TAP Vol 1 Issue 6

Triple–negative breast cancer 10

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NCCN patient guidelines 16

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VOLUME 1, ISSUE 6

Health-care reform 40

NOVEMBER 2010 ASCOPost.com

Editor-in-Chief, James O. Armitage, MD

35th ESMO Congress

‘Made in China’

Erlotinib More Than Doubles Progression-free Survival in Non–Small Cell Lung Cancer

By Caroline Helwick

I

n the phase III OPTIMAL study, which was conducted in China, first-line single-agent erlotinib (Tarceva) given to patients with advanced non–small cell lung cancer (NSCLC) extended median progression-free survival (PFS) to 13.1 months, a highly significant increase over a PFS of 4.6����������������� ���������������� months with gemcitabine/carboplatin, reported Caicun Zhou, MD, of Tongji University in Shanghai, at the 35th ESMO Congress, held October 8-12 in Milan, Italy.1 The study, which included a population expected to be sensitive to inhibitors of the epidermal growth

Erlotinib in NSCLC ■■ In the phase III OPTIMAL trial, median PFS

was increased from 4.6 months with standard treatment to 13.1 months with single-agent erlotinib.

factor receptor (EGFR), was the first trial to compare erlotinib head-tohead with a platinum doublet regimen. Investigators screened 549 patients with NSCLC for EGFR-activating mutations, requiring that patients have exon 19 deletions or exon 21 point Caicun Zhou, MD mutations, as these genetic variations are associated with particular sensitivity to anti-EGFR agents. They randomly assigned 165 patients to receive erlotinib (150 mg/d) or gemcitabine (1,000 mg/m2) plus carboplatin (AUC 5), which is standard first-line treatment for NSCLC in China.

Consistent Benefit In the intent-to-treat analysis, erlotinib reduced the risk of progression by 84% (P < .0001) over

■■ Erlotinib reduced the risk of progression by 84%, and benefit was consistent across all subgroups.

See page 52

continued on page 3

JCO Spotlight

Two Pivotal Studies Help Fine-tune Use of Panitumumab in Colorectal Cancer

By Caroline Helwick

T

wo important studies recently published online in the Journal of Clinical Oncology have clarified the role of panitumumab (Vectibix) in metastatic colorectal cancer (mCRC). Panitumumab, a fully human monoclonal antibody against the epidermal growth factor recepJean-Yves Douillard, MD tor (EGFR), was effective in both the first- and second-line settings when combined with chemotherapy in patients with wild-type (WT) KRAS tumors, but not in patients with mutated (MT) KRAS. The findings underscore the importance of KRAS testing in patients with mCRC and tailoring treatment accordingly, as this agent enters the treatment armamentarium.

The PRIME study, led by Jean-Yves Douillard, MD, was an international open-label phase III trial in

1,183 mCRC patients with no prior chemotherapy for metastatic disease.1 Patients were randomly assigned to receive FOLFOX4 (infusional fluorouracil [5-FU], leucovorin, and oxaliplatin) every 2 weeks alone or FOLFOX4 plus panitumumab, 6.0 mg/kg, every 2 weeks until disease progression.

The study was originally designed to test the treatment effect in all patients, but was amended to compare progression-free survival (PFS), the primary endpoint, and overall survival (OS) according to KRAS status. Patients were followed for a median of 11 to 13 months.

Outcomes were prospectively analyzed on an intent-totreat basis by tumor KRAS status, which was available for 93% of the patients.

In patients with WT KRAS, median PFS was significantly improved with the addition of panitumumab (Fig. 1), from 8.0 months with FOLFOX4 alone to 9.6 months with the addition of panitumumab (P = .02). A nonsignificant increase in OS was also observed,

By Tony Mok, MD

W

hat do a pair of Nike sneakers, a pair of Levi’s jeans, and a global-scale lung cancer trial have in common? They are all either solely or partly produced in China. But while we may be perfectly comfortable in our Nikes and Levi’s, we may not be so at ease with a clinical trial that can change the daily management of lung cancer patients. Thus, it is important to recognize and understand the ability and status of lung cancer clinical research in China.

Clinical Trial Triad Investigator, sponsor, and patient are the three essential participants in any clinical trial, but each has his/her own motivation for participation. The primary objective of the investigator should be scientific advancement. However, the coprimary objective closely linked to scientific advancement is publication in high-impact, peer-review journals. Investigators in academic medicine need to publish in order to sustain their credentials and advance their careers. The same principle applies in China. Until the past decade, Chinese investigators could publish in local journals and still get continued on page 2

Dr. Mok is Professor in the Department of Clinical Oncology, The Chinese University of Hong Kong, China, and is a member of The ASCO Post’s International Editorial Board.

MORE IN THIS ISSUE Oncology Meetings Coverage

35th ESMO Congress �������1, 3, 8, 17, 20 AACR International Conference ����18, 19 2010 Breast Cancer Symposium �����10, 11 Best of ASCO ���������������������������� 33, 35, 38 Direct from ASCO ������������������������������������ 21 Maintenance chemo in NSCLC �������������� 54

continued on page 6

A Harborside Press Publication

The ASCO Post | NOVEMBER 2010

PAGE 2

Perspective

‘Made in China’ continued from page 1

Conor Lynch, Executive Editor Conor@harborsidepress.com

Wendy McGullam, Director of Production Wendy@harborsidepress.com

Cara H. Glynn, Director of Editorial Cara@harborsidepress.com

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recognition, but this practice is no longer acceptable. International publication has become a cornerstone for academic promotion in China, and thus, Chinese investigators are now highly motivated to participate in high-quality clinical studies.

The sponsors generally are the pharmaceutical companies, and they undoubtedly share an interest in scientific advancement. However, their primary objective for sponsoring a clinical trial must be drug approval. This is the only way for a new drug to become commercially available and the business investment to be viable.

The Chinese pharmaceutical market was worth over $40 billion in 2004 and continues to grow at a rapid rate of 16% to 18% annually. International pharmaceutical companies hold less than 20% of the market share, and the domestic pharmaceutical companies hold the rest. The only way for international pharmaceutical companies to gain a bigger share is to invest in new drug development and clinical trials in China. Multiple pharmaceutical companies including Roche, AstraZeneca, and Pfizer have established R&D facilities in China. They are well equipped and highly motivated to conduct clinical trials in China.

Scientific advancement is certainly not the prime reason a lung cancer patient agrees to participate in a clinical trial. The patient’s motive is usually the hope that an experimental drug will control the cancer and improve his chance of survival. For certain underprivileged populations, participation in a clinical trial may be the only means of receiving therapy. China has the world’s second largest economy—second only to the United States—but universal health care is not accessible to a large portion of its population. Only a small fraction of the cost of running governmentowned hospitals comes from the Chinese government. The majority is raised from direct charges to insurance companies and patients. And the majority of patients from impoverished regions will simply not be able to afford any of the expensive anticancer drugs. Clinical trials are their only hope.

Andrew Nash, Associate Director of Editorial Andrew@harborsidepress.com

Anthony Cutrone, President Anthony@harborsidepress.com

Lung Cancer Research in China

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

John A. Gentile, Jr., Chairman Jack@harborsidepress.com

Editorial Board James O. Armitage, MD Editor-in-Chief

William T. McGivney, PhD, National Comprehensive Cancer Network

Elizabeth Reed, MD Deputy Editor Division of Hematology & Oncology University of Nebraska Medical Center Omaha, Nebraska

James L. Mulshine, MD Rush University Medical Center

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University

Richard Boxer, MD University of Miami

Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University

Harold J. Burstein, MD Dana-Farber Cancer Institute

Lynn D. Wilson, MD Yale University School of Medicine

Robert W. Carlson, MD Stanford University Medical Center

Stanley H. Winokur, MD Singer Island, Florida

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

Michael P. Link, MD Stanford University Medical Center

Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan

John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press Publishing Staff

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Laurie Fisher, Alice Goodman, Caroline Helwick, Larry Rosenberg, PhD, Matthew Stenger

Contributing Artists: Alexandra and David Baker, DNA Illustrations; Portraits by Keith Witmer, Keith Witmer Illustrations

Financial disclosure information available at ASCOPost.com.

Lung cancer is the most fatal malignancy in China. There are over half a million new cases annually, which is about three times the number in the United States. The World Health Organization estimates the smoker prevalence rate in China to be 36%, and the total number of smokers has been rising steadily, estimated at 350 million in 2009. This im-

plies that the incidence of lung cancer will continue to rise in the coming decades.

Thus, sponsors would have a huge interest in this market and in this patient pool for clinical trials.

Over the past decade, Chinese investigators have contributed a significant portion of the enrollment in global lung cancer studies. For example, China enrolled 372 patients (31%) to the landmark Iressa Pan Asia Study (IPASS) that defined the role of gefitinib (Iressa) as standard first-line therapy for pulmonary adenocarcinoma with EGFR mutation.

The data from China is of world-class quality, with less than a 3% deviation from protocol. Given favorable experience and meaningful contributions to major trials, China has become an important partner in many large-scale global studies on lung cancer.

For certain underprivileged populations, participation in a clinical trial may be the only means of receiving therapy.

In Conclusion Investigators are motivated, sponsors are obligated, and patients are attracted to participate in lung cancer clinical trials in China. Based on the experience from major global studies in the past decade, research centers in China have developed high-quality infrastructure and research staffs. The Chinese Thoracic Oncology Group (CTONG) was founded by five research centers in 2007. Since then, the group has grown into a moderate-sized study group with 15 active centers and has activated 9 clinical trials over the past 3 years. Among these investigations, the OPTIMAL study—now completed—is a randomized phase III study comparing erlotinib (Tarceva) and chemotherapy in pulmonary adenocarcinoma associated with EGFR mutation. The results of this study were presented at this year’s ESMO (see page 1).

Being comfortable in a pair of jeans or sneakers manufactured in China is now a routine part of daily living. In the future, I believe we will come to accept that China is also equipped to conduct high-quality clinical research that will likely make a difference to many lung cancer patients around the world.

■

ASCOPost.com | NOVEMBER 2010

PAGE 3

35th ESMO Congress Erlotinib More Than Doubles Progression-free Survival in NSCLC continued from page 1

gemcitabine/carboplatin. All subgroup analyses heavily favored erlotinib, with hazard ratios ranging from 0.13 to 0.27.

“Consistent benefit was observed regardless of histology, smoking history, age, gender, or disease stage,” Dr. Zhou reported.

In addition to improvements in PFS, the erlotinib-treated patients also had a significantly higher response rate (83% vs 36%; P < .0001) and disease control rate (96% vs 82%; P = .002). The overall survival data are not yet mature.

Erlotinib was highly effective regardless of the mutation type as well, though longer PFS was observed in patients with exon 19 deletions. Baseline c-MET amplification status was not predictive of efficacy in either arm.

Safety Data Safety data confirmed the favorable tolerability profile of erlotinib, with a lower incidence of adverse events and serious adverse events vs gemcitabine/

carboplatin. However, grade 1-2 rash was observed in about 70% of patients receiving the EGFR inhibitor. Grade 3-4 rash was rare, and there were no unexpected toxicities.

After the presentation, Tony Mok, MD, who led the pivotal IPASS trial (see story below) of gefitinib (Iressa), commented from the audience that OPTIMAL was “an excellent study” that produced “an outstanding hazard ratio.” He added, “Although the PFS of the control arm at 4.6 months is shorter than expected, I have no doubt that this is a significantly positive trial.”

■

References 1. Zhou C, Wu Y-L, Chen G, et al: Efficacy results from the randomized phase III OPTIMAL (CTONG 0802) study comparing first-line erlotinib versus carboplatin plus gemcitabine in Chinese advanced non-small cell lung cancer patients with EGFR activating mutations. 35th ESMO Congress. Abstract LBA13. Presented October 9, 2010.

2. Maemondo M, Inoue A, Kobayashi K, et al: Gefitinib or chemotherapy for non-small-cell lung cancer with mutated EGFR. N Engl J Med 362:2380-2388, 2010.

Expert Point of View

F

ederico Cappuzzo, MD, of the Istituto Toscano Tumori in Livorno, Italy, discussed the OPTIMAL study of erlotinib at the recent ESMO meeting, first noting that the other small molecular EGFR inhibitor, gefitinib, has generally become standard treatment today for metastatic NSCLC with activating EGFR mutations, based largely on studies in Asian populations. Data are needed for other populations, he added, pointing out that two Federico Cappuzzo, MD important trials are now underway. OPTIMAL studied erlotinib in Asians as well, and benefit was shown in all subgroups, he noted, “including those who usually do worse, such as males, smokers, and persons with nonadenomatous tumors.”

“This gives us important clinical information,” he said. “It means it does not matter what the clinical characteristics are—whether male or female, smoker or not, adenomatous or not—and it probably does not matter whether the patient is Asian or Caucasian. What is important is tumor biology, and specifically the presence of an activating EGFR mutation. In addition, the data on skin toxicity were interesting, in that the incidence of grade 3 toxicity was incredibly low—just 2%. This is less than seen in other erlotinib trials, and is comparable to what we see with gefitinib in trials of similar patient populations.”

In gefitinib trials, median PFS is long—up to 10.8 months, with a 0.30 hazard ratio2—but Dr. Cappuzzo commented that the 13-month PFS with erlotinib is “incredible.” He concluded that these results “potentially suggest erlotinib may be superior to gefitinib, but a direct comparison of the drugs that allows us to conclude this has yet to be conducted.”

■

Gefitinib Fails to Improve Survival in IPASS Trial

By Caroline Helwick

I

n the final analysis of the pivotal IPASS trial,1 overall survival, which was a secondary endpoint, was similar for gefitinib and carboplatin/paclitaxel, reported Chih-Hsin James Yang, MD, of National Taiwan University Hospital and College of Medicine in Taipei, Taiwan.

“But the true effect of the initial randomized treatment on overall survival is likely to have been confounded by subsequent therapy—in particular, the switching of patients to the alternative study treatment,” Dr. Yang noted at the Presidential Symposium of ESMO 2010. “Only 31% of the gefitinib group and 38% of the chemotherapy group did not receive additional treatment,” he emphasized. In fact, about 40% received two more regimens post-study.

The Iressa Pan-Asia Study (IPASS) included 1,217 Asian patients with NSCLC, and the study population was clinically enriched for sensitivity to anti-EGFR–tyrosine kinase therapy. The main analysis demonstrated robust See page 52

results for gefitinib in patients with mutated EGFR2 and essentially changed clinical practice for this subset of patients with NSCLC. In the 2010 updated survival analysis of the intent-to-treat population, median overall survival was 18.8 months with gefitinib and 17.4 months with standard chemotherapy (HR = 0.90; P = .109). Patients known to be EGFR mutation–positive also demonstrated no overall survival differences according to treatment, and no clinical or biomarker subgroup was predictive of better overall survival with gefitinib, Dr. Yang reported. “This is for the first time, a matured overall survival analysis is reported in a large randomized phase III study comparing an first-line EGFRTKI with combination chemotherapy.”

The study validated, however, that positive EGFR mutation status is predictive of good outcomes with gefitinib over chemotherapy in terms of PFS, response rate, and health-related quality of life, he added. IPASS also demonstrated the importance of biomarker testing in NSCLC, “making a significant step toward personalized medicine.”

EGFR Mutation Positivity a Good Sign Jean-Charles Soria, MD, of Gustave Roussy Institute in Villejuif, France, suggested another reason for the similar survival outcomes in IPASS, apart from subsequent post-study treatment. “EGFR mutation positivity is not only a predictive marker [for good results with gefitinib] but a prognostic marker as well,” he said.

Dr. Soria pointed out that patients with an EGFR mutation seem to have an intrinsically good prognosis compared to patients without the mutation. Of additional benefit, their less aggressive tumors allow such patients to undergo multiple lines of therapy, he noted.

“It is not the sequence of therapy that counts but the fact that such patients are exposed to an EGFR tyrosine kinase inhibitor in general, and whether it is given first-line or later translates into the same overall survival. There is no relevance in delaying therapy if EGFR status is not available at the initial consultation, especially in symptomatic patients,” Dr. Soria maintained. Nevertheless, he advo-

Jean-Charles Soria, MD

cated using front-line gefitinib (rather than chemo) on the basis of superior symptom improvement, better quality of life, better PFS, and oral availability of the drug.

■

References 1. Yang C-H, Fukuoka M, Mok TS, et al: Final overall survival results from a phase III randomized, open-label, first-line study of gefitinib V carboplatin/paclitaxel in clinically selected patients with advanced non-small cell lung cancer in Asia.

35th ESMO Congress. Abstract LBA2.

Presented October 11, 2010.

2. Mok TS, Wu YL, Thongprasert S, et al: Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 361:947-957, 2009.

The ASCO Post | NOVEMBER 2010

PAGE 4

Expert’s Corner Lung Cancer

A Conversation with Paul A. Bunn, Jr, MD Personalized Medicine and Lung Cancer

By Laurie M. Fisher

L

ung cancer expert Paul A. Bunn, Jr, MD, Dudley Professor at the University of Colorado Cancer Center, Aurora, Colorado, spoke at the American Association of Cancer Researchers’ symposium “Molecular Diagnostics in Cancer Therapeutic Development: Challenges and New Horizons,” which was held recently in Denver. (See pages 18 and 19 for news from AACR.) Subsequently, he discussed his views on personalized medicine and lung cancer with The ASCO Post.

Paul A. Bunn, Jr, MD

Personalized Therapy Can you define what personalized care means to you?

Dr. Bunn: Personalized therapy can be an overused term that is misinterpreted and misused. In my view, you measure some properties of the patient’s tumor or genetic makeup and decide what treatment to use based on that information. One could argue that personalized therapy for breast cancer and prostate cancer, as formulated by measuring hormone receptor levels, has been around for some time. However, this has not been the case in lung cancer until recently.

At the moment, EGFR mutation and ALK fusion testing are “ready for prime time” in non–small cell lung cancer (NSCLC). Also, on the horizon, some new biomarker testing will identify chemotherapy sensitivity. Hopefully, more biomarkers will be discovered that will improve predictability of treatment response.

Paradigm Shift In your presentation, you refer to a paradigm shift in lung cancer therapy. Could you please discuss this paradigm shift and what it means to the oncology community?

Dr. Bunn: The paradigm shift stems from the fact that we used to treat everyone the same way, and we didn’t use information that came from the tumor to guide treatment. Now we need to analyze the tumor to select the best approach. The oncologist needs to work with the radiologist, surgeon, and pulmonologist to get an adequate biopsy that can be analyzed. Then a pathologist is consulted to find out which tests need to be ordered as part of the decisionmaking process.

Crizotinib Can you discuss the ongoing phase III trial of crizotinib in ALK-positive NSCLC and, in particular, when any data might become available?

Dr. Bunn: The phase III data won’t be available for several years. If phase I and phase II trials demonstrate impressive response rates and progression-free survival of more than 6 months, these data would far exceed historical comparison and thus may be appropriate

10 Key Facts about Personalized Therapy for NSCLC ■■ Tumors can be biopsied for molecular analyses.

■■ Reliable predictive biomarker results can be available in clinically relevant time frame (1-2 weeks).

■■ Molecular features trump clinical features.

■■ More predictive biomarkers are available for breast cancer than for lung cancer.

■■ More potential targets are available for lung cancer than for breast cancer.

■■ Some target populations, however, are small.

■■ Chemotherapy is antagonistic with many targeted therapies.

■■ Complete responses are rare.

■■ Resistance is still universal.

■■ Histology matters.

Courtesy of Paul A. Bunn, Jr, MD. AACR Symposium, September 2010, Denver.

for accelerated approval. So I’d hope the drug would be widely available before the phase III trial results are known.

ALK Assay Is it difficult to determine ALK activation at laboratories outside of the University of Colorado (or the other investigational sites)? What advice would you offer to oncologists at other institutions regarding the determination of ALK activation status in patients with lung cancer?

Dr. Bunn: Abbott has a commercial ALK test. This assay identifies activation of ALK by fusion with another gene, usually EML4, that turns ALK on. Many academic institutions and commercial laboratories have that capability. How-

ever, application of the ALK assay is limited because of restricted access to crizotinib, which is confined to clinical trials.

Immunohistochemistry for ALK overexpression and quantitative RT-PCR are also under evaluation as predictive tests.

Lung Cancer in Asian Women What is it about the biology of lung adenocarcinoma in Asian, nonsmoking women that makes their cancer so uniquely responsive to targeted therapy?

Dr. Bunn: We don’t know if this particular group’s cancer biology is the result of environmental factors or genetic tendencies. The frequency of EGFR mutations is much higher in Asian, nonsmoking women than in African or Cau-

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ASCOPost.com | NOVEMBER 2010

PAGE 5

Expert’s Corner

casian nonsmoking women. However, ALK fusion is the same worldwide. That means that either there is an ongoing genetic difference in susceptibility or this group has been exposed to a carcinogen that hasn’t been identified. Some investigators have theorized that there may be a connection with breathing in fumes when cooking over a stove. The question is, why do those fumes cause EFGR mutation in Asian women but don’t cause ALK fusion?

ought to know that patients should undergo genetic testing before initial treatment. These physicians need to work with colleagues to get an adequate biopsy. If they don’t know about these new options, they should call a colleague and/or attend a CME course. The days of giving treatment without understanding the genetics of the tumor are over.

The good news is that these new treatments are oral therapies that have far fewer side effects.

The number of oncologists educated in the new treatments is increasing, but not as quickly as anyone would want.

