve as a medical oncologist. He also will serve as chair and medical director of the Developmental Therapeutics Committee and member of the Genitourinary Committee for US Oncology Research. Dr. Vogelzang was director of the NVCI from 2004 to 2009. His prior experience includes serving as a faculty member at the University of Chicago and later as the director of the University of Chicago Cancer Research Center. John Ruckdeschel, MD, has accepted the position of chief executive officer (CEO) and director of the Nevada Cancer Institute, Las Vegas. He is a nationally

known lung cancer researcher. Dr. Ruckdeschel was formerly the CEO of the Barbara Ann Karmanos Cancer Institute, Detroit. Before that, he was director and CEO at the H. Lee Moffitt Cancer Center and Research Institute at the University of South Florida in Tampa, Fla. Debasish (Debu) Tripathy, MD, has accepted a position at the University of Southern California’s (USC) Norris Comprehensive Cancer Center, Los Angeles. He will hold the Art and Priscilla Ulene Chair in Women’s Cancer and will head the Women’s Cancers Section in the Division of Oncology. Dr. Tripathy previously worked at the University of Texas Southwestern

9

Medical Center, Dallas, where he served as professor of internal medicine, director of the Komen/UT Southwestern Breast Cancer Research Program and where he held the Annette Simmons Distinguished Chair in Breast Cancer Research. He also was president and CEO of Physicians’ Education Resource in Dallas, a continuing medical education and publishing company specializing in oncology and hematology.

ASTRO Picks Honorary Member The American Society for Radiation Oncology (ASTRO) has selected worldrenowned neurosurgeon Philip H. Gutin, MD, as its honorary member for 2009. Dr. Gutin will be honored at the awards ceremony on Nov. 3, 2009, during ASTRO’s 51st annual meeting in Chicago. Dr. Gutin has devoted his career to scientific and clinical investigations of the treatment of brain tumors and has collaborated with many of the world’s

leading radiation oncologists and radiation biologists in advancing this practice. He has been an associate member of ASTRO for 28 years. He is the chairman of the Department of Neurosurgery and the Fred Lebow Chair in Neuro-Oncology at Memorial Sloan-Kettering Cancer Center and professor of neurological surgery at Cornell University’s Weill Medical College, both in New York City. He previously held leadership positions at the University of California Medical Center in San Francisco. Dr. Gutin also has had leadership roles in several of the nation’s top medical organizations, including the Radiation Therapy Oncology Group, the American College of Surgeons, and the Neurosurgical Society of America. He has published close to 200 articles in peer-reviewed journals, co-authored two textbooks on radiation injury to the nervous system and the diagnosis and treatment of intracranial tumors, respectively, and has made innumerable presentations at medical meetings throughout his career.

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