Key cancer center leaders are doing genetic testing, but if you survey community oncologists, the results are more

variable. Within the next year, the International Association for the Study of Lung Cancer and the College of American Pathology will issue guidelines for physicians about genetic testing. Such testing is already available in Clinical Laboratory Improvement Amendments (CLIA)-certified academic and commercial labs.

■

Improving Outlook What do you think is the most hopeful recent improvement in clinical outlook for patients with lung cancer?

Dr. Bunn: In the past 2 years, the most exciting thing has been the finding that patients with EFGR mutation have a 70% response rate to specific agents.

These oral agents have far fewer side effects than chemotherapy. Although these medications are not curative, patients may live longer and feel better.

That said, we still have a long way to go.

The most important factor in lung cancer incidence has been a decrease in smoking. As a result, the lung cancer mortality rate has fallen dramatically.

Like the screenings tests developed for breast cancer, we are developing tests that will be helpful for early detection, prevention, and better therapy. These improvements happen step by step and not with some huge overnight finding.

ASCO’s Role As a past ASCO President, what do you think ASCO can do (or is doing) to help further improvements in the prevention, early detection, and treatment of lung cancer?

Dr. Bunn: ASCO can inform the public and health-care professionals about advances in prevention, early detection, and treatment. Also, they should lobby Congress and other agencies to provide appropriate levels of funding, given the new opportunities for research. Funding for lung cancer is not in the same ballpark as funding for breast or prostate cancers.

In addition, ASCO can do more to increase educational efforts and fight tax incentives that currently promote tobacco use by Native Americans on reservations.

Closing Remarks What closing message would you like to share with ASCO members about personalized care in regard to lung cancer (or cancer care in general)?

Dr. Bunn: The average oncologist

Other pathways can contribute to prostate cancer promotion.5 References: 1. Montgomery RB, Mostaghel EA, Vessella R, et al. Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11): 4447-4454. 2. Locke JA, Guns ES, Lubik AA, et al. Androgen levels increase by intratumoral de novo steroidogenesis during progression of castration-resistant prostate cancer. Cancer Res. 2008;68(15):64076415. 3. Stanbrough M, Bubley GJ, Ross K, et al. Increased expression of genes converting adrenal androgens to testosterone in androgen-independent prostate cancer. Cancer Res. 2006;66(5):2815-2825.

4. Titus MA, Schell MJ, Lih FB, Tomer KB, Mohler JL. Testosterone and dihydrotestosterone tissue levels in recurrent prostate cancer. Clin Cancer Res. 2005;11(13):4653-4657. 5. Pienta KJ, Bradley D. Mechanisms underlying the development of androgen-independent prostate cancer. Clin Cancer Res. 2006;12(6):1665-1671.

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JCO Spotlight Colorectal Cancer

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A

1.0

Probability of progression-free survival

tus in patients with previously treated mCRC,” the authors noted. continued from page 1 The study randomly assigned 1,186 from 19.7 months to 23.9 months, repatients, with KRAS status available in spectively (P = .072), for an absolute 91%. The coprimary endpoints of PFS difference of 4.2 months, Douillard et al and OS were prospectively analyzed by reported. Skin toxicity was significantly KRAS status. Median follow-up was 9.5 related to outcome. to 13.3 months.

Interestingly, panitumumab exerted In the WT KRAS population, the an unfavorable effect in carriers of muaddition of panitumumab to chetated KRAS. PFS was 7.3 months with motherapy yielded a statistically sigthe combination vs 8.8 months with nificant 27% reduction in the risk of Median months Events FOLFOX4 alone, representing a 29% inprogression or death. Median PFS (95% CI) n (%) Median OS152was was 3.9 months with FOLFIRI alone crease in risk (P = .02).Panitumumab (69) 15.5 (13.1 to 17.6) 15.5 and 19.3 months,+respectively, for a but rose to 5.9 months with panituFOLFOX 142 (65) 19.3 (16.5 to 21.8) FOLFOX 24% increased risk (P = .068). mumab on board (HR = 0.73; 95% HR + 1.24 (95% CI, 0.98 to 1.57) “The study met its primary endpoint, CI = 0.59–0.90; P = .004). Median OS P = .068 PFS. Overall survival data are still imwas numerically but not significantly mature, with just 51% of events having improved from 12.5 months with occurred. The final analysis should be FOLFIRI to 14.5 months with the combination (HR = 0.85; 95% CI = presented at a later meeting,” Dr. Douil0.70–1.04; P = .12), and response rates lard, of the Centre René Gauducheau, were improved from 10% to 35%. The Nantes, France, told The ASCO Post. authors noted that this was the highest “But even with just half the events occur0 ring, 4 you8 see 12 16 20 36 rate reported in a random24 in 28 32 response a numerical difference (months) ized phase III second-line study. survival—aboutTime a 4-month benefit.” imbalance in subsequent He emphasized that the study pro221 211 199 183 168 145 125 114 100 91 76 58 37 29 18 10 4 “The 0 0 219 212 206 199 181 166 149 132 120 112 96 69 55 39 25 11 2 0 0 EGFR inhibitor use may have attenuspectively obtained tumor samples for ated the estimated treatment effect of the biomarker analysis, showing the panitumumab on OS,” the investigators “huge impact” of KRAS. suggested. Upon disease progression, Second-line Setting fewer patients in the experimental arm In the second-line setting, an internareceived both irinotecan and an EGFR tional randomized phase III open-label inhibitor (9%), as compared to the study by Marc Peeters, MD, and colFOLFIRI arm (24%). leagues evaluated panitumumab paired Patients with MT KRAS derived no with FOLFIRI (5-FU, leucovorin, and additional benefit from panitumumab, irinotecan).2 “This is the first study to with a median PFS of approximately 5 prospectively anamonths in each arm and a median OS of lyze the treatment about 11 months. effect of an antiAdverse event rates were generally EGFR monoclonal comparable across arms, with the excepantibody according tion of the known toxicities associated See page 52 to tumor KRAS stawith panitumumab.

B

Median months (95% CI)

Events n (%) Panitumumab + FOLFOX4 FOLFOX4

0.8 0.6

199 (61) 9.6 (9.2 to 11.1) 215 (65) 8.0 (7.5 to 9.3)

HR = 0.80 (95% CI, 0.66 to 0.97) P = .02

0.4 0.2 0

No. of patients at risk Panitumumab + FOLFOX4 FOLFOX4 alone

0

2

4

6

325 331

294 296

254 242

204 185

8 10 12 14 16 18 20 22 Time (months) 156 127

111 82

73 41

39 28

22 16

10 10

Panitumumab + FOLFOX FOLFOX

0.8 0.6

1 2

0 1

Median months (95% CI)

Events n (%)

1.0

Probability of progression-free survival

Two Pivotal Studies of Panitumumab

167 (76) 7.3 (6.3 to 8.0) 157 (72) 8.8 (7.7 to 9.4)

HR = 1.29 (95% CI, 1.04 to 1.62) P = .02

0.4 0.2 0

0

2

4

6

No. of patients at risk Panitumumab + FOLFOX4 221 219 FOLFOX4 alone

178 197

152 168

118 132

8 10 12 14 16 18 20 22 Time (months) 75 98

37 59

23 35

16 14

9 9

7 3

2 1

1 0

Fig. 1: Progression-free survival in patients with (A) wild-type (WT) KRAS and (B) mutant (MT) KRAS. CI = confidence interval; FOLFOX4 = infusional fluorouracil, leucovorin, and oxaliplatin; HR = hazard ratio. Adapted with permission from Douillard et al.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

References 1. Douillard J-Y, Siena S, Cassidy J, et al: Randomized, phase 3 study (PRIME) of panitumumab with FOLFOX4 versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer. J Clin Oncol.

October 4, 2010 (early release online).

2. Peeters M, Price TJ, Cervantes A, et al: Randomized phase 3 study of panitumumab with FOLFIRI versus FOLFIRI alone as second-line treatment in patients with metastatic colorectal cancer. J Clin Oncol. October 4, 2010 (early release online)

Skin Toxicity Appears Essential for Panitumumab Benefit Analysis yielded some surprises

T

he occurrence of serious skin toxicity is strongly associated with the efficacy of panitumumab, according to an analysis of the PRIME study presented at the 2010 ASCO Annual Meeting by Dr. Douillard.1 Over 95% of all patients receiving panitumumab developed some degree of skin toxicity, and this reached maximum grade by day 28 (after two cycles) in 50%. For patients with WT KRAS and grade 2-4 skin toxicity, median PFS was 11.1 months, vs 6.0 months for with patients WT KRAS and grade 0-1 toxicity (HR = 0.562; P = .001).

Interestingly, even patients with mutated KRAS, who derived no benefit from panitumumab in the main analysis, had better PFS if they developed skin toxicity.

PFS was 7.6 months for those with grade 2-4 toxicity vs 6.1 months for grade 0-1, Dr. Douillard reported.

Overall survival followed the same pattern and was striking in the WT KRAS subset, reaching 28.3 months in the presence of grade 2-4 toxicity, compared with 11.5 months with grade 0-1 (HR = 0.455; P < .0001). For the MT KRAS subset,

OS was 17.0 vs 10.1 months, respectively (HR = 0.595; P = .0042). Response rates were associated with skin toxicity only in the WT subset.

“These findings were a big surprise,” Dr. Douillard told The ASCO Post. “WT patients with no toxicity had a PFS of just 6 months. Skin toxicity in WT patients is a very strong predictor of efficacy, and this raises the question: If the patient does not develop skin toxicity, should we stop panitumumab?”

He noted that without the rash, patients with WT and MT KRAS had similar outcomes on panitumumab therapy.

■

Reference 1. Douillard JY, Cassidy J, Jassem J, et al: Randomized, �������������������������������������������� open-label, phase 3 study of panitumumab (pmab) with FOLFOX4 vs FOLFOX4 alone as first-line treatment (tx) for metastatic colorectal cancer (mCRC): Efficacy by skin toxicity (ST). 2010 ASCO Annual Meeting. Abstract 3528. Presented June 8, 2010.

ASCOPost.com | NOVEMBER 2010

PAGE 7

JCO Spotlight

Expert Point of View ducted outside of the United Kingdom?

Meanwhile, from a practical standpoint, Dr. Grothey suggested that EGFR antibodies should not be combined with bevacizumab, but rather, should be used sequentially—though the optimal strat-

egy for this is still unclear. As for the appropriate line of therapy, he noted that the benefit appears to be greater when used as salvage treatment vs earlier in the disease course. And finally, the two EGFR antibodies can be used sequentially without

compromising efficacy, he said.

■

Reference 1. Grothey A: EGFR antibodies in colorectal cancer: Where do they belong? J Clin Oncol. October 4, 2010 (early release online).

Axel Grothey, MD

I

n an editorial accompanying the panitumumab publications,1 Axel Grothey, MD, Professor of Oncology at the Mayo Clinic, Rochester, commented that not only do the studies uphold the emerging role of EFGR antibodies in colorectal cancer, but that efficacy was demonstrated when paired with different chemotherapy backbones in first- and second-line settings. The studies are also the first EGFR antibody trials in which the primary endpoint was prospectively adjusted to focus on KRAS wild-type tumors, he emphasized.

“It seems safe to say that panitumumab and cetuximab appear to be equally effective and interchangeable in clinical practice, either as monotherapy or in combination with cytotoxic chemotherapy, he said.”

Many Questions Remain Data are building from six phase III trials and numerous single-arm and randomized phase II studies. However, there are still many open questions, he said. For example: 1. Why do EGFR antibodies show a detrimental effect in patients with mutant KRAS when added to oxaliplatin/fluoropyrimidine–based chemotherapy but not when added to an irinotecan-based regimen?

2. Why did of EGFR antibodies added to bevacizumab in a fluoropyrimidine-based regimen exhibit antagonistic effects, while cetuximab plus bevacizumab, with and without irinotecan, may have activity?

3. Why did the addition of cetuximab to FOLFOX not improve outcomes in the adjuvant setting but result in higher response rates vs FOLFOX alone in advanced KRAS wild-type tumors?

4. How can the negative results of the COIN trial for cetuximab plus FOLFOX in the first-line setting be reconciled with data from trials con-

References : 1. Gregory CW, Johnson RT Jr, Mohler JL, French FS, Wilson EM. Androgen receptor stabilization in recurrent prostate cancer is associated with hypersensitivity to low androgen. Cancer Res. 2001;61:2892-2898. 2. Holzbeierlein J, Lal P, LaTulippe E, et al. Gene expression analysis of human prostate carcinoma during hormonal therapy identifies androgen-responsive genes and mechanisms of therapy resistance. Am J Pathol. 2004;164(1):217-227. 3. Montgomery RB, Mostaghel EA, Vessella R, et al.

Maintenance of intratumoral androgens in metastatic prostate cancer: a mechanism for castration-resistant tumor growth. Cancer Res. 2008;68(11):4447-4454.

© Centocor Ortho Biotech Inc. 2010 9/10 08ADA10027

The ASCO Post | NOVEMBER 2010

PAGE 8

35th ESMO Congress Encouraging Early Data Reported for Bevacizumab in First-line Therapy for Ovarian Cancer

By Alice Goodman

T

he addition of bevacizumab (Avastin) to standard first-line chemotherapy for newly diagnosed ovarian cancer reduced the risk of disease progression at a median follow-up of 19.4 months in the phase III Gynaecologic Cancer InterGroup (GCIC) ICON7 trial. The results were presented at the 35th ESMO Congress, held October 8-12 in Milan.1 “ICON7 met its primary endpoint and demonstrated that at 12 months, the absolute risk of See page 52 further progression of ovarian cancer was reduced by 15% with the addition of bevacizumab compared with chemotherapy alone,” said Tim Perren, MD, Leeds Teaching Hospital NHS Trust, Leeds, UK.

Different Perspectives “This is an exciting step forward.

Bevacizumab is the first new drug since the mid 1990s to show a significant treatment effect [in ovarian cancer],” he noted. These results will undoubtedly influence the discussion between oncologists and patients about treatment selection and affect design of the next generation of clinical trials.”

Formal discussant of this trial, Michael Bookman, MD, Section Chief of Hematology/Oncology at University of Arizona Cancer Center in Tucson, was more temperate in his remarks, noting that bevacizumab should not be considered standard therapy for ovarian cancer at this point (see sidebar).

Dr. Perren told listeners that these data compliment the Gynecologic Oncology Group (GOG) 218 study showing a benefit for bevacizumab in ovarian cancer, which was presented at the

ASCO Annual Meeting this past June.2 Preliminary results of ICON7 demonstrated a trend toward fewer deaths in the bevacizumab arm, but Dr. Perren cautioned that the data need to mature for 2 more years before a true survival advantage can be claimed.

Study Details The large ICON7 randomized, controlled trial enrolled 1,528 women from 263 centers with early-stage highrisk, or advanced-stage, epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer. Baseline characteristics were well balanced between the two arms. Median age was 57 years.

Following surgery, women were randomly assigned to either 6 cycles of standard chemotherapy with carboplatin/paclitaxel given once every 3 weeks or the same chemotherapy plus concurrent bevacizumab (7.5 mg/kg) for 6 cycles followed by bevacizumab as maintenance therapy for 12 additional cycles.

Bevacizumab improved progression-free survival (PFS) from a median of 17.3 months with standard chemotherapy to a median of 19 months, a statistically significant difference (P = .0041). The absolute difference in PFS was 1.7 months in this preliminary analysis, with a hazard ratio of 0.81.

The maximum effect of bevacizumab on PFS was observed at about 12 months after initiation of treatment; after that, the curves for the two arms converged. Dr. Perren said that it was unusual for survival curves to diverge and then converge and attributed this to the nonproportional hazards between the two arms of the trial. This means that the benefit of the addition of bevacizumab varies over time, as described above. A separate analysis

First-line Bevacizumab for Ovarian Cancer ■■ Interim analysis of ICON7, a large phase III trial, found a progressionfree survival benefit for the addition of bevacizumab to standard chemotherapy as first-line treatment of ovarian cancer.

■■ This is the second large phase III trial to demonstrate a benefit for bevacizumab in this setting.

■■ Bevacizumab is the first effective new drug for first-line treatment of ovarian cancer in over 17 years.

■■ Longer follow-up is needed to determine the true effect on overall

survival and how to integrate bevacizumab into treatment regimens.

Expert Point of View

F

ormal discussant of ICON7, Michael Bookman, MD, said that bevacizumab targets one small piece of a complex angiogenic pathway with origins in the physiology of the normal ovarian surface epithelium. “We are scratching the surface [with this drug],” he told listeners at the 35th ESMO Congress.

He pointed out that although both GOG 218 and ICON7 showed a significant PFS benefit for Michael Bookman, MD bevacizumab, survival data for both trials are not mature. and there is no evidence that a survival advantage will emerge in either trial. In both trials, the benefit of bevacizumab was more striking in advanced disease, Dr. Bookman said.

Based on the available data, it appears unlikely that a transient benefit in PFS will translate to improved overall survival. “In part, this reflects ‘the uncertainty principle’ in determination of PFS, which is most often based on small changes in CT imaging without emergence disease-related symptoms.

Which raises the question, where is the clinical benefit?”

The field of ovarian cancer treatment needs to move forward to achieve true clinical benefit, he continued—a point he also emphasized in a separate Educational Session on Challenges in Ovarian Cancer.

“We need to be able to select patients who can benefit from new treatments, the best regimen, and optimal doses; and refine the timing and duration of therapy to maximize benefit, and avoid treatment where benefit is unlikely,” Dr. Bookman stated.

“Optimal integration of bevacizumab remains open to conjecture,” he concluded. When asked whether there is a new standard of care for ovarian cancer that includes bevacizumab, he said, “From my perspective, no.”

■

(required by regulatory authorities) assessed patients who were still alive and progression-free at the data cutoff point. These patients were censored at the date of the last CT scan rather than the date of the last clinical follow-up. In that analysis, the median PFS was 16 months for the standard chemotherapy arm vs 18.3 months for the experimental arm (HR = 0.79, P = .0041).

‘Complicated’ Benefits Regarding the two different analyses of PFS he presented (academic and regulatory), Dr. Perren stated, “Due to nonproportional hazard ratios, the benefits are complicated to describe.”

A consistent benefit for the addition of bevacizumab was observed across all subgroups, regardless of age, FIGO stage, and grade. An exploratory analysis showed that patients with advanced disease (ie, stage III suboptimally debulked or stage IV debulked) had a superior PFS if they received bevacizumab: Median PFS was 10.5 months for standard chemotherapy vs 15.9 months for the

bevacizumab-containing arm (P < .001).

The treatment was well tolerated, with no new safety signals for bevacizumab.

Selected adverse events known to be associated with bevacizumab included hypertension (6.2% for standard chemotherapy, 25.9% for bevacizumab) and minor bleeding (11% vs 40%, respectively). Approximately 18% of patients treated with bevacizumab required additional antihypertensive drugs.

Identifying Patient Subgroups “In summary, we demonstrated for the second time that adding bevacizumab to standard chemotherapy significantly delays progression of ovarian cancer,” Dr. Perren said. “The difference between the two treatment arms is reduced over time.”

Moving forward, as in all cancers, it will be important to identify which patient characteristics are associated with treatment benefit. The ICON7 continued on page 9

ASCOPost.com | NOVEMBER 2010

PAGE 9

35th ESMO Congress Bevacizumab in Ovarian Cancer continued from page 8

investigators have collected blood and tumor samples from women at different time points in the trial, and these samples will be helpful in identifying subgroups of patients that will benefit from bevacizumab.

■

References 1. Perren T, Swart AM, Pfisterer J, et al: ICON7: A phase III randomized gynaecologic cancer intergroup trial of concurrent bevacizumab and chemotherapy followed by maintenance bevacizumab versus chemotherapy alone in women with newly diagnosed epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

35th ESMO Congress. Abstract LBA4.

Presented October 11, 2010.

2. Burger RA, Brady MF, Bookman MA, et al: Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. 2010 ASCO Annual Meeting. Abstract LBA1. Presented June 6, 2010.

November is

Lung Cancer Awareness month.

See pages 1, 3, and 33 for lung cancer news in The ASCO Post.

Inside The ASCO Post – Don't miss these important perspectives: Page 1 Dr. Tony Mok comments on the three essential participants in any clinical trial—investigator, sponsor, and patient—and discusses the motivation for participation by each entity. He shares his personal perspective on the status of lung cancer research in China and explains how the country has become an important partner in many large-scale global studies on lung cancer.

Page 42 Dr. Richard Boxer offers his view on unnecessary treatment for prostate cancer and discusses how over the past 30 years nearly 1 million American men have received radiation therapy and/or radical prostatectomy for prostate cancer that would have a very low risk of ever leading to their death. Such unnecessary treatment, in Dr. Boxer’s opinion, may have resulted in a decline in quality of life for these men.

Now Enrolling A Phase III clinical trial to evaluate the efficacy and safety of trastuzumab-DM1 (T-DM1)*† vs capecitabine and lapatinib in patients with HER2+ MBC. T-DM1 is a novel antibody-drug conjugate (ADC) being studied in the treatment of HER2+ MBC. Enrolling Patients With: • Histologically or cytologically confirmed invasive breast cancer • HER2+ disease based on prospective, centralized testing • Prior trastuzumab and taxane-based therapy • Documented progression post- or during treatment in the metastatic setting If you would like more information about the trial or recruiting centers, please call the Genentech Trial Information Support Line (TISL) at 888-662-6728 or e-mail genentechclinicaltrials@druginfo.com and refer to the ClinicalTrials.gov or Sponsor Study Identifier. Information provided here is taken from ClinicalTrials.gov.

Plus: Page 54 Dr. Joan H. Schiller and Dr. Thomas Stinchcombe each offer an individual perspective on whether maintenance chemotherapy is appropriate for metastatic non– small cell lung cancer.

Protocol as of September 2010.

*Products under investigation have not been approved for the use under investigation. This information is presented only for purposes of providing an overview of clinical trials and should not be construed as a recommendation for use of any product for unapproved uses. †

This agent is being developed in collaboration with ImmunoGen.

ClinicalTrials.gov Identifier: NCT00829166

Sponsor Study Identifier: TDM4370g

Erratum In the September 2010 issue of The ASCO Post, Edith A. Perez, MD, was mistakenly identified as Edith P. Perez, MD. We apologize for this error.

© 2010 Genentech USA, Inc. All rights reserved. TDM0000036800 Printed in USA.

The ASCO Post | NOVEMBER 2010

PAGE 10

2010 Breast Cancer Symposium Breast Cancer

Better Outcomes Seen for Triple-negative Breast Cancers if BRCA Mutation Is Present

By Caroline Helwick

I

n a study from The University of Texas M. D. Anderson Cancer Center, Houston, women with triple-negative breast cancers who harbored a BRCA mutation actually had better outcomes than those with triple-negative disease without the mutation.1 The study was reported at the 2010 Breast Cancer Symposium by Ana Maria Gonzalez-Angulo, MD, who commented, “It is interesting to see this difference in survival.”

The study, which involved 77 women, sought to determine the incidence of mutations in the BRCA1 or BRCA2 genes (both germline and somatic) in women with triple-negative breast cancer and to look for their possible prognostic significance.

“The study was interesting because of how it was done.

Most studies look at BRCA mutation carriers and then deterSee page 52 mine how many have

triple-negative disease. Here we looked at patients with triple-negative disease and then sequenced the tumors and normal tissue to see how many had BRCA mutations,” she said.

Key Data Fifteen patients (19.5%) had a BRCA mutation, including BRCA1 in 15.6% and BRCA2 in 3.9%. All but one was a germline mutation (BRCA1). Patients received standard anthracycline/taxane-based adjuvant chemotherapy and were followed for a median of 43 months.

The 5-year relapse-free survival was 51.7% for patients with triple-negative

disease without mutations compared to 86.2% for mutation carriers (P = .031).

Similarly, the estimated 5-year overall survival was 52.8% and 73.3%, respectively, which was numerically though not statistically significantly different (P = .225), she reported.

In the multivariate analysis, the hazard ratios favoring those with mutations were 0.17 for recurrence (P = .016) and 0.45 for overall survival (P = .138). The greatest hazard ratios, however, were for stage III disease (vs earlier stages), which were 5.32 (P < .0001) and 4.44 (P < .0001), respectively, in the overall population.

The results stand in contrast to previ-

BRCA Mutations in Triple-negative Breast Cancer ■■ Triple-negative breast cancer patients who also have BRCA mutations

have better relapse-free and possibly better overall survival than those without the mutation.

■■ These patients often lack other factors associated with genetic risk, such as family history, and may not be receiving genetic counseling.

ous studies done looking at all breast cancer subtypes, which have not shown differences in outcomes between these types of patients, Dr. Gonzalez-Angulo said.

Lack of Genetic Counseling She emphasized another important finding, which is that many of these patients had not received genetic counseling.

“Based on our findings, we may be missing many of these patients,” she said.

The study showed that 6 of the 14 germline mutation carriers and the one patient with a somatic mutation had not been referred for counseling. Nine of the 14 germline mutation carriers had no firstdegree relative with breast cancer, and 2 patients did not meet the standard guidelines for genetic testing.

■

Reference 1. Gonzalez-Angulo M, Chen H, Timms K, et al: Incidence and outcome of BRCA mutation carriers with triple receptor-negative breast cancer. 2010 Breast Cancer Symposium.

Abstract 160. Presented October 2, 2010.

At 10 Years, Anastrozole’s Superiority over Tamoxifen Increases

Breast Cancer

By Caroline Helwick

T

he 10-year follow-up of the ATAC trial (Arimidex, Tamoxifen, Alone or in Combination) upholds the disease control advantage seen for anastrozole over tamoxifen in the longest running clinical trial of aromatase inhibitors in early breast cancer. The new data were presented at the 2010 Breast Cancer Symposium.1 “At 10 years of median follow-up, anastrozole is significantly superior to tamoxifen in preventing breast cancer recurrences,” reported Aman Buzdar, MD, of The University of Texas M. D. Anderson Cancer Center, Houston.

At 10 years, patients on the anastrozole arm experienced an absolute 4.3% reduction in recurrence risk compared with patients treated with tamoxifen, amounting to a 21% relative risk reduction. This is

an increase over the 2.7% absolute difference observed at completion of therapy, which occurred at 60 months. Blinding of the study has been maintained over time.

Although patients on the aromatase inhibitor experienced more fractures and arthralgia while on treatment, at 10 years (5 years off treatment) these differences had disappeared. During the study, the anastrozole group had a 33% increase in risk of fracture (P < .0001) but this equalized by year 6, when patients went off the drug.

ATAC randomly assigned 6,241 postmenopausal women to 5 years of anastrozole or tamoxifen. At 10 years, recurrences were observed in 24.0% of the tamoxifen arm compared with 19.7% of the anastrozole arm (P = .0002). At 60 months,

ATAC Follow-up ■■ Anastrozole reduced the risk of breast cancer recurrence by 21% over tamoxifen at 10 years.

■■ The absolute difference in recurrence increased from 2.7% at year 5 to 4.3% at year 10, favoring the anastrozole arm.

recurrences were seen in 12.5% and 9.8%, respectively.

Carryover Effect “Recurrence rates continue to be lower with anastrozole after treatment completion,” Dr. Buzdar said. “The absolute difference in recurrence increased, and there was a statistically significant larger carryover effect for anastrozole after 5 years.”

This carryover effect amounted to a risk reduction in years 5 through 9 of 50% with anastrozole, compared with 33% for tamoxifen (P = .03), which has been reported with tamoxifen overview data from Oxford Trialists Group, he added.

Distant recurrence risk at 10 years was 17.7% with anastrozole and 15.1% with tamoxifen, for a 15% relative risk reduction (P = .02). Contralateral breast cancers occurred in 4.9% and 3.2%, respectively, for a 36% reduction (P = .003).

Deaths occurred in approximately 24% in each arm.

Jennifer C. Obel, MD, of NorthShore University HealthSystems in Evanston, Illinois, served as a spokesperson to the press at the meeting. She commented,

Jennifer C. Obel, MD

“Women want to know not only what the side effects of these drugs are on them today, but what See page 52 the side effects are over time. These findings also reassure patients that the superiority of an aromatase inhibitor, compared to tamoxifen, holds up at 10 years, and continues to reduce their risk of recurrence.”

■

Reference 1. Buzdar A, Cuzick J, Sestak I, et al: Tenyear analysis of the ATAC trial. 2010 Breast Cancer Symposium. Abstract 256. Presented October 2, 2010.

ASCOPost.com | NOVEMBER 2010

PAGE 11

2010 Breast Cancer Symposium Breast Cancer

Risks Associated with BRCA-mutated Breast Tumors Can Vary Factors to Consider When Counseling Patients

By Caroline Helwick

A

were available for 801 women. A BRCA1 or BRCA2 mutation was identified in either the patient (88%) or a family member (12%).

The mean age at diagnosis was 42 years. Approximately half had undergone a unilateral mastectomy, and the other half underwent lumpectomy, usually with radiation therapy. No patient had a bilateral mastectomy.

Contralateral breast cancer was diagnosed in 18.4% at an average of 5.7 years after diagnosis. The 15-year actuarial risk was 33.8%, the 10-year risk was 22.0%, and the 5‑year risk was 13.1%. Risk was slightly higher for BRCA1 mutation carriers.

lthough about one-third of women with BRCA-mutated breast cancer will develop contralateral breast cancer in 15 years, the risk is actually much higher for certain women, and they should be counseled accordingly, said Kelly Metcalfe, RN, PhD, of the University of Toronto, who led a multicenter study to identify relevant risk factors.1

Risk Highest among Certain Groups “Age was an important predictor,” Dr. Metcalfe announced. “Women with a young age at onset were at significant risk.”

For women aged 40 and younger at diagnosis, the risk of contralateral breast cancer was over 40% at 15 years, compared with approximately 35% for those aged 40 to 49 and 15% for those aged 50 or older (P = .001; see Fig. 1). Annually, this amounted to a 2.8% annual risk for the youngest group vs a 1.3% annual risk for those aged 50 and up.

The decision to undergo oophorectomy or not also significantly affected the patient’s risk, as oophorectomy conveyed a 47% reduction in risk, primarily seen in the BRCA1 subset, she said.

Age at diagnosis was also important with regard to oophorectomy, as women younger than 50 with intact ovaries had a 60% 15-year risk, compared with 20% for those aged 50 and up when diagnosed (P = .0003). Women younger

Kelly Metcalfe, RN, PhD

Probability of contralateral breast cancer

“Data suggest that women with a BRCA mutation have an increased risk of contralateral breast cancer, but we don’t know whether there may be modifiers of this contralateral risk,” Dr. Metcalfe said at the 2010 Breast Cancer Symposium.

The study found that age at diagnosis, strong family history of breast cancer, and oophorectomy significantly influenced the patient’s risk for contralateral disease. The study population included 846 women (N = 669, plus 177 deceased) with stage I or II disease diagnosed by age 65 between 1975 and 2008. Of these women, 810 had an intact contralateral breast and were included in See page 52 the analysis. Pedigrees 0.8

Age < 40 yr, 81 events/354 patients

0.7

Age 40–49 yr, 51 events/296 patients Age ≤ 50 yr, 16 events/151 patients

0.6

P = .001

0.5 0.4 0.3 0.2 0.1 0.0 0

1

2

3

4

5

6

7

8

9 10 11 12 13 14 15

Years after diagnosis Fig. 1: Risk of contralateral breast cancer by age at first breast cancer diagnosis. Courtesy of Kelly Metcalfe, RN, PhD.

BRCA Mutation and Contralateral Breast Cancer Risk ■■ Women younger than 50 years with BRCA-mutated breast tumors have a 38% risk of developing contralateral breast cancer at 15 years.

■■ This risk is modified by age at diagnosis, family history, and oophorectomy.

■■ A 68% risk is observed in a woman who is diagnosed before age 50, chooses to keep her ovaries, and has two first-degree relatives also diagnosed with breast cancer before age 50.

■■ When counseling BRCA-positive patients these risk factors should be taken into account.

than 50 who underwent oophorectomy reduced their risk by 55%.

“Women with early-onset breast cancer have the highest risk and get the most protection from oophorectomy,” Dr. Metcalfe concluded.

Family history was also a significant risk factor, especially when affected relatives were young at the time of diagnosis. For every first-degree relative with breast cancer under age 50, the risk of breast cancer rose 33% (P = .008). For women with two or more relatives with breast cancer under age 50, risk was increased by close to 80% compared to those with no affected relatives younger than 50 when diagnosed (P = .006).

Neither chemotherapy nor the use of tamoxifen was protective, overall or by mutation or age subgroup.

Identifying Those at Greatest Risk Dr. Metcalfe emphasized how these risk factors can be used in counseling women.

For example, while the 15-year risk for a woman diagnosed before age 50 is 37.6%, it greatly increases if she decides against oophorectomy and nearly doubles if she has two or more first-degree relatives diagnosed at a young age.

“These are the women we really need to identify and counsel appropriately about surgery to prevent contralateral breast cancer,” she said. “Our strongest recommendation is to remove the breast, which can bring their risk down to almost zero.”

Dr. Metcalfe and colleagues will be following this cohort to determine the impact of these factors on survival.

The Breast Cancer Symposium was cosponsored by the American Society of Breast Disease, The American Society of Breast Surgeons, ASCO, the American Society for Radiation Oncology, the National Consortium of Breast Centers, and The Society of Surgical Oncology.

■

Reference 1. Metcalfe KA, Lynch HT, Ghadirian P, et al: Predictors of contralateral breast cancer in BRCA1 and BRCA2 mutation carriers. 2010 Breast Cancer Symposium. Abstract 159. Presented October 1, 2010.

Expert Point of View

R

obert R. Kuske, MD, of Arizona Breast Cancer Specialists, Phoenix, said that close surveillance of women with BRCA-mutated breast cancer can lead to early detection of second cancers and thus would negate the impact of prophylactic mastectomy on survival. Dr. Kuske moderated the session on prevention and risk at the 2010 Breast Cancer Symposium.

“Lumpectomy and radiation therapy remains a viable option for some women who have breast cancer in the presence of the BRCA gene. I alternate MRI and mammography every 6 months in these patients in order to detect very early-stage cancers that are curable. However, based on these data, I would think twice about this approach in women with a first-degree relative diagnosed with breast cancer younger than age 50,” he told The ASCO Post.

“If they are over 50 when diagnosed and they have either no first-degree relative or a relative diagnosed after the age of 50,” he continued, “then I think lumpectomy and radiation therapy are still reasonable, and many of my patients choose this.”

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With the first and only IV mTOR inhibitor indicated for advanced renal cell carcinoma (RCC)1...

Change

expectations

for overall survival

Important portant Safety Information • TORISEL is contraindicated in patients with bilirubin >1.5 x ULN and should be used with caution when treating patients with mild hepatic impairment (bilirubin >1–1.5 x ULN or AST >ULN but bilirubin ≤ULN). If TORISEL must be given to patients with mild hepatic impairment, reduce the dose of TORISEL to 15 mg/week. In a phase 1 study, the overall frequency of ≥grade 3 adverse reactions and deaths, including deaths due to progressive disease, was greater in patients with baseline bilirubin >1.5 x ULN. • Hypersensitivity reactions manifested by symptoms, including, but not limited to anaphylaxis, dyspnea, flushing, and chest pain have been observed with TORISEL. • Serum glucose, serum cholesterol, and triglycerides should be tested before and during treatment with TORISEL. – The use of TORISEL is likely to result in hyperglycemia and hyperlipemia. This may result in the need for an increase in the dose of, or initiation of, insulin and/or oral hypoglycemic agent therapy and/or lipid-lowering agents, respectively.

• The use of TORISEL may result in immunosuppression. Patients should be carefully observed for the occurrence of infections, including opportunistic infections.

• Cases of interstitial lung disease, some resulting in death, have occurred. Some patients were asymptomatic and others presented with symptoms. Some patients required discontinuation of TORISEL and/or treatment with corticosteroids and/or antibiotics.

• Cases of fatal bowel perforation occurred with TORISEL. These patients presented with fever, abdominal pain, metabolic acidosis, bloody stools, diarrhea, and/or acute abdomen.

• Cases of rapidly progressive and sometimes fatal acute renal failure not clearly related to disease progression occurred in patients who received TORISEL. • Due to abnormal wound healing, use TORISEL with caution in the perioperative period.

• Patients with central nervous system tumors (primary CNS tumor or metastases) and/or receiving anticoagulation therapy may be at an increased risk of developing intracerebral bleeding (including fatal outcomes) while receiving TORISEL.

TORISEL—Significant overall survival benefit as first-line therapy1 Kaplan-Meier curves for overall survival (OS)*—TORISEL vs IFN 1

Results from a phase 3, multicenter, 3-arm, randomized, open-label study conducted in 626 previously untreated patients with advanced RCC.1

• Studied first-line in patients with ≥3 of 6 preselected prognostic risk factors1

The advanced RCC pivotal study included patients with2 • Clear-cell or non–clear-cell tumor histologyII • Any nephrectomy status

mTOR=mammalian target of rapamycin.

IFN =interferon alpha.

CI=confidence interval. * Time from randomization to death.1 † A comparison is considered statistically significant if the P-value is <.0159 (O’Brien-Fleming boundary at 446 deaths).1 ‡ Based on log-rank test stratified by prior nephrectomy and region.1 § Based on Cox proportional hazard model stratified by prior nephrectomy and region.1 II 82% and 82.5% of patients had known clear-cell histology for TORISEL and IFN , respectively.2 ¶ NCCN Category 1 recommendations are based on high-level evidence (eg, randomized controlled trials) and uniform NCCN consensus.3 # TORISEL was approved by the FDA in 2007.1

• Category 1 NCCN recommendation— first-line for poor-prognosis patients3¶ • >3 years experience since FDA approval#

Median duration of treatment was 17 weeks (range 1-126 weeks) for the TORISEL arm and 8 weeks (range 1-124 weeks) for the IFN arm.1

• Live vaccinations and close contact with those who received live vaccines should be avoided.

• Patients and their partners should be advised to avoid pregnancy throughout treatment and for 3 months after TORISEL therapy has stopped.

• The most common (incidence ≥30%) adverse reactions observed with TORISEL are: rash (47%), asthenia (51%), mucositis (41%), nausea (37%), edema (35%), and anorexia (32%). The most common laboratory abnormalities (incidence ≥30%) are anemia (94%), hyperglycemia (89%), hyperlipemia (87%), hypertriglyceridemia (83%), elevated alkaline phosphatase (68%), elevated serum creatinine (57%), lymphopenia (53%), hypophosphatemia (49%), thrombocytopenia (40%), elevated AST (38%), and leukopenia (32%).

• In the randomized, phase 3 trial, complete blood counts (CBCs) were checked weekly, and chemistry panels were checked every 2 weeks.

Laboratory monitoring for patients receiving TORISEL may need to be performed more or less frequently at the physician’s discretion.

• Most common grades 3/4 adverse events and laboratory abnormalities included asthenia (11%), dyspnea (9%), hemoglobin decreased (20%), lymphocytes decreased (16%), glucose increased (16%), phosphorus decreased (18%), and triglycerides increased (44%).

• Strong inducers of CYP3A4/5 (eg, dexamethasone, rifampin) and strong inhibitors of CYP3A4 (eg, ketoconazole, atazanavir) may decrease and increase concentrations of the major metabolite of TORISEL, respectively. If alternatives cannot be used, dose modifications of TORISEL are recommended.

• St. John’s Wort may decrease TORISEL plasma concentrations, and grapefruit juice may increase plasma concentrations of the major metabolite of TORISEL, and therefore both should be avoided.

• The combination of TORISEL and sunitinib resulted in dose-limiting toxicity (Grade 3/4 erythematous maculopapular rash, and gout/cellulitis requiring hospitalization).

Please see the brief summary of the full Prescribing Information on the next page.

References: 1. TORISEL® Kit (temsirolimus) Prescribing Information, Wyeth Pharmaceuticals Inc. 2. Data on file, Pfizer Inc. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

Change expectations

The ASCO Post | NOVEMBER 2010

PAGE 16

Guidelines

New NCCN Patient Guidelines for Breast and Lung Cancer Available Online

By Alice Goodman

P

atients with a diagnosis of breast edgeable and involved in their care. To cancer or non–small cell lung make this work, patients need the right cancer (NSCLC) have a new tool to tools, and that includes timely, accuhelp guide them through the difficult rate information.” journey ahead. Patient versions of Physicians all over the world rely the National Comprehensive Cancer on NCCN professional guidelines to Network’s (NCCN’s) professional guide cancer treatment. In addition to treatment guidelines for breast canproviding patients access to the same cer and NSCLC are now available online.

According to a media teleconference held recently, NCCN patient guidelines for at least four more common cancers will be available by year end, and plans are underway to develop patient versions of the proWilliam T. McGivney, PhD Musa Mayer fessional guidelines for additional common cancers by the end of 2011.

“NCCN is proud to make this new evidence-based information as their resource [for patients] available tophysicians, the new NCCN Guidelines day. We recognize the need to provide for PatientsTM may help them gain coverage for treatments that may not be patients the same timely high-quality included in their insurance plan. information to aid in shared decisionmaking between patients and phyTarget Audience sicians and to help patients underThe NCCN Guidelines for Patients stand the complexity of care,” stated are written for educated people; they William T. McGivney, PhD, who is contain few visual graphics except for Chief Executive Officer of NCCN. complex treatment algorithms that “Informed patients make a real differmight not be understood by less eduence in cancer care.” cated patients. But well-educated paAl B. Benson, III, MD, a gastrotients tend to be proactive about their intestinal cancer expert and NCCN treatment. The NCCN website ofBoard Member, commented, “These fers simpler treatment summaries for guidelines represent a ‘giant step’ formany common cancers for patients ward by giving patients access to the who may be seeking less complex insame information that physicians use formation. to make decisions.” He added, “Gone “It is important to let clinicians are the days… of passive acceptance know that [in addition to the patient [for patients]. Today’s patients are and versions of NCCN guidelines] simshould be active information seekers pler treatment summaries are availand active partners in their care. The able on our website for both patients norm today is for patients to be knowl-

NCCN Guidelines for Patients ■■ NCCN has released patient versions of their professional guidelines for breast and non–small cell lung cancer.

■■ These are the first two of a planned series of patient versions of the professional NCCN guidelines covering common cancers.

■■ The patient versions of the guidelines are intended to be tools for facilitating shared decision-making with physicians.

■■ They are written at a sophisticated level and will likely be of use for educated, savvy patients who are proactive about their treatment.

■■ The patient guidelines are available online at www.nccn.com as well as through a link on the Susan G. Komen for the Cure® website (www.komen.org).

and clinicians,” said Patricia J. Goldsmith, who is Executive Vice President and Chief Operating Officer of NCCN. Off-label uses of drugs and updates for the patient guidelines will be handled the same way as for the standard professional NCCN guide-

vocate, author, and coordinator of two websites: www.AdvancedBC. org and www.BrainMetsBC.org. The algorithms in the new guidelines demonstrate oncologists’ thinking process about treatment for an individual patient, she continued. “This could be of interest to patients, who might otherwise think of treatment recommendations as a ‘black box’,” she said. Also, the new guidelines give patients an understanding of the standard of care.

Ms. Mayer’s concern is that for well-informed patients like herself, the “why” is missing from Al B. Benson, III, MD Patricia J. Goldsmith these guidelines. That is, no references are provided for those who lines. Results of important clinical triwant to click on an assertion and als will be incorporated into both the read the evidence supporting speprofessional and patient versions of cific guidelines.

NCCN guidelines in as timely a manIt would have been a good idea to ner as possible, Ms. Goldsmith said. provide the references as clickable links, she said.

When to Use the Patient Guidelines

According to Christina Koenig, a breast cancer survivor and Director of Communications and Media Relations for Breast Cancer Network of Strength (formerly Y-ME), these guidelines could be too much for a patient to absorb when first diagnosed.

“We know from the questions we receive on our 24-hour hotline that too much information can be overwhelming. You wouldn’t want this [treatment guideline] to be the first thing to read in a ‘Welcome to Cancer’ folder,” she said.

Once a patient has digested her diagnosis, these guidelines could be helpful, said Ms. Koenig, “depending on the person’s aptitude and coping style.” She added, “Breast cancer is many different diseases, and people are treated differently. The guidelines could help a patient understand why her friend with breast cancer got different treatment than her own treatment,” Ms. Koenig commented.

Fine-tuning Suggested “These guidelines are intended for patients with a high level of understanding,” agreed Musa Mayer, breast cancer survivor, patient ad-

Availability The patient guidelines are available online at www.nccn.com as well as through a link on the Susan G. Komen for the Cure® website (www.komen. org). (The Komen organization provided a $160,000 grant for development and distribution of the patient version of the breast cancer guideline, Dr. McGivney explained.) Currently, 10,000 hard copies of the breast cancer patient guideline and 5,000 of the NSCLC patient guideline have been printed for distribution.

The NCCN patient guidelines for NSCLC are named in honor of Dana Reeve, who died in 2006 from this disease. Dana’s sister, Deborah Morosini, MD, NCCN Foundation Board of Directors, said that the new guidelines were “a fitting tribute” to Dana. “Dana [widow of Christopher Reeve], was instrumental in developing a comprehensive guide and a paralysis resource center for patients and caregivers. These guidelines for NSCLC give patients a resource for finding out about new therapies they might otherwise not have known about,” Dr. MoroSee page 52 sini said.

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ASCOPost.com | NOVEMBER 2010

PAGE 17

35th ESMO Congress ESMO 2010 Breaks Records — A ‘Milestone’ in Society’s History

By Caroline Helwick

T

he 35th Congress of the European Society of Medical Oncology (ESMO) will be “a congress of records,” ESMO President David J. Kerr, MBChB, MD, PhD, announced at the meeting, held October 8-12 in Milan, Italy.

The ICON7 trial validated emerging data showing the benefit of bevacizumab (Avastin) in ovarian cancer (see page 6). And for patients with triple-negative breast cancer, the PARP inhibitor iniparib improved overall survival by nearly 4 months when

given in combination with chemotherapy.

Essentially, the theme that emerged across the tumor types was the need to identify subsets of patients who will benefit from targeted (and expensive) agents. Dr. Kerr said that what has be-

come clear “is that we need to get back to our laboratories to understand more about the disease. We need more biology and a better insight so that we can treat the right patient, at the right time, with the right drug, and at the right dose.”

■

There are thousands of ways to show you care: working to improve health is one of them.

David J. Kerr, MBChB, MD, PhD

Nearly 16,000 delegates from 115 different countries attended 130 different sessions, and investigators reported on trials involving 60,000 patients altogether.

The organizers reported a 67% increase in abstract submissions, and a 200% increase in submissions of late-breaking abstracts.

“We couldn’t be more pleased, ” Dr. Kerr told The ASCO Post.

“The 35th ESMO Congress is a milestone in our Society’s history. It has been not only our biggest, but also our best congress ever,” Dr. Kerr said at the event’s closing press conference. “We believe this success is due to the excellent program that the ESMO Scientific Committee put together this year, including a large amount of original research,” he said.

Sanofi-aventis U.S. is the U.S. affiliate of sanofi-aventis, a leading global pharmaceutical company that discovers, develops and distributes therapeutic solutions

Higher Standard for Research Martine Piccart, MD, Professor of Medicine at Jules Bordet Institute, Brussels, Belgium, and ESMO President-Elect commented that ESMO has raised its standard for research presentations, and the Presidential Symposium included only clinical trials of the highest quality and with a potential to change clinical practice.

Fortunato Ciardiello, MD, PhD, Professor of Medical Oncology at Second University of Naples, Italy, and the ESMO 2010 Press Officer, added that several studies were practice-changing, especially a phase III trial that showed improved overall survival with abiraterone acetate for patients with metastatic castration-refractory prostate cancer. “The findings contribute to a new era in drugs for prostate cancer,” said Dr. Ciardiello (see page 20 in this issue).

In addition, improved survival was shown in patients receiving erlotinib (Tarceva) for advanced non–small cell lung cancer in the OPTIMAL trial (see page 1).

to help improve the lives of patients and their families.

To find out more about our research, please visit www.sanofi-aventisoncology.com

© sanofi-aventis 174, Avenue de France 75635 Paris, France sanofi-aventis U.S. www.sanofi-aventis.us US.XON.10.04.049

The ASCO Post | NOVEMBER 2010

PAGE 18

AACR International Conference Personalized Medicine

Biomarkers in Early Clinical Trials: Too Much Too Soon?

By Laurie M. Fisher

U

nfortunately, several recently approved treatments for various cancers have yielded only meager gains in life expectancy. More than ever, a paradigm shift is needed in the development of novel drugs in the clinical venue. Biomarkers—substances measured biologically and associated with an increased risk of disease—represent a potentially useful tool for bringing about this change. However, that tool is not always used to its best advantage.

in early clinical trials.

First, the most potent target may not be the most relevant; the toxicity-driven model of selecting dosage based on maximum tolerated dose vs biologically relevant dose could define a target for toxicity that supersedes the target for efficacy. Next, as early as clinically possible, researchers need to find the right subset of patients, which may be difficult to define, identify, and recruit in a timely fashion. This is espe-

We need to design trials and develop drugs, one drug at a time, taking into account the unique characteristics of that drug when beginning to put it into clinical trials in man.

— Patricia LoRusso, DO

“It’s time to marry the science, whenever possible, with clinical drug design,” said Patricia LoRusso, DO, Director of the Center for Experimental Medicine at the Karmanos Cancer Institute in Detroit. Dr. LoRusso discussed the benefits and challenges of using biomarkers in early clinical trials at the Fourth American Association for Cancer Research (AACR) International Conference on Molecular Diagnostics in Cancer Therapeutic Development, held September 27-30 in Denver. She said there is a need to explore smarter drug development paths, learn from previous experience, and, in the era of targeted agents, more efficiently and effectively develop novel agents. “We need to design trials and develop drugs, one drug at a time, taking into account the unique characteristics of that drug when beginning to put it into clinical trials in man.”

Challenges in Biomarker-based Trials Dr. LoRusso believes biomarkers should be used whenever possible “to help make sure that we do not stop development of a valuable drug due to inappropriate patient selection.” However, multiple challenges confront both the basic scientist and the clinical investigator when trying to develop and use biomarkers in the various phases of clinical drug development, especially

cially true if the target under investigation is only defined in a small subset of patients.

In addition, with many clinical experiments, upfront tissue collection is crucial. “You can’t go back in time if you never collected tissue,” Dr. LoRusso noted. She also acknowledged that, since many drugs are multitargeted, there are often challenges stemming from target inhibition toxicity vs efficacy. Further, an array of other challenging issues involve technology, tissue handling, preselection, and false-negatives, among others. “Progress will take time, and the challenges we face are real, ” she said.

Dr. LoRusso questioned the ramifications of not properly evaluating the target when the target is known. For example, she cited a phase III study of erlotinib (Tarceva), the TRIBUTE trial, which demonstrated a marked benefit in one subgroup (EGFR mutation–positive) but a negative effect in a second (KRAS mutation–positive).

The overall end result of the study— no survival benefit—may have been defined by the disparity of these two populations. Combination therapy with erlotinib was subsequently abandoned due, at least in part, to this “artificial” negative impact that resulted in a low P value.

Sometimes, when a translational science discovery follows regulatory

Patients and Trials Benefit from Use of Defined Subsets ■■ Progress has been made in the development of biomarker-driven clinical trial designs.

■■ Many challenges still exist.

■■ The sooner a subset of patients can be identified for a trial, the greater the benefit.

■■ We must always reassess a trial’s successes and failures.

ing an unselected population, a good drug can be abandoned from development due to the subset getting “lost” in the general patient population.

In addition, generic recruiting to studies may result in patients missing out on potentially effective treatments as well as exposing a significant number of patients to a drug with no benefit. Perhaps most significantly, researchers risk incorrectly concluding that a drug is ineffective, rather than effective for a small subset of the population.

Although the costs of molecular assessments and targeting may be high, long-term costs of traditional approaches are much higher, Dr. LoRusso emphasized. “We need small

drug approval, the finding can go unnoticed or may be less influential in how the drug is used, Dr. LoRusso said. “What if some of these findings had been evaluated prospectively and were used as predictors of differential response?” she asked.

Finding the Correct Subset “You have to match the right study with the right subset,” Dr. LoRusso said. Otherwise, clinical trials may result in costly failures—both in terms of financial resources and patient outcomes. A simulated study from a recent Journal of Clinical Oncology article

by Stewart and colleagues,1 showed how subpopulation characteristics might affect study outcome. When us-

Linking Molecular Diagnostics to Targeted Therapies

W

e are entering a time of incredible excitement,” said Gordon Mills, MD, PhD, of The University of Texas M. D. Anderson Cancer Center in Houston and program committee chair for the AACR International Conference on Molecular Diagnostics in Cancer Therapeutic Development.

“This conference helps pave the way to fulfilling the promise of personalized medicine.”

He added, “We are entering an era where we are finally able to utilize the new sets of drugs that Gordon Mills, MD, PhD are becoming available as targeted therapeutics, to implement the promise of personalized medicine.” However, researchers have learned over the past decade that targeted therapeutics that are now available only demonstrate benefit in a select population of patients, and all too frequently, the benefit is transient. “Thus, the lesson learned is that we must link molecular diagnostics in order to identify patients who are likely to respond, or who are likely not to respond, if we are going to optimally implement targeted therapeutics to benefit our patients.”

Specifically, this conference focused on the opportunities, challenges, and lessons learned in linking molecular diagnostics with targeted therapeutics to improve patient outcomes. “We will review new opportunities for success, examine failures, and discuss the regulatory environment so that we may move this process forward,” Dr. Mills said.

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ASCOPost.com | NOVEMBER 2010

PAGE 19

AACR International Conference studies aiming at big gains, not big studies aiming at small gains.” When the focus is on small subsets of patients who are selected in advance, and significant benefits are realized, the study may result in sufficiently positive outcomes that could prevent the need for a costly, patient-intensive randomized phase III trial.

Advice for Clinicians Whenever possible, if a target is known and the agent under investigation is selective, clinical trials should be designed with an eye toward patient and tumor subtype enrichment, Dr. LoRusso advises. “The sooner you can identify the target, the more information you will know, and in the long run it will benefit many more patients,” she said.

For example, in the case of non– small cell lung cancer, less than 5% of patients express the EML4/ALK fusion oncogene. Early results from a study of the experimental agent crizotinib demonstrated an objective response rate of approximately 60% with a disease control rate of 87% for

this subgroup of patients—an overwhelmingly positive response. Success rates such as these make patient screening and recruitment to studies more straightforward and exciting for physicians.

The alliance between basic science and the clinic continues to move forward despite numerous barriers. Time

is needed to develop tools and find resources. “It takes a lot of effort and a lot of money,” Dr. LoRusso said, “but if we do not develop these agents appropriately, it is significantly more costly, both in terms of dollars wasted on ineffective treatments and in toxicities inflicted on the patient. We have a long way to go. We need to constantly reas-

sess whether we can do it, because we are obligated to try. And we won’t get there unless we try.”

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Reference 1. Stewart DJ, Whitney SN, Kurzrock R: Equipoise lost: Ethics, costs, and the regulation of cancer clinical research. J Clin Oncol 28:2925-2935, 2010.

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CilENgitide in combination with Temozolomide and Radiotherapy In newly diagnosed glioblastoma phase III randomized Clinical trial A randomized multicenter, open-label, controlled phase III study to evaluate cilengitide in combination with standard treatment (TMZ with concomitant RT, followed by TMZ maintenance therapy) versus standard therapy alone in newly diagnosed glioblastoma patients with methylated MGMT gene promoter status.

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Cilengitide in subjects with newly diagnOsed glioblastoma multifoRme and unmethylated MGMT genE promoter A randomized multicenter, open-label phase II study, investigating two cilengitide regimens in combination with standard treatment (temozolomide with concomitant radiation therapy, followed by temozolomide maintenance therapy).

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The ASCO Post | NOVEMBER 2010

PAGE 20

35th ESMO Congress Genitourinary Cancer

Abiraterone Extends Survival in Metastatic Castration-resistant Prostate Cancer, Phase III Trial Finds

By Alice Goodman

A

biraterone acetate, an investigational oral drug, extended survival in patients with metastatic castrationresistant prostate cancer (mCRPC) by about 4 months compared with placebo in a large phase III trial reported at the 35th ESMO Congress, held October 8-12 in Milan, Italy.1

Johann de Bono, MD

“This should be considered a major step forward in prostate cancer therapeutics,” stated lead investigator Johann de Bono, MD, of The Institute of Cancer Research and The Royal Marsden NHS Foundation Trust, London. “These results are likely to be practice-changing for men with advanced prostate cancer that has progressed on docetaxel-based chemotherapy, which has been a critical unSee page 52 met need.”

Abiraterone is designed to treat hormone-resistant tumors by inhibiting androgen production in the testes, adrenal glands, and prostate tumors themselves. The phase III trial included 1,195 participants from 13 countries. All men had mCRPC previously treated with chemotherapy that included docetaxel.

Dr. de Bono said this oral compound, which was developed at Royal Marsden, inhibits CYP17, a key enzyme involved in the synthesis of estrogen and testosterone. Advanced

prostate cancer tumors themselves produce testosterone, even in castrated men, he explained. “These cancers are not hormone-refractory as we once assumed, but are generally hormone-driven, even after castration,” he said.

Trial Design and Results Patients were randomly assigned, in a 2:1 scheme, to either abiraterone plus prednisone or placebo plus prednisone. Median overall survival was 14.8 months in the treatment arm vs 10.9 months for placebo recipients (P < .0001). The trial was unblinded early by an Independent Data Monitoring Committee after a prespecified interim analysis of the trial showed a survival benefit. “We thought it would be unethical to withhold this drug from placebo patients in the trial,” he noted.

“A difference of 3.9 months may not seem like much, but only four other drugs have extended survival in prostate cancer. We plan to study this drug earlier in treatment and we hope it will extend survival,” he said.

Secondary endpoints of the trial all favored treatment, including progression-free survival (PFS) according to time to prostate-specific antigen (PSA) progression, radiographic progression, and PSA response rate. Median time to progression was 10.2 vs 6.6 months for abiraterone and placebo, respectively (P < .0001). Median PFS was 5.6 vs 3.6 months (P < .0001), and PSA response was 38% vs 10%, respectively (P < .0001).

Abiraterone was well tolerated. Adverse events related to the drug were amenable to medical management and different from those associated with cytotoxic chemotherapy. Treatmentrelated adverse events included fluid retention (30.5% vs 22.3%, respectively) and hypokalemia (17.1% vs

Abiraterone in Metastatic Castration-resistant Prostate Cancer ■■ A phase III trial showed that abiraterone acetate, an investigational drug that decreases androgen production, extends survival in metastatic castration-resistant prostate cancer.

■■ These results are practice-changing.

■■ This is one of four major positive trials reported in prostate cancer in 2010.

Expert Point of View

A

biraterone is the first new antiandrogen on the scene.… This study had the most impressive results I’ve seen in a long time,” said Cora Sternberg, MD, of San Camillo and Forlanini Hospitals, Rome, the formal discussant of the abiraterone trial presented at the 2010 ESMO meeting. “A 35% reduction in risk of death is important. It will also be important to see the final overall results.”

The drug showed favorable survival in all subgroups. “To be fair, those with ECOG performance Cora Sternberg, MD status 2 and two prior lines of chemotherapy had broad 95% confidence intervals,” she commented.

Of note, Dr. Sternberg said this is the first trial to use the Prostate Cancer Working Group 2 criteria to measure progression, which is a soft endpoint that can be difficult to measure.

She noted that the adverse events of interest in the trial (slightly more frequent grade 3 fluid retention and hypokalemia) might have to do with corticosteroids and the disease itself rather than abiraterone. “One question is whether patients can tolerate abiraterone without corticosteroids. Other trials are looking at this, and we need to work out the exact dose of corticosteroids,” she told listeners.

Side effects of long-term androgen deprivation include obesity, osteoporosis, fracture, and sarcopenia, and the long-term effects of continuous abiraterone treatment are not known, she added.

“The study provides unequivocal evidence of the importance of the androgen signaling axis and opens the field for studies of other drugs coming up. MDV3100 is the one furthest along in development,” Dr. Sternberg said.

“It has been a long time since 2004 [when the FDA approved docetaxel for hormone-refractory metastatic prostate cancer]. Four positive trials in 2010 are exciting and represent a breakthrough. Abiraterone sets a new standard therapy for mCRPC after docetaxel therapy. We have raised the bar and once abiraterone becomes available we will no longer be able to perform placebo-controlled trials,” she concluded.

■

8.4%), but these events were mostly grades 1 and 2 and were manageable.

Liver function test abnormalities were observed in 10.4% vs 8.1%, and cardiac disorders were observed in 12.5% vs 9.4%, respectively.

Unresolved Issues “2010 is a good year for prostate cancer. Three positive phase III trials showed a survival benefit for sipuleucel-T (Provenge), docetaxel, and cabazitaxel ( Jevtana). Abiraterone results were as good,” Dr. de Bono told listeners.

Unresolved issues related to abiraterone include the need to identify which subgroups of patients benefit.

“Although this is a significant advance, there is still a lot of work to do to improve outcomes for patients with advanced prostate cancer,” Dr. de Bono stated.

■

Reference 1. de Bono J, Logothetis CJ, Fizazi K, et al: Abiraterone acetate (AA) plus low dose prednisone (P) improves overall survival (OS) in patients (pts) with metastatic castration-resistant prostate cancer (mCRPC) who have progressed after docetaxel-based chemotherapy (chemo): Results of COU-AA-301, a randomized, double-blind, placebo-controlled phase III study. 35th ESMO Congress. Abstract LBA5. Presented October 11, 2010.

Watch for coverage of the ESMO and ASCO joint symposium on “The future of antiangiogenesis therapy” in the December issue of The ASCO Post.

Concerned about CYP2D6 in breast cancer?

Fareston may be the answer. ®

Fareston helps reduce the guess work FARESTON (toremifene citrate) 60 mg Tablets: indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen receptor positive or unknown tumors.

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500,000 PATIENT YEARS

UNIQUE METABOLISM

PATIENT SAVINGS

Parent compound binds to and blocks estrogen receptors

Metabolized principally by CYP3A4 CYP2D6 does not play a significant role in the activity of FARESTON No known drug interactions with SSRI antidepressants

Proven clinical profile Efficacy comparable to tamoxifen in head to head trials

Savings coupons offer up to $50 off each prescription for eligible patients Patient Assistance Program available for Medicare Part D and uninsured patients who qualify

Important safety information: FARESTON is contraindicated in patients with known hypersensitivity to the drug. FARESTON has been shown to prolong the QTc interval in a dose and concentration dependent manner. FARESTON should not be prescribed to patients with congenital/acquired QT prolongation, uncorrected hypokalemia or uncorrected hypomagnesemia. The administration of FARESTON with agents that are strong CYP3A4 inhibitors (e.g., ketoconazole, grapefruit juice and others) increases the steady-state concentration in serum and should be avoided. Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. As with other antiestrogens, tumor flare, hypercalcemia, and vaginal bleeding have been reported in some breast cancer patients being treated with FARESTON. During clinical trials involving 1157 patients treated with FARESTON or tamoxifen, the incidence of serious side effects were as follows: cardiac events (2.03% vs. 2.42%), ocular events (10.30% vs. 9.38%), thromboembolic events (3.21% vs. 3.28%), and elevated liver tests (26.2% vs. 23.7%), respectively.

References: FARESTON® Prescribing Information, 2004. Data on file, GTx, Inc.

Please see full prescribing information on the following page.

For more information about Fareston call 1-877-362-7595 or visit www.fareston.com

© 2010 GTx, Inc., Memphis, TN 38103. All rights reserved. FAR-071R0 June 2010

FARESTON® (toremifene citrate) tablets DESCRIPTION FARESTON (toremifene citrate) Tablets for oral administration each contain 88.5 mg of toremifene citrate, which is equivalent to 60 mg toremifene.

FARESTON is a nonsteroidal antiestrogen. The chemical name of toremifene is: 2-{p-[(Z)-4-chloro1,2-diphenyl-1-butenyl]phenoxy}-N,N-dimethylethylamine citrate (1:1). The structural formula is: OCH2CH2N

C C CH2 CH2Cl

CH3 CH3

CH2COOH HO

C

COOH

CH2COOH

and the molecular formula is C26H28CINO • C6H8O7. The molecular weight of toremifene citrate is 598.10. The pKa is 8.0. Water solubility at 37˚C is 0.63 mg/mL and in 0.02N HCI at 37˚C is 0.38 mg/mL. FARESTON is available only as tablets for oral administration. Inactive ingredients: colloidal silicon dioxide, lactose, magnesium stearate, microcrystalline cellulose, povidone, sodium starch glycolate, and starch.

CLINICAL PHARMACOLOGY Mechanism of Action: Toremifene is a nonsteroidal triphenylethylene derivative. Toremifene binds to estrogen receptors and may exert estrogenic, antiestrogenic, or both activities, depending upon the duration of treatment, animal species, gender, target organ, or endpoint selected. In general, however, nonsteroidal triphenylethylene derivatives are predominantly antiestrogenic in rats and humans and estrogenic in mice. In rats, toremifene causes regression of established dimethylbenzanthracene (DMBA)-induced mam-mary tumors. The antitumor effect of toremifene in breast cancer is believed to be mainly due to its antiestrogenic effects, ie, its ability to compete with estrogen for binding sites in the cancer, blocking the growthstimulating effects of estrogen in the tumor.

Toremifene causes a decrease in the estradiol-induced vaginal cornification index in some postmenopausal women, indicative of its antiestrogenic activity. Toremifene also has estrogenic activity as shown by decreases in serum gonadotropin concentrations (FSH and LH).

Pharmacokinetics: The plasma concentration time profile of toremifene declines biexponentially after absorption with a mean distribution half-life of about 4 hours and an elimination half-life of about 5 days. Elimination half-lives of major metabolites, N-demethyltoremifene and (deaminohydroxy) toremifene were 6 and 4 days, respectively. Mean total clearance of toremifene was approximately 5L/h.

Absorption and Distribution: Toremifene is well absorbed after oral administration and absorption is not influenced by food. Peak plasma concentrations are obtained within 3 hours.

Toremifene displays linear pharmacokinetics after single oral doses of 10 to 680 mg. After multiple dosing, dose proportionality was observed for doses of 10 to 400 mg. Steady-state concentrations were reached in about 4-6 weeks. Toremifene has an apparent volume of distribution of 580 L and binds extensively (>99.5%) to serum proteins, mainly to albumin.

Metabolism and Excretion: Toremifene is extensively metabolized, principally by CYP3A4 to N-demethyltoremifene, which is also antiestrogenic but with weak in vivo antitumor potency.

Serum concentrations of N-demethyltoremifene are 2 to 4 times higher than toremifene at steady state. Toremifene is eliminated as metabolites predominantly in the feces, with about 10% excreted in the urine during a 1-week period. Elimination of toremifene is slow, in part because of enterohepatic circulation.

Special Populations: Renal insufficiency: The pharmacokinetics of toremifene and N-demethyltoremifene were similar in normals and in patients with impaired kidney function.

Hepatic insufficiency: The mean elimination half-life of toremifene was increased by less than twofold in 10 patients with hepatic impairment (cirrhosis or fibrosis) compared to subjects with normal hepatic function. The pharmacokinetics of N-demethyltoremifene were unchanged in these patients. Ten patients on anticonvulsants (phenobarbital, clonazepam, phenytoin, and carbamazepine) showed a twofold increase in clearance and a decrease in the elimination half-life of toremifene.

Geriatric patients: The pharmacokinetics of toremifene were studied in 10 healthy young males and 10 elderly females following a single 120 mg dose under fasting conditions. Increases in the elimination half-life (4.2 versus 7.2 days) and the volume of distribution (457 versus 627 L) of toremifene were seen in the elderly females without any change in clearance or AUC. Race: The pharmacokinetics of toremifene in patients of different races has not been studied.

Drug-drug interactions: No formal drug-drug interaction studies with toremifene have been performed.

CLINICAL STUDIES Three prospective, randomized, controlled clinical studies (North American, Eastern European, and Nordic) were conducted to evaluate the efficacy of FARESTON for the treatment of breast cancer in postmenopausal women. The patients were randomized to parallel groups receiving FARESTON 60 mg (FAR60) or tamoxifen 20 mg (TAM20) in the North American Study or tamoxifen 40 mg (TAM40) in the Eastern European and Nordic studies. The North American and Eastern European studies also included high-dose toremifene arms of 200 and 240 mg daily, respectively. The studies included postmenopausal patients with estrogen-receptor (ER) positive or estrogen-receptor (ER) unknown metastatic breast cancer. The patients had at least one measurable or evaluable lesion. The primary efficacy variables were response rate (RR) and time to progression (TTP). Survival (S) was also determined. Ninety-five percent confidence intervals (95% CI) were calculated for the difference in RR between FAR60 and TAM groups and the hazard ratio (relative risk for an unfavorable event, such as disease progression or death) between TAM and FAR60 for TTP and S. Two of the 3 studies showed similar results for all effectiveness endpoints. However, the Nordic Study showed a longer time to progression for tamoxifen (see table).

Clinical Studies Study North American Eastern European Nordic Treatment Group FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 No. Patients 221 215 157 149 214 201 Responses 14+33 11+30 7+25 3+28 19+48 19+56 CR1 + PR2 RR3 (CR + PR)% 21.3 19.1 20.4 20.8 31.3 37.3 Difference in RR 2.2 -0.4 -6.0 95% CI4 for Difference in RR -5.8 to 10.2 -9.5 to 8.6 -15.1 to 3.1 Time to Progression (TTP) Median TTP (mo.)

5.6 5.8 4.9 5.0 7.3 10.2 Hazard Ratio (TAM/FAR) 1.01 1.02 0.80 95% CI4 for Hazard Ratio (%) 0.81 to 1.26 0.79 to 1.31 0.64 to 1.00 Survival (S) Median S (mo.)

33.6 34.0 25.4 23.4 33.0 38.7 Hazard Ratio (TAM/FAR) 0.94 0.96 0.94 95% CI4 for Hazard Ratio (%) 0.74 to 1.24 0.72 to 1.28 0.73 to 1.22 1 CR = complete response; 2PR = partial response; 3RR = response rate; 4CI = confidence interval The high-dose groups, toremifene 200 mg daily in the North American Study and 240 mg daily in the Eastern European Study, were not superior to the lower toremifene dose groups, with response rates of 22.6% AND 28.7%, median times to progression of 5.6 and 6.1 months, and median

survivals of 30.1 and 23.8 months, respectively. The median treatment duration in the three pivotal studies was 5 months (range 4.2-6.3 months).

Race: Fourteen percent of patients in the North American Study were non-Caucasian. No significant race-related differences in FARESTON effectiveness or safety were noted.

INDICATION AND USAGE FARESTON is indicated for the treatment of metastatic breast cancer in postmenopausal women with estrogen-receptor positive or unknown tumors.

ADVERSE REACTIONS Adverse drug reactions are principally due to the antiestrogenic hormonal actions of FARESTON and typically occur at the beginning of treatment.

The incidences of the following eight clinical toxicities were prospectively assessed in the North American Study. The incidence reflects the toxicities that were considered by the investigator to be drug related or possibly drug related.

North American Study FAR60 TAM20 n = 221 n = 215 Hot Flashes 35% 30% Sweating 20% 17% Nausea 14% 15% Vaginal Discharge 13% 16% Dizziness 9% 7% Edema 5% 5% Vomiting 4% 2% 4% Vaginal Bleeding 2%

CONTRAINDICATIONS FARESTON is contraindicated in patients with known hypersensitivity to the drug.

WARNINGS Hypercalcemia and Tumor Flare: As with other antiestrogens, hypercalcemia and tumor flare have been reported in some breast cancer patients with bone metastases during the first weeks of treatment with FARESTON. Tumor flare is a syndrome of diffuse musculoskeletal pain and erythema with increased size of tumor lesions that later regress. It is often accompanied by hypercalcemia. Tumor flare does not imply failure of treatment or represent tumor progression. If hypercalcemia occurs, appropriate measures should be instituted and if hypercalcemia is severe, FARESTON treatment should be discontinued.

Tumorigenicity: Since most toremifene trials have been conducted in patients with metastatic disease, adequate data on the potential endometrial tumorigenicity of long-term treatment with FARESTON are not available. Endometrial hyperplasia has been reported. Some patients treated with FARESTON have developed endometrial cancer, but circumstances (short duration of treatment or prior antiestrogen treatment or premalignant conditions) make it difficult to establish the role of FARESTON. Endometrial hyperplasia of the uterus was observed in monkeys following 52 weeks of treatment at ≥1 mg/kg and in dogs following 16 weeks of treatment at ≥3 mg/kg with toremifene (about 1/4 and 1.4 times, respectively, the daily maximum recommended human dose on a mg/m2 basis).

Pregnancy: FARESTON may cause fetal harm when administered to pregnant women. Studies in rats at doses ≥1.0 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) administered during the period of organogenesis, have shown that toremifene is embryotoxic and fetotoxic, as indicated by intrauterine mortality, increased resorption, reduced fetal weight, and fetal anomalies; including malformation of limbs, incomplete ossification, misshapen bones, ribs/spine anomalies, hydroureter, hydronephrosis, testicular displacement, and subcutaneous edema. Fetal anomalies may have been a consequence of maternal toxicity. Toremifene has been shown to cross the placenta and accumulate in the rodent fetus.

In rodent models of fetal reproductive tract development, toremifene produced inhibition of uterine development in female pups similar to diethylstilbestrol (DES) and tamoxifen. The clinical relevance of these changes is not known.

Embryotoxicity and fetotoxicity were observed in rabbits at doses ≥1.25 mg/kg/day and 2.5 mg/ kg/day, respectively (about 1/3 and 2/3 the daily maximum recommended human dose on a mg/mt basis); fetal anomalies included incomplete ossification and anencephaly.

There are no studies in pregnant women. If FARESTON is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus or potential risk for loss of the pregnancy.

PRECAUTIONS General: Patients with a history of thromboembolic diseases should generally not be treated with FARESTON. In general, patients with preexisting endometrial hyperplasia should not be given long-term FARESTON treatment. Patients with bone metastases should be monitored closely for hypercalcemia during the first weeks of treatment (see Warnings). Leukopenia and thrombocytopenia have been reported rarely; leukocyte and platelet counts should be monitored when using FARESTON in patients with leukopenia and thrombocytopenia.

Information for Patients: Vaginal bleeding has been reported in patients using FARESTON. Patients should be informed about this and instructed to contact their physician if such bleeding occurs.

Patients with bone metastases should be informed about the typical signs and symptoms of hypercalcemia and instructed to contact their physician for further assessment if such signs or symptoms occur.

Laboratory Tests: Periodic complete blood counts, calcium levels, and liver function tests should be obtained.

Drug-drug Interactions: Drugs that decrease renal calcium excretion, eg, thiazide diuretics, may increase the risk of hypercalcemia in patients receiving FARESTON. There is a known interaction between antiestrogenic compounds of the triphenylethylene derivative class and coumarin-type anticoagulants (eg, warfarin), leading to an increased prothrombin time. When concomitant use of anticoagulants with FARESTON is necessary, careful monitoring of the prothrombin time is recommended.

Cytochrome P450 3A4 enzyme inducers, such as phenobarbital, phenytoin, and carbamazepine increase the rate of toremifene metabolism, lowering the steady-state concentration in serum.

Metabolism of toremifene may be inhibited by drugs known to inhibit the CYP3A4-6 enzymes.

Examples of such drugs are ketoconazole and similar antimycotics as well as erythromycin and similar macrolides. This interaction has not been studied and its clinical relevance is uncertain.

Carcinogenesis, Mutagenesis, and Impairment of Fertility: Conventional carcinogenesis studies in rats at doses of 0.12 to 12 mg/kg/day (about 1/100 to 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years did not show evidence of carcinogenicity. Studies in mice at doses of 1.0 to 30.0 mg/kg/day (about 1/15 to 2 times the daily maximum recommended human dose on a mg/m2 basis) for up to 2 years revealed increased incidence of ovarian and testicular tumors, and increased incidence of osteoma and osteosarcoma.

The significance of the mouse findings is uncertain because of the different role of estrogens in mice and the estrogenic effect of toremifene in mice. An increased incidence of ovarian and testicular tumors in mice has also been observed with other human antiestrogenic agents that have primarily estrogenic activity in mice.

Toremifene has not been shown to be mutagenic in in vitro tests (Ames and E. coli bacterial tests). Toremifene is clastogenic in vitro (chromosomal aberrations and micronuclei formation in human lymphoblastoid MCL-5 cells) and in vivo (chromosomal aberrations in rat hepatocytes).

No significant adduct formation could be detected using 32P post-labeling in liver DNA from rats administered toremifene when compared to tamoxifen at similar doses. A study in cultured human lymphocytes indicated that adducting activity of toremifene, detected by 32P post-labeling, was about 1/6 that of tamoxifen at approximately equipotent concentrations. In addition, the DNA adducting activity of toremifene in salmon sperm, using 32P post-labeling, was 1/6 and 1/4 that observed with tamoxifen at equivalent concentrations following activation by rat and human microsomal systems, respectively. However, toremifene exposure is fourfold the exposure of tamoxifen based on human AUC in serum at recommended clinical doses.

Toremifene produced impairment of fertility and conception in male and female rats at doses ≥25.0 and 0.14 mg/kg/day, respectively (about 3.5 times and 1/50 the daily maximum recommended human dose on a mg/m2 basis). At these doses, sperm counts, fertility index, and conception rate were reduced in males with atrophy of seminal vesicles and prostate. In females, fertility and reproductive indices were markedly reduced with increased pre- and post-implantation loss. In addition, offspring of treated rats exhibited depressed reproductive indices. Toremifene produced ovarian atrophy in dogs administered doses ≥3 mg/kg/day (about 1.5 times the daily maximum recommended human dose on a mg/m2 basis) for 16 weeks. Cystic ovaries and reduction in endometrial stromal cellularity were observed in monkeys at doses ≥1 mg/kg/day (about 1/4 the daily maximum recommended human dose on a mg/m2 basis) for 52 weeks.

Pregnancy: Pregnancy Category D: (see WARNINGS).

Nursing mothers: Toremifene has been shown to be excreted in the milk of lactating rats. It is not known if this drug is excreted in human milk. (See WARNINGS and PRECAUTIONS).

Pediatric use: There is no indication for use of FARESTON in pediatric patients.

Geriatric use: The median ages in the three controlled studies ranged from 60 to 66 years. No significant age-related differences in FARESTON effectiveness or safety were noted.

Approximately 1% of patients receiving FARESTON (n = 592) in the three controlled studies discontinued treatment as a result of adverse events (nausea and vomiting, fatigue, thrombophlebitis, depression, lethargy, anorexia, ischemic attack, arthritis, pulmonary embolism, and myocardial infarction).

Serious adverse events occurring in patients receiving FARESTON in the three major trials are listed in the table below.

Adverse Events North American Eastern European Nordic FAR60 TAM20 FAR60 TAM40 FAR60 TAM40 n=221(%) n=215(%) n=157(%) n=149(%) n=214(%) n=201(%) Cardiac Cardiac Failure 2 (1) 1 (<1) 1 (<1) 2 (1) 3 (1.5) Myocardial Infarction 2 (1) 3 (1.5) 1 (<1) 2 (1) 1 (<1) Arrhythmia 3 (1.5) 1 (<1) Angina Pectoris 1 (<1) 1 (<1) 2 (1) Ocular* Cataracts 22 (10) 16 (7.5) 5 (3) Dry Eyes 20 (9) 16 (7.5) Abnormal Visual Fields 8 (4) 10 (5) 1 (<1) Corneal Keratopathy 4 (2) 2 (1) Glaucoma 3 (1.5) 2 (1) 1 (<1) 1 (<1) Abnormal Vision/Diplopia 3 (1.5) Thromboembolic Pulmonary Embolism 4 (2) 2 (1) 1 (<1) 1 (<1) Thrombophlebitis 2 (1) 1 (<1) 1 (<1) 4 (2) 3 (1.5) Thrombosis 1 (<1) 1 (<1) 3 (1.5) 4 (2) CVA/TIA 1 (<1) 1 (<1) 4 (2) 4 (2) Elevated Liver Tests** SGOT 11 (5) 4 (2) 30 (19) 22 (15) 32 (15) 35 (17) Alkaline Phosphatase 41 (19) 24 (11) 16 (10) 13 (9) 18 (8) 31 (15) Bilirubin 3 (1.5) 4 (2) 2 (1) 1 (<1) 2 (1) 3 (1.5) Hypercalcemia 6 (3) 6 (3) 1 (<1) * Most of the ocular abnormalities were observed in the North American Study in which on-study and biannual opthalmic examinations were performed. No cases of retinopathy were observed in any arm. ** Elevated defined as follows: North American Study: SGOT >100 IU/L; alkaline phosphatase >200 IU/L; bilirubin > 2 mg/dL. Eastern European and Nordic studies: SGOT, alkaline phosphatase, and bilirubin – WHO Grade 1 (1.25 times the upper limit of normal).

Other adverse events of unclear causal relationship to FARESTON included leukopenia and thrombocytopenia, skin discoloration or dermatitis, constipation, dyspnea, paresis, tremor, vertigo, pruritis, anorexia, reversible corneal opacity (corneal verticulata), asthenia, alopecia, depression, jaundice, and rigors.

In the 200 and 240 mg FARESTON dose arms, the incidence of SGOT elevation and nausea was higher. Approximately 4% of patients were withdrawn for toxicity from the high-dose FARESTON treatment arms. Reasons for withdrawal included hypercalcemia, abnormal liver function tests, and one case each of toxic hepatitis, depression, dizziness, incoordination, ataxia, blurry vision, diffuse dermatitis, and a constellation of symptoms consisting of nausea, sweating, and tremor.

OVERDOSAGE Lethality was observed in rats following single oral doses that were ≥1000 mg/kg (about 150 times the recommended human dose on a mg/m2 basis) and was associated with gastric atony/dilatation leading to interference with digestion and adrenal enlargement.

Vertigo, headache, and dizziness were observed in healthy volunteer studies at a daily dose of 680 mg for 5 days. The symptoms occurred in two of the five subjects during the third day of the treatment and disappeared within 2 days of discontinuation of the drug. No immediate concomitant changes in any measured clinical chemistry parameters were found. In a study in postmenopausal breast cancer patients, toremifene 400 mg/m2/day caused dose-limiting nausea, vomiting, and dizziness, as well as reversible hallucinations and ataxia in one patient.

Theoretically, overdose may be manifested as an increase of antiestrogenic effects, such as hot flashes; estrogenic effects, such as vaginal bleeding; or nervous system disorders, such as vertigo, dizziness, ataxia, and nausea. There is no specific antidote and the treatment is symptomatic.

DOSAGE AND ADMINISTRATION The dosage of FARESTON is 60 mg, once daily, orally. Treatment is generally continued until disease progression is observed.

HOW SUPPLIED FARESTON Tablets, containing toremifene citrate in an amount equivalent to 60 mg of toremifene, are round, convex, unscored, uncoated, and white, or almost white.

FARESTON Tablets are identified with TO 60 embossed on one side.

FARESTON Tablets are available as: NDC 11399-005-30 bottles of 30 NDC 11399-005-01 bottles of 100 Store at 25°C (77°F) excursions permitted to 15-30°C (59-86°F) [see USP Controlled Room Temperature].

Protect from heat and light.

Distributed by GTx, Inc. Memphis, TN 38163, USA Product covered by Orion Product Patents and related patent numbers. © 2004 GTx, Inc. All rights reserved.

1E Rev. 12/2004

ASCOPost.com | NOVEMBER 2010

PAGE 23

Direct from ASCO

Candidates Nominated for Society Leadership Positions Voting opened to eligible members October 13

F

ourteen candidates have been nominated for seven open positions on the ASCO Board of Directors and Nominating Committee.

Active, Active-Junior, and Emeritus (formerly Active) members are eligible to vote for new Society leadership.

Online voting began October 13, 2010 (https://www.directvote.net/asco/); eligible members without e-mail addresses will receive paper ballots by mail in mid- to late October. Members may vote only once. Voting closes on November 23, 2010, at 11:59 PM. ASCO members can get better acquainted with the candidates by visiting 2011 ASCO Election News (www. asco.org/electionnews), which includes biographies and interviews of all candidates, plus video interviews with President-Elect candidates.

Election results will be announced in January 2011. New officers will begin their terms at the conclusion of the 2011 ASCO Annual Meeting.

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© 2010. American Society of Clinical Oncology. All Rights Reserved.

2011 ASCO Election Candidates President-Elect • S andra M. Swain, MD Washington Cancer Institute; Georgetown University; Uniformed Services University of the Health Sciences • J amie H. Von Roenn, MD Northwestern University Feinberg School of Medicine; Robert H. Lurie Comprehensive Cancer Center; Northwestern Memorial Hospital

Board of Directors—Community Oncologist •G ary I. Cohen, MD, FACP Greater Baltimore Medical Center; Johns Hopkins University •W . Charles Penley, MD Tennessee Oncology, PLLC

Board of Directors—Undesignated Specialty (2 seats open) •D aniel F. Hayes, MD University of Michigan Comprehensive Cancer Center •N eal J. Meropol, MD University Hospitals Case Medical Center; Case Western Reserve University; Fox Chase Cancer Center •L illian L. Siu, MD, FRCPC Princess Margaret Hospital; University of Toronto; Cancer Care Ontario •E ric P. Winer, MD Dana-Farber Cancer Institute; Harvard Medical School

Nominating Committee (2 seats open)

Board of Directors—Surgical Oncologist •H . Kim Lyerly, MD Duke University Comprehensive Cancer Center; Duke University Medical Center; Womack Army Hospital •C arolyn D. Runowicz, MD University of Connecticut Health Center

•H arold J. Burstein, MD, PhD Dana-Farber Cancer Institute; Brigham & Women’s Hospital; Harvard Medical School • Kathy D. Miller, MD Indiana University School of Medicine; Indiana University Hospital •H oward M. Sandler, MD Cedars-Sinai Medical Center •D avid R. Spriggs, MD Memorial Sloan-Kettering Cancer Center; Weill Cornell Medical College; Memorial Hospital

ASCO Journals Launch on New Web 2.0 Platform Journal of Clinical Oncology and Journal of Oncology Practice have launched on a new Web 2.0 platform.

T

he improved site design and layout, combined with new Web 2.0 features and functionality, make for greater readability and easier navigation around the sites. In addition, the

new color palette and three-column layout clearly and cleanly order the information provided into main text, associated tools, and information links.

The new sites will better serve the

reader’s need to obtain fast and efficient access to the most important research in clinical oncology and the latest information in oncology practice.

Please e-mail any comments about

the new sites to James Kim (james. kim@asco.org).

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© 2010. American Society of Clinical Oncology. All Rights Reserved.

The ASCO Post | NOVEMBER 2010

PAGE 24

Direct from ASCO

2011 Genitourinary Cancers Symposium to Highlight Multidisciplinary Management, Translational Science February 17–19 in Orlando

A

ttending the upcoming meeting on genitourinary (GU) cancers is likely to change your practice.

And that’s the point. Clinicians from around the world and from multiple disciplines come to the 3-day Genitourinary Cancers Symposium to learn, and they take home new awareness and strategies that they can use in managing GU cancers.

‘How My Practice Will Change’ The following are just a few of the dozens of comments from the participants in last year’s symposium about how they expected to change their practice after the meeting: ■■ Increase cytoreductive nephrectomy ■■ Change our screening practice for prostate cancer ■■ Be more proactive about advocating partial nephrectomy ■■ Look for opportunities to use biomarkers in prostate cancer ■■ Use cabazitaxel [once available] in second-line chemotherapy for prostate cancer ■■ Re-treat with sunitinib (Sutent) in patients with renal cancer ■■ Biopsy small renal masses ■■ Use second-line mitoxantrone more often as palliative therapy in patients with prostate cancer ■■ Consider hypofractionation with stereotactic body radiation for prostate cancer “The primary goal of the meeting

is to present the state of the art— what’s going on in genitourinary oncology today—and try to limit rehashing what’s been done over the last few years,” says Leonard G. Gomella, MD, Chair of the Urology Department at Thomas Jefferson University and the Kimmel Cancer Center in Philadelphia and Chairelect of the symposium’s Planning Committee. One of the ways the symposium will meet that goal is by having translational science sessions on prostate cancer, urothelial carcinomas, and renal cancer, the three broad areas addressed. “The translational science component is where people can learn about what’s coming down the pike in the near term,” Dr. Gomella notes.

In addition to translational science sessions, each cancer type has panel presentations, oral abstracts, and poster presentations. “Best of Journals” sessions are also offered for both prostate cancer and renal cancer.

cancer. This meeting fits that bill perfectly.”

The Planning Committee made changes based on feedback from the previous meeting’s participants. For example, planning for the upcoming meeting will include input from imaging and interventional radiology specialists. The popularity of presentations using case studies also led to program enhancements. “Built into each tumor section, we have a series

of clinical case studies that will be used as a stepping-off point for the discussion of very specific topics,” Dr Gomella notes.

Since the first Genitourinary Cancers Symposium in 2005, the attendance has doubled. More than 2,000 professionals are expected at the 2011 event.

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© 2010. American Society of Clinical Oncology. All Rights Reserved.

Meeting Site: The Orlando World Center Marriott

Deadline for early, discounted registration: January 12, 2011

Multidisciplinary Approach Important to Successful Treatment The symposium emphasizes a multidisciplinary approach. “Our best clinical outcomes are when we approach cancer from an interdisciplinary aspect,” Dr. Gomella says.

“Over the past 10 years, we have recognized that we are not in silos in the management of genitourinary

F

lorida in February—the perfect spot for taking a breather from harsh winter weather. The Orlando World Center Marriott offers all the amenities of a world-class resort coupled with high-tech conference space and eco-friendly policies.

For more information and to register for the symposium, visit www.gucasym.org/2011.

Save the Date December 9-11, 2010 Chicago Chicago Multidisciplinary Symposium in Thoracic Oncology www.astro.org/Meetings

January 20-22, 2011 San Francisco Gastrointestinal Cancers Symposium www.gicasymposium.org

February 17-19, 2011 Orlando, Florida Genitourinary Cancers Symposium www.gucasymposium.org

ASCOPost.com | NOVEMBER 2010

PAGE 25

Direct from ASCO

Clinical Trials Participation Awards Recognize Efforts of Community-based Practices

A

t the 2010 Annual Meeting in June, ASCO presented its 2010 Clinical Trials Participation Awards (CTPAs) to 10 community oncology practices for their commitment to improving the care of patients with cancer through increased participation in clinical trials.

consin); New Hanover Radiation Oncology Center (Wilmington, North Carolina); Oncology Alliance (Wauwatosa, Wisconsin); Saint Francis Medical Center/ Cancer Treatment Center (Grand Island, Nebraska); Sandra and Malcolm Berman Cancer Institute,

The CTPAs are presented to communitybased practices participating in clinical trials, which are vital to ensuring continued advancement of cancer therapies.

The CTPAs are designed to recognize and promote high-quality clinical research sites with the intent of increasing the awareness of and participation in clinical trials among physicians. The awards are presented to community-based practices participating in clinical trials, which are vital to ensuring continued advancement of cancer therapies.

The 2010 award recipients include Dean Hematology Oncology (Madison, Wisconsin); Gundersen Lutheran Center for Cancer and Blood Disorders (La Crosse, Wis-

Greater Baltimore Medical Center (Baltimore, Maryland); Sanford Hematology and Oncology (Sioux Falls, South Dakota); Southeastern Medical Oncology Center (Goldsboro, North Carolina); The Virginia Mason Cancer Institute (Seattle, Washington); and The West Clinic (Memphis, Tennessee).

Dedication and Commitment of Resources “Clinical research activities in the community continue to be critical to the successful comple-

tion of trials and the advancing of the continuum of cancer care,” said Robin Zon, MD, FACP, Chair of the CTPA Review and Selection Subcommittee. “The Clinical Trial Participation Awards recognize sites that have proven dedication and commitment of resources while achieving high standards of performance in their clinical trial program,” she added.

ASCO supports patient access to investigational and proven therapies offered in clinical research studies. For many patients, clinical trials provide the best means for accessing a new cancer therapy, and these awards are efforts to both reward practices and provide public recognition for their efforts.

Winners were determined to have a high-quality, community-based research program with exemplary audit reports and investigators in good standing. Practices that had received this award in the past 5 years were considered ineligible.

ASCO solicits award nominees from each of the NCI Cooperative Groups and the NCI Community Clinical Oncology Program. Nominations are also solicited from major community-based oncology

research networks. All nominated practices were invited to formally submit an application, which was then peer-reviewed by the CTPA Review and Selection Subcommittee of the ASCO Cancer Research Committee. Additional members of this subcommittee include James Feusner, MD; Stephen Grubbs, MD; Rogerio Lilenbaum, MD; Alan P. Lyss, MD; and Gregory H. Reaman, MD. The CTPAs were established in 2003 after a recommendation of the 2001 Clinical Trials Task Force to increase initiatives that enhance physician awareness of and participation in clinical trials. Since 2003, a total of 81 awards have been bestowed. The CTPAs are sponsored by the Coalition of Cancer Cooperative Groups. For additional information about the CTPA, please send an e-mail to grants@asco.org or visit www.ascocancerfoundation. org/CTPA.

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Selected portions reprinted from ASCO Daily News. © American Society of Clinical Oncology. “Clinical Trials Participation Awards Recognize Efforts of Community-based Practices.” ASCO Daily News 13:28C, 2010. All rights reserved.

What’s Hot in JCO

Top 10 most-accessed articles recently published in Journal of Clinical Oncology Vol 28, No 20

July 10, 2010

J OURNAL OF C LINICAL O NCOLOGY Comments and Controversies: Research on Early-Stage Carcinogenesis: Are We Approaching Paradigm Instability? S.G. Baker et al Editorial: Microsatellite Instability and Adjuvant Fluorouracil Chemotherapy: A Mismatch? K. Ng et al Editorial: Defective Mismatch Repair in Colon Cancer: A Prognostic or Predictive Biomarker? D.J. Kerr et al Editorial: Wrestling With the High Price of Cancer Care: Should We Control Costs by Individuals’ Ability to Pay or Society’s Willingness to Pay? J.L. Malin Confirmation of Defective Mismatch Repair As a Predictive Marker for Lack of Efficacy of FU-Based Adjuvant Therapy in Colon Cancer. D.J. Sargent et al Comparison of Anticancer Drug Coverage Decisions in the United States and United Kingdom. A. Mason et al Randomized Phase III Trial of Ixabepilone Plus Capecitabine Versus Capecitabine in Patients With Metastatic Breast Cancer Previously Treated With an Anthracycline and a Taxane. J.A. Sparano et al EGFR Inhibitor Gefitinib Added to Chemoradiotherapy in Locally Advanced Head and Neck Cancer. E.E.W. Cohen et al Review Article: Emerging Targeted Therapies for Breast Cancer R.H. Alvarez et al Biology Of Neoplasia: Clinical Relevance of Microsatellite Instability in Colorectal Cancer. A. de la Chapelle et al ASCO Special Article: American Society of Clinical Oncology 2009 Clinical Practice Guideline on Uses of Serum Tumor Markers in Adults With Germ Cell Tumors. T. Gilligan et al Official Journal of the American Society of Clinical Oncology

www.jco.org

1. Host Factors and Cancer Outcome Pamela J. Goodwin, et al 28(26):4019 2. Radiation Therapy After R-CHOP for Diffuse Large B-Cell Lymphoma: The Gain Remains Joachim Yahalom 28(27): 4105 3. Using Lifetime Risk Estimates to Recommend Magnetic Resonance Imaging Screening for Breast Cancer Survivors Rinaa S. Punglia, et al 28(27):4108

4. Is It Time to ReSET the Standard for Estrogen Receptor Testing in Breast Cancer?

Steffi Oesterreich, et al 28(27):4101

8. Pitfalls of Using Composite Primary End Points in the Presence of Competing Risks Loren K. Mell 28(28):4297

5. Human Epidermal Growth Factor Receptor 2 Testing: Where Are We? Pradip De, et al 28(28):4289

9. Human Epidermal Growth Factor Receptor 2 Testing in 2010: Does Chromosome 17 Centromere Copy Number Make Any Difference?

Jeffrey S. Ross 28(28): 4293

6. Genomic Index of Sensitivity to Endocrine Therapy for Breast Cancer W. Fraser Symmans, et al 28(27):4111 7. A Cello for Michayla David P. Steensma 28(28): 4400

10. Benefit of Consolidative Radiation Therapy in Patients With Diffuse Large B-Cell Lymphoma Treated With R-CHOP Chemotherapy Jack Phan, et al 28(27):4170

The ASCO Post | NOVEMBER 2010

PAGE 26

Direct from ASCO

ASCO in Action: Your Resource for Public Policy and Clinical Affairs Initiatives from ASCO

A

SCO is constantly working for its members in the areas of public policy and clinical affairs to ensure patient access to high-quality cancer care.

In an effort to better communicate ASCO’s work in these arenas, ASCO has developed the ASCO in Action Web page (www.asco.org/ascoaction).

From research policy to clinical affairs, quality of care, and government relations, this is the “one-stop shop” for the latest updates on ASCO’s initiatives

NOW RECRUITING

Investigators Study of the long-term safety and efficacy of darbepoetin alfa in anemic patients with Non-Small Cell Lung Cancer (NSCLC) receiving chemotherapy Phase 3 study with approximately 3,000 subjects at 500 study sites globally

• Overall survival

• Receiving 1st-line chemotherapy

SECONDARY ENDPOINTS

• Hemoglobin (Hb) ≤ 11 g/dL

• Progression-free survival

transfusion or Hb ≤ 8.0 g/dL

2:1 Randomization (darbepoetin alfa: placebo)

End of Investigational Product

End of Treatment Period

Long-term Follow-up

Placebo Q3W

Week 0

Week 1

Updated almost daily, regular postings include policy recommendations submitted to the Center for Medicare and Medicaid Services (CMS), comments sent to the FDA, guideline and clinical practice updates, electronic health record program updates, and high-priority legislative and regulatory action. You will also hear directly from the society in videos and opinion pieces published on an as-needed basis.

Developed in the summer of 2009, ASCO in Action was initially designed to serve as a resource regarding news on the health-care reform legislation.

Although health-care reform was a hot issue at the time, it soon became clear that the need was not just for what was going on outside of ASCO, but rather for what ASCO considered priorities in terms of public policy.

Officially relaunched in March 2010, the ASCO in Action Web page continues to evolve to better serve our members. While ASCO had communicated with membership on public policy issues through the Cancer Policy Today newsletter, and timely Grassroots Action Alerts, the cohesion among the different communication vehicles needed to be addressed.

This past summer, in conjunction with the ASCO in Action Web page, the Society launched the ASCO in Action Brief—a stand-alone newsletter dedicated to more in-depth feature articles about the topics featured on the ASCO in Action Web page. Members who wish to get involved with ASCO’s public policy efforts also receive ASCO in Action Alerts—a call to action around a particular issue or legislation.

For the Society’s positions on hotbutton policy issues and more information on how ASCO’s initiatives impact policymakers and stakeholders across the cancer community, visit ASCO in Action.

• Incidence of ≥ 1 red blood cell (RBC)

Darbepoetin alfa 500 mcg Q3W

Updated Regularly

Evolving Forum

KEY INCLUSION CRITERIA* PRIMARY ENDPOINT • Advanced NSCLC

and projects out of the Cancer Policy and Clinical Affairs Department.

Disease progression or end of chemotherapy treatment

*Complete inclusion/exclusion criteria can be found in the protocol.

For more information, please visit www.782study.com or call 1-866-965-0782 (US and Canada only).

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

© 2010 Amgen. All rights reserved.

MC45038-D-6

04-10

ASCOPost.com | NOVEMBER 2010

PAGE 27

Direct from ASCO

Young Investigator and Career Development Awards Support Next Generation of Researchers

T

he ASCO Cancer Foundation® (TACF) is committed to supporting high-quality, clinically relevant research throughout an oncologist’s career. TACF supports both the Young Investigator Award (YIA), which is intended specifically for investigators at the beginning of their careers, and the Career Development Award (CDA), which supports investigators establishing an independent clinical cancer research program.

Young Investigator Awards First awarded in 1984, the YIA has helped launch the careers of more than 600 investigators. YIAs are offered to physicians who are currently in the last 2 years of their final subspecialty training at an academic medical institution, during the transition from a fellowship program to a faculty appointment.

Recipients should also be working in an oncology laboratory or clinical research setting. The YIA is a $50,000 grant awarded to the recipient’s sponsoring institution over 1 year.

In 2010, YIAs were awarded to 53 promising oncology professionals. Six YIAs are sponsored by entities within or in collaboration with ASCO and TACF: • Holbrook Edwin Kohrt, MD,

Help Your Patients Understand Clinical Trials

D

irect your patients to Cancer.

Net (www.cancer.net), ASCO’s patient information website, to learn about the purpose, design, and funding of clinical trials; how patient safety is upheld in the process; what is involved in the different phases of clinical trials; how to decide whether to participate; what questions to ask the research team; how to find a clinical trial; and more (www.cancer.net/clinicaltrials).

This information is also available in Spanish (www.cancer.net/espanol).

© 2010. American Society of Clinical Oncology. All Rights Reserved.

recipient of one of the TACF-sponsored YIAs, is conducting a phase I trial studying the safety and therapeutic efficacy of a matched cancer-peptide vaccine given to healthy donors before hematopoietic cell transplantation and to recipients with myeloid malignancies after transplantation.

• Shom Goel, MBBS, the other TACF-sponsored YIA recipient, is studying the mechanism of lapatinib (Tykerb) resistance in cerebral metastases of HER2-positive breast cancer.

• Nicole Chau, MD, who was awarded the YIA sponsored by the Boards of Directors for ASCO and TACF, is assessing the modulation of biomarkers for patients with resectable oral cavity cancer using a panHER inhibitor.

• Keerthi Gogineni, MD, received the ASCO Clinical Practice Committee–sponsored YIA and is studying community and provider determinants of breast cancer stage at diagnosis, treatment, and mortality.

• A legacy of George P. Canellos, MD, the Journal of Clinical Oncology–sponsored YIA was awarded to Christopher Hanyoung Lieu, MD. Dr. Lieu is investigating the role of basic fibroblast growth factor in re-

sistance to anti-VEGF therapy for colorectal cancer.

• The American Association for Cancer Research (AACR)/TACF Young Investigator Translational Cancer Research Award is supporting Aude Georgiana Chapuis, MD, in her immunotherapy-focused research project, “Targeting melanoma with anti-CTLA-4 and NY-ESO-1–specific cytotoxic T cells.”

Career Development Awards The $200,000 CDA grant, disbursed over 3 years to the recipient’s sponsoring institution, alleviates costs associated with supporting the recipient’s research endeavors. The CDA is offered to physicians who are in the 1st to 3rd year of a full-time, primary faculty appointment in a clinical department at an academic medical institution. Applications are peer-reviewed by the TACF Grants Selection Committee, whose criteria include a focus on patient-oriented clinical investigation; the significance, originality, appropriateness, feasibility, and adequacy of the proposed research program; the availability of institutional resources for support; prior research experience and accomplishments; and the quality of the mentor

and plan for mentor interactions.

Scott Kopetz, MD, Assistant Professor in the Department of Gastrointestinal Medical Oncology at The University of Texas M. D. Anderson Cancer Center, received a CDA in 2008 to study oxaliplatin-resistance mechanisms. Dr. Kopetz described the CDA as a bridge across the vulnerable first few years of an academic career, as the award provided the protected laboratory time and financial support to learn from unexpected results.

“While one metric of success may be publications and successfully completed trials, I have learned equally from the unpublished failures,” he said.

Since receiving his award Dr. Kopetz has completed one trial and begun a second with partial grant support, and published his laboratory studies in Cancer Research. He presented his first clinical study results at the 2010 ASCO Annual Meeting in Chicago.

For a full list of 2010 grant recipients and for more information about the complete portfolio of grants and awards offered by The ASCO Cancer Foundation, visit: www.ascocancerfoundation.org.

■

© 2010. American Society of Clinical Oncology. All Rights Reserved.

The ASCO Diversity in Oncology Initiative, funded by Susan G. Komen for the Cure® Application Period Loan Repayment Program (LRP)

September 16 – December 16, 2010

Resident Travel Award (RTA)

October 31, 2010 – January 31, 2011

Medical Student Rotation (MSR)

October 31, 2010 – January 31, 2011

How to Apply For application forms and complete application criteria for all three awards, visit The ASCO Cancer Foundation website at www.ascocancerfoundation.org and click on “Awards.” For further information about the Diversity in Oncology Initiative, please e-mail grants@asco.org. © 2010. American Society of Clinical Oncology. All Rights Reserved.

ASCOPost.com | NOVEMBER 2010

PAGE 31

TAP on Technology Prostate Cancer

Robot-assisted Laparoscopic Radical Prostatectomy: Risks and Benefits

By Matthew Stenger ith robot-assisted laparoscopic radical prostatectomy (LRP), the prostate gland can be removed via several 1- to 2-inch incisions in the patient’s abdomen. The procedure involves use of a robotic system consisting of a device that holds surgical instruments and a laparoscopic camera (Fig. 1); the device is guided by the surgeon through computer interface near the operating table. Open retropubic radical prostatectomy (ORP) is the gold standard for definitive prostate resection. However, enthusiasm for and adoption of robot-assisted LRP has grown rapidly, and has done so despite a lack of high-quality evidence showing superiority to ORP. Few randomized trials have compared ORP and LRP, and relatively few observational studies have been conducted. Moreover, most of the available data involve a small number of surgeons and patients from a single institution.1,2 Two large population-based analyses were limited by lack of data on tumor characteristics.3,4 Most observational data indicate reduced blood loss and reduced duration of hospital stay with LRP.2

cific antigen and Gleason scores.

The primary study findings were as follows: ■■ Median length of hospital stay was 2.0 days with LRP and 3.0 days with ORP, with length of stay being 35%

surgeon volume, unmarried status, and higher clinical stage were predictive of complications. Bladder neck/ urethral obstruction occurred in 29% of both groups; after adjustment for patient/tumor characteristics, LRP

Artwork by Alexandra and David Baker © 2010 DNA Illustrations, Inc.

W

Featured Study In a recently reported study using Surveillance, Epidemiology, and End Results (SEER) cancer registry data linked with Medicare claims, Lowrance and colleagues5 compared outcomes of ORP and LRP in men with clinically localized prostate cancer, while controlling for patient and tumor characteristics. They also assessed the impact of surgeon volume on outcome with LRP. The analysis included 5,923 men aged 66 years or older with clinical stage T1 or T2 prostate cancer in the SEER-Medicare database who received LRP (n = 1,065, 18%) or ORP (n = 4,858, 82%) in 2003–2005. It could not be directly ascertained that all LRP procedures were robot-assisted. However, based on manufacturer information, it could be estimated that most LRPs were robot-assisted.

LRP increased in use as a proportion of all procedures in each successive year of the study. LRP patients were more likely to live in a metropolitan area, the West or Northeast, and in census tracts with the highest quartile of median income.

LRP patients generally had a lower clinical T stage and, when known, pathologic T stage, and were less likely to have any regional lymph nodes examined (57% vs 80%). LRP and ORP patients had similar distributions of categorical prostate-spe-

Fig. 1: Miniaturized instruments are inserted through small incisions in the abdomen and guided by the surgeon via computer interface to access and remove the prostate.

shorter with LRP after controlling for patient and tumor characteristics (P < .0001). Length of stay was longer in patients who were older, nonwhite, unmarried, lived in census tracts in the lowest median income quartile, had greater comorbidity, had surgery earlier in the study period, or were operated on by lower-volume surgeons.

■■ The 90-day mortality rate was < 0.5% in both groups.

■■ The 90-day rate of general medical or surgical complications was 21% with LRP and 24% with ORP, with no significant difference between groups after adjustment for covariates. Risk of complications was greater with older age, greater comorbidity, and lowervolume surgeons.

■■ Within 1 year after surgery, genitourinary or bowel complications occurred in 40% of LRP patients and 35% of ORP patients, with no significant difference in risk after adjustment for patient/tumor characteristics. Lower

was associated with a significant 26% reduction in risk. Bladder neck/urethral obstruction was more common in men who were unmarried, lived in the Northeast, had a clinical stage T2 tumor, or did not have pelvic lymphadenectomy, and in those treated by lower-volume surgeons.

■■ In the year following surgery, cancer therapy (radiation therapy, androgen deprivation therapy, or both) was received by 9% of LRP patients and 12% of ORP patients, with no significant difference between groups after adjustment for patient/tumor characteristics.

■■ More than half of all patients receiving LRP had a surgeon with an annual volume of fewer than 5 LRP procedures; less than one-fifth had a surgeon with an annual volume of at least 30 LRPs. After adjustment for patient/tumor characteristics, greater surgeon volume was significantly associated with shorter hospital length of stay among

LRP patients (P < .001) and reduced risk for genitourinary/bowel complications (P < .01), but not with a difference in risk for general medical/surgical complications. The probability of bladder neck/urethral obstruction at 1 year after surgery was 31% among patients with surgeons performing fewer than 5 LRPs in the preceding year, compared with 16% for patients with surgeons performing 30 or more.

Thus, overall, this study showed no difference between LRP and ORP with regard to 90-day mortality or complication rates or subsequent additional cancer therapy, and advantages to LRP in reducing length of stay and reducing risk of bladder neck/urethral obstruction.

Other studies have shown that blood loss, which was not examined in the current study, is reduced with LRP.

Pros and Cons A potential problem with the widespread availability and marketing of robot-assisted LRP is overstatement of benefits. Thus, for example, the economic benefit resulting from reduced hospital stay may not be robust. Cost comparisons indicate that savings in hospital stay costs do not always offset the additional operative costs of robotassisted LRP, particularly in low LRP volume settings.6,7 Further, as noted by Lowrance and colleagues,5 standardization of care pathways may reduce differences between length of stay associated with the two procedures. With regard to the effect of marketing on patient expectations, a survey of 400 men undergoing radical prostatectomy showed that those undergoing ORP were four times more likely to express satisfaction with their procedure than were those undergoing robot-assisted LRP, whereas the latter were more than three times more likely to express dissatisfaction with their procedure.8 However, it should also be noted that overall (LRP and ORP combined) in the current study, higher surgeon volume was consistently associated with benefits, including shorter hospital stay, lower risk of general medical/surgical complications, and lower risk of genitourinary/bowel complications, including bladder neck/ urethral obstruction. Most of these benefits were also seen with higher surgeon volume in the LRP group when considered alone. The increased adoption of robot-assisted LRP implies that the procedure is being used by a large number of

The ASCO Post | NOVEMBER 2010

PAGE 32

TAP on Technology

Robot-assisted Laparoscopic Radical Prostatectomy continued from page 29

less-experienced surgeons. As with ORP, increased surgeon experience with LRP can be expected to improve outcomes.

Lowrance and colleagues5 suggest that regionalization of robot-assisted LRP might serve to increase surgeon volume

and increase clinical and economic benefits of the procedure.

Conclusions Lowrance and colleagues5 concluded that LRP and ORP are associated with similar rates of postoperative morbidity and use of subsequent cancer therapies.

They urged that men who are consider-

ing prostate cancer surgery should understand the expected benefits and risks of both ORP and LRP and have realistic expectations regarding outcomes with each approach.

With regard to expectations regarding outcomes of treatment of prostate cancer, it is also important to note that the rapid adoption of robot-assisted LRP ap-

pears to have increased the proportions of patients opting for surgical treatment of localized prostate cancer vs nonsurgical treatment or watchful waiting. In a recent New England Journal of Medicine “Perspective” piece on robotic technology, Barbash and Glied9 report a recent striking increase in hospital discharges for prostatectomy despite an overall reduction in the background incidence of prostate cancer, with the increase being contemporaneous with a dramatic increase in performance of robot-assisted LRP procedures. The authors note that in this setting, robotic technology may have increased both the cost per surgical procedure and the volume of cases treated surgically, with there as yet being no evidence that robot-assisted LRP improves long-term patient outcomes or quality of life. It may thus be important to increase efforts to ensure that patients with localized prostate cancer understand the relative risks and benefits of surgical vs nonsurgical treatments, as well.

■

REALIGNING REIMBURSEMENT. REWARDING QUALITY CARE.

More than 1,000 leading oncologists agree: It’s time for reimbursement to change. The entire United Network of US Oncology is working to realign reimbursement policies to recognize high-quality care. Join us as we collaborate with like-minded insurers and policymakers, and be a part of the future for community-based oncology.

To learn more about the United Network of US Oncology, visit usoncology.com/TAP

Copyright © 2010 US Oncology, Inc. All rights reserved.

References 1. Guazzoni G, Cestari A, Naspro R, et al: Intra- and peri-operative outcomes comparing radical retropubic and laparoscopic radical prostatectomy: Results from a prospective, randomised, single-surgeon study.

Eur Urol 50:98-104, 2006.

2. Ficarra V, Novara G, Artibani W, et al: Retropubic, laparoscopic, and robotassisted radical prostatectomy: A systematic review and cumulative analysis of comparative studies. Eur Urol 55:1037-1063, 2009.

3. Hu JC, Hevelone ND, Ferreira MD, et al: Patterns of care for radical prostatectomy in the United States from 2003 to 2005. J Urol 180:1969-1974, 2008.

4. Hu JC, Wang Q, Pashos CL, et al: Utilization and outcomes of minimally invasive radical prostatectomy. J Clin Oncol 26:2278-2284, 2008.

5. Lowrance WT, Elkin EB, Jacks LM, et al: Comparative effectiveness of surgical treatments for prostate cancer: A population-based analysis of postoperative outcomes. J Urol 183:1366-1372, 2010.

6. Lotan Y, Cadeddu JA, Gettman MT: The new economics of radical prostatectomy: Cost comparison of open, laparoscopic and robot assisted techniques. J Urol 172:1431-1435, 2004.

7. Scales CD Jr, Jones PJ, Eisenstein EL, et al: Local cost structures and the economics of robot assisted radical prostatectomy. J Urol 174:2323-2329, 2005.

8. Schroeck FR, Krupski TL, Sun L, et al: Satisfaction and regret after open retropubic or robot assisted laparoscopic radical prostatectomy. Eur Urol 54:785-793, 2008.

9. Barbash GI, Glied SA: New technology and health care costs—the case of robot-assisted surgery. N Engl J Med 363:701704, 2010.

ASCOPost.com | NOVEMBER 2010

PAGE 33

Best of ASCO® Lung Cancer

Nab-paclitaxel Boosts Response Rates over Standard Paclitaxel in Carboplatin Doublet for Advanced NSCLC

By Barbara Boughton

T

he initial results of a randomized phase III clinical trial of nanoparticle albumin bound (nab)-paclitaxel (Abraxane) used with carboplatin indicates that this combination results in superior objective response rates in advanced non–small cell lung cancer (NSCLC) compared with paclitaxel/ carboplatin. The trial—a multicenter study that randomly assigned more than 1,000 patients from Russia, the Ukraine, Japan, North America, and Australia to one of the two combinations—was designed in conjunction with the FDA to determine whether nab-paclitaxel should receive an indication in NSCLC.1

Alan Sandler, MD

Survival Analysis Forthcoming The positive results concerning objective response rates—if bolstered by upcoming overall and progression-free survival data—may help make the case for nab-paclitaxel to receive an indication in NSCLC, said Alan Sandler, MD, Professor of Medicine and Chief of the Hematology and Medical Oncology Division at the Oregon Health & Science University’s Knight Cancer Institute. Dr. Sandler presented the study results at the Best of ASCO Meeting in San Francisco.1 “Since this is an agent that is a derivative of another approved agent

(paclitaxel), all the study needs to show is similarities in outcome. In this case, the study was designed to show improvements in response rate,” Dr. Sandler said. Objective response as determined by an independent radiologic review committee according to RECIST criteria was the primary endpoint of the study. The investigators also assessed objective response.

Secondary endpoints included progression-free survival (PFS), overall survival, disease control rate, and safety and toxicities. The PFS analysis will be presented later this year, said lead researcher Mark A. Socinski, MD, of the University of North Carolina at Chapel Hill.

In the study, 1,050 patients with stage IIIB or IV NSCLC with a performance status of 0 or 1 were randomly assigned to receive carboplatin at an AUC of 6 every 3 weeks and either nab-paclitaxel at 100 mg/m2 weekly with no premedication or paclitaxel at 200 mg/m2 every 3 weeks with dexamethasone and antihistamine premedication. Patients received a median of six cycles of therapy.

Key Data Results indicated that the objective response rate for nab-paclitaxel/ carboplatin was 33% vs 25% for paclitaxel/carboplatin, as determined by independent radiologic review.

As judged by investigator assessment, the objective response rate for patients treated with nab-paclitaxel was again superior to those who received paclitaxel (37% vs 30%). The nab-paclitaxel/carboplatin combination was particularly beneficial for patients with squamous cell carcinoma, with an objective response

Nab-paclitaxel in Advanced Lung Cancer ■■ A large phase III trial found that the combination therapy of nab-

paclitaxel and carboplatin achieved significantly superior objective response rates in advanced NSCLC compared with paclitaxel/carboplatin.

■■ Significantly fewer toxicities such as neuropathy, myalgia, and

neutropenia were seen in the nab-paclitaxel arm of the study. However, more thrombocytopenia and anemia was observed with nab-paclitaxel.

■■ Benefits were more pronounced for NSCLC patients with squamous cell histology than for those with non–squamous cell lung cancer.

■■ Upcoming trial data concerning progression-free and overall survival will

shed more light on the efficacy of the nab-paclitaxel/carboplatin doublet in NSCLC.

Expert Point of View

M

artin J. Edelman, MD, of the University of Maryland’s Greenebaum Cancer Center, said the nab-paclitaxel study indicates that this drug may be less toxic and possibly more efficacious than paclitaxel in NSCLC, when used with carboplatin.

“It shows that we should be exploring repackaging and retargeting drugs that are unquestionably effective in lung cancer—those that target tubulin and DNA, the cytotoxins,” he said. “These drugs have in some senses become stepchildren Martin J. Edelman, MD in recent years as researchers have pursued other therapies.” Dr. Edelman, Professor of Medicine at the University of Maryland’s Greenebaum Cancer Center, presented the study at the Best of ASCO Meeting in Boston.

The upcoming PFS and overall survival data will be critically important in evaluating the efficacy of nab-paclitaxel for NSCLC patients, he noted. “It’s probably an easier drug to use, safer and less toxic than paclitaxel. And there is some theoretical basis to the idea that it could be potentially a more effective drug.”

Qualifying Remarks Yet the potential role of nab-paclitaxel in treating NSCLC is somewhat unclear, Dr. Edelman said. In current practice, platinum/pemetrexed regimens have become standard, particularly for adenocarcinoma. Other options such as docetaxel/gemcitabine—when partnered with platinum-based chemotherapies—have shown similar efficacy to paclitaxel regimens but with fewer toxicities. “The [nab-paclitaxel] study is positive, but it may be addressing a question that was more relevant 5 or 10 years ago, when paclitaxel with carboplatin was the major doublet in the treatment of NSCLC,” he said.

Dr. Edelman noted that nab-paclitaxel might be a reasonable replacement for paclitaxel in NSCLC triplet regimens with carboplatin and bevacizumab (Avastin). However, because nab-paclitaxel is much more expensive than other drugs, the question of whether it will become a useful choice in the treatment of NSCLC remains an open one, he added.

■

rate of 41% vs 24% in the paclitaxel/ carboplatin arm, as assessed by radiologic review. Investigator assessment indicated that the objective response rate for patients with squamous cell carcinoma on nab-paclitaxel/carboplatin was 37% vs 29% for paclitaxel/ carboplatin.

Grade 3 or 4 sensory neuropathy, myalgia, and neutropenia occurred in significantly more patients on paclitaxel than nab-paclitaxel (10% vs 3%, 2% vs < 1%, and 56% vs 45%, respectively). In contrast, grade 3 or 4 thrombocytopenia and anemia were significantly more likely in patients who received nab-paclitaxel than among those on paclitaxel (17% vs 8% and 27% vs ~6%, respectively).

In addition to showing superior efficacy, the nab-paclitaxel combination had an improved safety profile com-

pared to the paclitaxel/carboplatin doublet, Dr. Socinski said at the Annual Meeting. “We have See page 52 to wait for additional data with respect to progression-free survival, but my guess is that this agent will obtain an indication in non–small cell lung cancer,” Dr. Sandler commented.

■

Reference 1. Socinski MA, Bondarenko IN, Karaseva NA, et al. Results of a randomized, phase III trial of nab-paclitaxel and carboplatin compared with cremophor-based paclitaxel and carboplatin as first-line therapy in advanced non-small-cell lung cancer. Best of ASCO Annual Meeting San Francisco. Abstract LBA7511. Presented July 17, 2010, by Alan Sandler, MD.

ABstrAct suBmission is oPEninG soon For the 47th Annual Meeting of the American Society of Clinical Oncology In mid-November, 2010 ASCO will begin accepting abstracts to be considered for presentation or publication at the 47th Annual Meeting, to be held June 3-7, 2011, at McCormick Place, Chicago, Illinois, with a Meeting theme of: Patients. Pathways. Progress.

Following the Meeting’s theme, ASCO encourages the submission of abstracts in the following areas: • Patients: focusing on the care delivered to cancer patients, how more patients are becoming cancer survivors, and the resultant survivorship and quality of life concerns • Pathways: highlighting the biologic pathways that help drive disease, the understanding of these pathways that is defining new clinical treatments, and leading to improved patient care • Progress: discussing how discoveries made at the lab bench are translated into ongoing progress against cancer, lower cancer mortality, and the partnering of the right treatments with the right patients Contribute to the premier oncology Meeting by submitting your original research abstract of 300-350 words, by visiting the Call for Abstracts section of ASCO’s Annual Meeting website, asco.org/cfa. There you’ll also find detailed information on Annual Meeting abstract policies, submission requirements, and the abstract selection process, as well as Coauthor Disclosure Forms and Frequently Asked Questions.

June 3-7, 2011 | mccormick Place | chicago, iL

ASCOPost.com | NOVEMBER 2010

PAGE 35

Best of ASCO® Lung Cancer

Figitumumab Fails to Improve Survival, Increases Toxicities, in First‑line Treatment of Patients with NSCLC

By Barbara Boughton

A

large multicenter phase III trial has found that the addition of figitumumab, a monoclonal antibody directed at insulin-like growth factor type 1 receptor (IGF-1R), to standard first-line chemotherapy for non–small cell lung cancer (NSCLC) does not improve overall survival and increases the risk for severe toxicities—even for patients with non-adenocarcinoma histology. Figitumumab is a monoclonal antibody that targets the insulinlike growth factor-1.

The trial was shut down early because See page 52 of an increased number of deaths related to figitumumab therapy, but a subset analysis offers clues about which patients are likely to experience toxicities with the treatment.

In the study, treatment with paclitaxel and carboplatin with the addition of 20 mg/kg of figitumumab was compared to chemotherapy alone in a population of patients that was comprised largely of

patients with squamous cell carcinoma.

“The bottom line with respect to toxicity in this study is that the addition of figitumumab to chemotherapy is more toxic than chemotherapy alone,” said Alan Sandler, MD, Professor of Medicine and Chief of the Hematology and Medical Oncology Division at the Oregon Health & Science University’s Knight Cancer Institute. Dr. Sandler presented the study’s results at the Best of ASCO Meeting in San Francisco.1

Subset Analysis Results of the study indicated that the overall survival of patients who received figitumumab in addition to chemotherapy was worse than for those who received chemotherapy alone—8.5 vs 10.3 months. Serious adverse effects (including those that resulted in fatalities) in the figitumumab arm of the study included asthenia, dehydration, hyperglycemia, hemoptysis, and cardiac events, Dr. Sandler said. However, a subset analysis of patient outcomes based on subjects’ levels of circulating IGF-1 sheds some

Expert Point of View

M

artin J. Edelman, MD, Professor of Medicine at the University of Maryland’s Greenebaum Cancer Center, said that the phase III study of figitumumab highlights the importance of identifying subpopulations that might benefit or experience toxicities from a drug before launching large-scale trials.

“This was a study that accrued over 600 patients in a trial that involved huge amounts of time and expense, and there was not that much compelling evidence to support it. But what it really shows us—more than the results of this specific trial—is that it’s wise to determine who might experience improved outcomes or toxicities in preliminary, smaller studies,” Dr. Edelman said in his presentation of the study’s findings at the Best of ASCO Meeting in Boston.

Open Question Dr. Edelman noted that whether the addition of figitumumab to chemotherapy might be an alternative for squamous cell patients with high IGF-1 levels is an open question. He noted that the data from the trial more strongly indicated that patients with low IGF-1 levels might be more at risk for early and severe side effects.

“The predictive marker of IGF-1 might not be as much an indicator of the activity of the drug as a way to isolate or screen out those patients who might experience early toxicities,” he said.

Dr. Edelman noted that the earlier phase II study showing benefits for adding figitumumab to chemotherapy in squamous cell lung cancer patients was a small single-institution study. “The IGF-1 receptor is an interesting target, and one would have hoped that the trial was more positive,” he said. But the results were not surprising given that the scientific evidence supporting the launch of the trial was not strong, he added. Nevertheless, because patients on the control arm fared better than those on the intervention arm, the trial provided additional information about the toxicities of the drug and how they impact survival, he noted.

■

Figitumumab in Lung Cancer ■■ A large phase III trial indicates that the addition of figitumumab to paclitaxel and carboplatin does not improve survival and increases the risk for grade 3–5 toxicities in NSCLC patients with non-adenocarcinoma histology.

■■ Although an earlier phase II study indicated that the addition of

figitumumab to chemotherapy may improve outcomes for squamous cell cancer patients, this larger phase III study indicates that the drug’s potential benefits may be compromiseçd by its side effects.

■■ Squamous cell lung cancer patients with low levels of circulating IGF-1 levels

are more likely to experience severe toxicities when figitumumab is added to chemotherapy, whereas those with higher levels may experience improved outcomes. These observations should be verified in further research.

light on who is most at risk for toxicities from the drug and offers a suggestion of who might benefit, Dr. Sandler noted.

Higher circulating levels of IGF-1 have been associated with increased risk of cancer death. Lower levels have been linked to increased risk of heart failure and myocardial events in previous studies, Dr. Sandler noted.

In the subset analysis, patients with circulating levels of IGF-1 of greater than 1 ng/mL experienced improved outcomes—including increased overall survival—with the addition of figitumumab to chemotherapy. Yet those patients with less than 1 ng/mL were more likely to have an increased risk of toxicity and death when treated with the drug. However, because provision of samples for pharmacodynamics was optional, only 125 patients were included in the analysis of patients with levels of IGF-1 greater than 1 ng/mL, and only 324 samples with levels of free IGF-1 less than 1 ng/mL were analyzed.

“For patients with higher IGF levels, the addition of figitumumab to chemotherapy actually looks better than chemotherapy alone—although the numbers are small, and you can’t make any definitive statements from these findings,” Dr. Sandler said. Patients with higher levels of IGF-1 who received figitumumab had an overall survival of 10.2 months, compared to 7 months with chemotherapy alone. Further, grade 5 (ie, fatal) adverse events were less likely in patients with higher levels of circulating IGF-1 than in those with lower levels (4.6% vs 8.6%), he noted.

In patients with lower levels of IGF-1, the addition of figitumumab also negatively impacted overall survival compared to those who received chemotherapy alone (7 vs 10.3 months)

Past and Future Studies A previous single-arm phase II study, published in the Journal of Clinical Oncology in 2009,2 indicated that figitumumab in combination with paclitaxel and carboplatin produced an overall response rate of 64% in patients with squamous cell NSCLC. There is also a theoretical basis for using figitumumab in squamous cell lung carcinoma, because these cancers have been found to have high IGF-1 receptor expression, Dr. Sandler said.

Yet results of the phase III trial led the researchers to conclude that the potential benefit of adding figitumumab to chemotherapy in non-adenocarcinoma NSCLC may be compromised by the monoclonal antibody’s side effects. They recommended additional research to verify whether figitumumab may have benefits for those with higher levels of IGF-1 and more risks for patients with low levels.

Figitumumab might be considered for additional study as an addition to chemotherapy in squamous cell cancer patients, but just in those patients whose circulating IGF-1 level is greater than 1 ng/mL, Dr. Sandler added.

■

References 1. Jassem J, Langer CJ, Karp DD, et al: Randomized, open label, phase III trial of figitumumab in combination with paclitaxel and carboplatin versus paclitaxel and carboplatin in patients with non-small cell lung cancer. Best of ASCO San Francisco.

Abstract 7500. Presented July 17, 2010, by Alan Sandler, MD. 2. Karp DD, Paz-Ares LG, Novello S, et al: Phase II study of the anti-insulin-like growth factor type 1 receptor antibody CP751,871 in combination with paclitaxel and carboplatin in previously untreated, locally advanced or metastatic non-small-cell lung cancer. J Clin Oncol 27:2516-2522, 2009.

Clinical challenge: Identification of patients with lower-risk MDS* and a poor prognosis Approximately two-thirds of patients with myelodysplastic syndromes (MDS) have lowerrisk disease, defined as Low- and Intermediate-1–risk per IPSS.* However, existing prognostic tools for MDS do not differentiate those patients with lower-risk disease who have a poor prognosis.1

The International Prognostic Scoring System (IPSS) The IPSS helps to estimate the overall survival of patients with MDS. Certain patients classified with lower-risk MDS by the IPSS system may benefit from the “wait and watch” approach currently used by many physicians. However, one limitation of the IPSS is that it does not identify patients with lower-risk MDS and poor prognosis who may be candidates for early therapeutic intervention.

A proposed prognostic scoring system for patients with lower-risk MDS This scoring system stratified patients with lower-risk MDS into 3 risk categories and evaluated the characteristics associated with survival.1 Following a multivariate analysis, the parameters below were found to be associated with decreased survival1: • Platelets (<50 x 109/L; 50–200 x 109/L) • Age (≥60 years) • Unfavorable cytogenetics† • Hemoglobin (<10 g/dL) • Percent of marrow blasts (≥4%–10%) The authors recommend the validation of this model by confirming the results in another patient population. Until these results are validated, the main use of this model will be to assign patients with poor prognoses to investigational clinical trials.1

Utility of proposed scoring system This scoring system may help to identify those patients with lower-risk MDS who may benefit from early therapy. Using this system, the authors determined that of the 673 patients in Risk Categories 2 and 3, 80% had a poor prognosis if untreated. They believed that the need to treat this population was further supported by the number of patients who died (90%) before their disease transformed to acute myelogenous leukemia.1 Results from 856 patients showed 31% of patients with a median survival of 14.2 months (1.2 years) (Risk Category 3), 48% with a median survival of 26.6 months (2.2 years) (Risk Category 2), and 21% with a median survival of 80.3 months (6.7 years) (Risk Category 1).1‡

Estimated Survival of Lower-risk MDS Patients by Risk Category1

Assigned Score

‡

0-2 3-4 ≥5

Cumulative Proportion Alive

1.0

Survival Total (%) Dead (No.) Median (mo) 4-yr (%) 182 (21) 408 (48) 265 (31)

43 212 173

80 27 14

65 33 7

0.8 0.6 0.4 0.2 0 0

12

24

36

48

60

72

84

96

Months from Referral Reprinted with permission from Garcia-Manero et al (2008).1

This study indicated that it is possible to identify those lower-risk MDS patients with a poor prognosis (those in Risk Categories 2 and 3) who may benefit from early therapeutic intervention. The proposed prognostic tool based on the IPSS classification of this specific patient type may have a significant impact on1: • MDS treatment approaches • When to treat lower-risk MDS • Clinical trial development

This proposed model may have implications for clinical trial design and potentially for the treatment decision process for patients with lower-risk MDS.1

*MDS, myelodysplastic syndromes; lower-risk MDS, Low- and Intermediate-1–risk per International Prognostic Scoring System. † In this scoring system, only diploid and 5q were considered favorable cytogenetics; all others were considered unfavorable.1 ‡ Category scoring based on: Category 1 = score 0-2, Category 2 = score 3-4, Category 3 = ≥5. Assigned score: age (≥60 years) = 2; platelets (<50 x 109/L) = 2, platelets (50–200 x 109/L) = 1; hemoglobin (<10 g/dL) = 1; bone marrow blasts (≥4%–10%) = 1; unfavorable cytogenetics = 1.1 Reference: 1. Garcia-Manero G, Shan J, Faderl S, et al. A prognostic score for patients with lower risk myelodysplastic syndrome. Leukemia. 2008;22(3):538-543.

©2010 Celgene Corporation

07/10

CELG10172T

The ASCO Post | NOVEMBER 2010

PAGE 38

Best of ASCO® Sarcoma

Interruption of Imatinib Therapy after 5 Years Increases Risk of Relapse in Patients with Advanced GIST

By Larry Rosenberg, PhD

P

atients with advanced gastrointestinal stromal tumors (GIST) treated with imatinib must continue to receive therapy continuously until disease progression or intolerance. These long-term data from the BFR14 French Sarcoma Group study confirmed earlier similar findings noted after 1 and 3 years postrandomization. These results were originally presented at the 2010 ASCO Annual Meeting by Isabelle Ray-Coquard, MD, PhD, of the Centre Léon Bérard, Lyon, France. Suzanne George, MD, Clinical Director, Center for Sarcoma and Bone Oncology, DanaFarber Cancer Institute, and Assistant Professor in Medicine, Harvard Medical School, summarized these findings at the Best of ASCO Meeting in Boston.1

Earlier Analysis Confirmed BFR14 was a prospective, randomized phase III trial comparing interruption and continuation of imatinib therapy in patients with advanced or metastatic GIST. Patients (N = 434) who responded or had stable disease with imatinib, after remaining on imatinib for 1, 3, or 5 years, were randomly assigned to cohorts that either continued imatinib or halted therapy (Fig. 1). Those who stopped drug treatment could resume imatinib upon disease progression. The trial started in 2002 and completed enrollment in 2009.

Previous analyses after interruptions at 1 and 3 years had demonstrated that progression-free survival (PFS), the primary endpoint, was significantly longer at both time points in the groups that continued to receive therapy.2 For example, in patients who were randomly assigned after 3 years, those who continued imatinib therapy had a 2-year PFS rate of 80%, compared to 16% in those who stopped treatment (logrank P < .0001). In the 5-year cohort, 25 patients with stable disease were randomly assigned to either the continued-therapy group or the treatment-interruption group.

The most recent update of BFR14, which randomly assigned patients with metastatic GIST who had been stable on 5 years of imatinib, again demonstrated very similar findings. After a median follow-up of 11.9 months postrandomization, relapse occurred in 7 of 13 patients in the interruption group vs 0 of 12 patients in the continued-therapy group (P = .032). For those who continued imatinib therapy, the relapse rate at 5 years was superior to the rates at 1 and 3 years (0% vs 20% and 8%, respectively).

■

References 1. Ray-Coquard I, Bin Bui N, Adenis A, et al: Risk of relapse with imatinib (IM) discontinuation at 5 years in advanced

Imatinib for Advanced/Metastatic GIST ■■ Results of the BFR14 trial indicate that interruption of imatinib

treatment in patients with metastatic/advanced GIST, even after 5 years of therapy, is associated with a significantly increased risk of disease progression compared with continuing such therapy.

■■ These data are consistent with earlier results from this trial in which treatment was interrupted after 1 or 3 years.

■■ Imatinib should therefore be administered continuously in patients with nonprogressing advanced GIST until relapse or intolerance.

■■ Additional follow-up is needed to demonstrate any differences in overall survival in patients randomly assigned after 5 years.

Evaluate for randomization at 1 yr, 3 yr, 5 yr

Advanced/ mestastatic GIST on imatinib

Stable disease or better

Surgery possible if resectable

R a n d o m i z a t i o n

STOP

imatinib

Disease progression

Restart imatinib 400 mg daily

Continue imatinib and follow-up

Continue imatinib 400 mg daily

Fig. 1: Design of BFR14 trial. GIST = gastrointestinal stromal tumor. Adapted from Le Cesne A, et al: 2009 ASCO Annual Meeting. Courtesy of Suzanne George, MD.

GIST patients: Results of the prospective BFR14 randomized phase III study comparing interruption versus continuation of IM at 5 years of treatment: A French Sarcoma Group Study. Best of ASCO Boston.

Abstract 10032. Presented July 23, 2010,

by Suzanne George, MD. 2. Blay JY, Adenis A, Ray-Coquard I, et al: Is there a role for discontinuing imatinib in patients with advanced gastrointestinal stromal tumour? Curr Opin Oncol 21:360-366, 2009.

Linking Molecular Diagnostics to Targeted Therapies

T

he BFR14 study is that nearly all patients in a very interesting the “stop” arm, whether at and important study,” 1 or 3 years, will develop commented Suzanne disease progression within George, MD, of the Da1 year. According to Dr. na-Farber Cancer CenGeorge, the majority of ter. The French Sarcoma patients in the “continue Group has designed a arm” maintain excellent trial in which patients disease control. “These with metastatic GIST, Suzanne George, MD findings suggest that instable on imatinib, are dependent of the time randomly assigned to either continon imatinib, patients with advanced ue or stop imatinib. Previous reports disease require continuous kinase from this trial have demonstrated inhibition with imatinib for ongoing

disease control in GIST,” she said.

Despite excellent disease control, imatinib may not eradicate all of the malignant cells in GIST, even after lengthy exposure.

In addition, earlier reports of BFR14 suggested there is no difference in overall survival between the “stop” and “continue” arms, nor is there a difference in time to secondary resistance, as nearly all patients have regained disease control after reinitiation of therapy at the time of disease progression. These results

remain to be confirmed in a larger population.

BFR14 was a rigorous and wellcontrolled trial. Dr. George emphasized that “these results do not encourage the discontinuation of imatinib, but rather support the finding that imatinib leads to suppression of disease in patients with metastatic disease. If, however, a patient requires an interruption in therapy, BFR14 suggests this is not detrimental to the long-term outcome of a patient with advanced GIST.”

■

Because every patient with advanced RCC is

Identifying prognostic risk is an important consideration.

Evaluate the following criteria to calculate prognostic risk status1,3

Prognostic risk is widely varied at diagnosis and significantly reflects survival1,2 Percentage of patients in each prognostic Evidence shows that it is important to calculate prognostic risk when managing advanced RCC3

risk group in RCC clinical trials1,2

Prognostic Category

MSKCC

Modified MSKCC*

Poor Risk

20%

28%

Intermediate Risk

62%

35%

Favorable Risk

18%

37%

www.PfizerOncology.com iPhone, iPod touch, and iTunes are trademarks of Apple Inc., registered in the U.S. and other countries. iTunes is for legal or rightholder-authorized copying only. Don’t steal music.

References: 1. Motzer RJ, Bacik J, Murphy BA, et al. Interferon-alfa as a comparative treatment for clinical trials of new therapies against advanced renal cell carcinoma. J Clin Oncol. 2002;20:289-296. 2. Mekhail TM, Abou-Jawde RM, BouMerhi G, et al. Validation and extension of the Memorial Sloan-Kettering prognostic factors model for survival in patients with previously untreated metastatic renal cell carcinoma. J Clin Oncol. 2005;23:832841. 3. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: kidney cancer. V.2.2010.

All rights reserved.

Indication of Elevated Risk

MSKCC

Modified MSKCC

Karnofsky Performance Status

≤70

✔

✔

Time From Diagnosis

<1 year

✔

✔

Corrected Calcium

>10 mg/dL

✔

✔

LDH Level

>1.5 times the upper limit of normal

✔

✔

Hemoglobin Level

<lower limit of normal

✔

✔

Sites of Metastasis

≥2

✔

FREE Advanced RCC Prognostic Calculator app

RCC=renal cell carcinoma. LDH=lactate dehydrogenase. Hb=hemoglobin. KPS=Karnofsky Performance Status. MSKCC=Memorial Sloan-Kettering Cancer Center.

© 2010 Pfizer Inc.

Criteria

MSKCC: 0=Favorable Risk, 1 - 2=Intermediate Risk, ≥3=Poor Risk.

Modified MSKCC: 0 - 1=Favorable Risk, 2=Intermediate Risk, ≥3=Poor Risk.

* MSKCC criteria + prior radiotherapy and additional sites of metastases.

TRS00091C

unique...

October 2010

To take advantage of this FREE tool on your iPhone® or iPod touch®, visit www.itunes.com/app/advancedrccprognosticcalculator for download.

The ASCO Post | NOVEMBER 2010

PAGE 40

Health-care Reform

Patient Protection and Affordable Care Act: Dispelling the Myths

By Caroline Helwick

T

he passage of health-care reform— the Patient Protection and Affordable Care Act—is a “world historical event,” having been attempted by five previous presidents over almost 100 years before being accomplished by the Obama administration, said Ezekiel J. Emanuel, MD, PhD, Special Advisor for Health Policy in the Office of Management and Budget, and Chair of the Department of Bioethics at the National Institutes of Health. But in spite of the legislation’s promise to increase coverage to about 94% of the American populace, there are many criticisms and efforts to derail it, he said.

At the 2010 Breast Cancer Symposium, Dr. Emanuel, himself an oncologist who once taught at Harvard Medical School, discussed the key components of the Act and noted how “the common criticisms are wrong,” including the following “myths”:

Myth: The reform is 90% coverage and only 10% cost control.

“Many provisions will reduce the amount of spending on health care,” Dr. Emanuel pointed out. The greatest reductions will come from the following reductions in spending: ■■ Cutting overpayment to Medicare Advantage ($136 billion) ■■ Reduction of payment update factor ($196 billion) ■■ Administrative simplification ($20 billion) ■■ Use of generic biologics ($7 billion) ■■ Enforcement of fraud and abuse laws ($3 billion) ■■ Payment change for complex imaging procedures ($1.2 billion) In addition, other provisions will slow the growth rate in spending, including the “Cadillac tax” (an excise tax on high-cost insurance plans), patientcentered outcomes research, hospital 30-day admission policy (ie, penalties imposed when patients are readmitted due to inadequate care), reduction in hospital-acquired infections and other nosocomial conditions, and use of medical homes, accountable care organizations, and bundled payments.

Myth: Even if passed, the cost control provisions will not be implemented.

“Au contraire,” Dr. Emanuel said, pointing out the following provisions: ■■ Reducing payment for high-cost imaging services is in the 2011 Medicare physician fee schedule

■■ Reducing payment updates for outpatient, hospital, and ambulatory surgical centers is in the 2011 Outpatient Hospital Prospective Payment Rules ■■ Pay-as-you-go (PAYGO) rules compel Congress not to add to the federal deficit when instituting new spending or tax changes.

Myth: Health-care reform will cost Americans.

“Reform will not add to the budget or budget deficit,” he emphasized, citing over $100 billion in savings. He noted that unlike Medicare Part D, health-care reform is “completely, totally paid for” with new resources and offsets. “Health-care reform is likely to be even cheaper than anticipated if cost controls work and health-care inflation is lower, reducing Medicare and Medicaid outlays and subsidies,” he added. “I think these reforms will have a synergistic effect.”

Myth: All the important parts of reform do not happen until 2014 or later.

“This is partly true,” Dr. Emanuel acknowledged. “But if hospitals, physicians, insurers, and others behave like my Harvard undergraduates, and wait until the night before the due date and pull an all-nighter, they will fail, and fail miserably.” Changes, therefore, were gradually initiated even prior to the Act’s passage.

What Health-care Reform Will Mean for Cancer Care The transformation of the delivery system, including the field of oncology, will occur in three main areas: information (using new technologies, primarily financial incentives for installing electronic health records, and comparative effectiveness research), infrastructure (using medical homes and accountable care organizations), and incentives (using bundled payments and other financial and quality instruments).

Bundled payments may be the most striking change oncologists will experience, but Dr. Emanuel put this in positive terms. “We have lots of guidelines, which will be used to determine bundled payments. This gives you flexibility in managing patients as you see fit to provide optimal care,” he said.

Reform will also ensure better coverage of breast, colon, and cervical screening tests with no copays, and will include a campaign for positive lifestyle changes.

Patients with cancer will particularly ben-

How Our Practices May Be Impacted

I

f you successfully address costs, access to health care, and quality, you’ve solved the health-care problem,” said Allen S. Lichter, MD, CEO of ASCO, at the 2010 Breast Cancer Symposium.

Unfortunately, each of these factors alone is monumental, and each is a huge issue in oncology.

But better access to care, in itself, may greatly improve cancer outcomes, he said. The uninsured who have cancer fare much worse than their insured counterparts, with a near doubling in deaths from the disAllen S. Lichter, MD ease. “The impact of being uninsured in the oncology setting is really dramatic. These patients are stuck. It’s impossible to get insurance if you are diagnosed with cancer,” Dr. Lichter noted.

But being on Medicaid, which is the new solution for about half the newly insured patients, is not much better, as cancer outcomes for Medicaid patients are no better than those of uninsured patients. “This is not a great step for us, and even if it were, it’s not in effect until 2014,” he said. “You do not help cancer patients by covering them with Medicaid. We would like to see these individuals be allowed to move to some other form of insurance to get lifesaving care.”

Encouraging Reforms, but Some Concerns Other patient protections afforded by health-care reform, however, are encouraging for oncologists, Dr. Lichter said. “And a lot is happening by 2011,” he noted, such as the 50% discount on drugs in the “doughnut hole” (the Medicare Part D coverage gap). This will be further remedied by 2014, and also kicking in will be insurance exchanges, protection against denials, and the initiation of subsidies to help pay for insurance premiums.

“But there is still much to be done,” he continued. For example, the bill contains the phrase, “the Secretary shall…” 684 times, according to Dr. Lichter’s search of the document. “And there are another 300 or so references to new regulations. This means a huge amount of this law remains to be implemented through regulations,” he said.

“ASCO will be at the table to make sure these regulations are produced in a way that advances oncology care,” he stated.

One very positive change is the mandate for coverage of routine clinical trial expenses, an action that ASCO has advocated for 20 years. But Dr. Lichter is worried that “routine care” remains undefined and thus could become a coverage loophole. He is also concerned that phase I trials and “grandfathered plans” may be exempted. ASCO will convene a meeting with payers to try to hammer out some agreements this year, he said.

ASCO is also involved in pilot projects with the Center for Innovation (spearheading comparative effectiveness research) and is pushing its members toward quality improvement initiatives.

But there is still “relatively little” in health-care reform for specialty physicians, he added. Most importantly, we still have no permanent fix for the sustainable growth rate problem.

“Try running an oncology practice when you don’t know if you will have revenue from one of your largest payers next month,” he commented. “This will be the thread unraveling the fabric of Medicare if it cannot be permanently fixed.”

■

efit through the elimination of preexisting conditions exclusions and annual and lifetime limits. The Act also mandates coverage of routine costs of clinical trials.

The oncology community has a big role to play to enhance reform, Dr. Emanuel told attendees. “Oncologists should get their offices wired and use

the financing that is available for installing electronic medical records,” he said. “Develop treatment guidelines and protocols that will assess therapeutically similar interventions by how they affect costs. And develop bundles for treating common cancers that can be used by payers.”

■

ASCOPost.com | NOVEMBER 2010

PAGE 41

Opinion

How Do We Eliminate Unnecessary Treatment for Prostate Cancer?

By Richard J. Boxer, MD

P

rostate cancer was diagnosed in nearly 200,000 American men in 2009. Approximately 50% to 62% of the men who were diagnosed have low-risk prostate cancer defined as: (1) prostatespecific antigen (PSA) of 10 ng/mL or less; (2) Gleason histologic score of the primary and secondary microscopic patterns each assigned a value of 1 to 5 (an indication of the tumor’s potential aggressiveness) and less than a total of 7 (with no patterns of 4 or 5 in biopsies); and (3) no more than 10% to 50% cancer (various opinions) found in no more than 2 of 12 biopsy cores.

Over the past 30 years, nearly 1 million American men have received radiation therapy and/or radical prostatectomy for prostate cancer that would have a very low risk of ever leading to their death. These men, however, have been subjected to the attendant morbidity associated with therapy—morbidity that may have resulted in a decline of their quality of life.1 Willet F. Whitmore, Jr, Chairman of the Urology Service at Memorial Sloan-Kettering Cancer Center for more than 30 years, said of prostate cancer in 1990, “Is cure possible? Is cure necessary? Is cure possible only when it is not necessary?”2 It may be that nothing has fundamentally changed in the past 20 years.

Surgical or radiation treatment for early-stage disease cures 98% of men at 10 years. Those men who receive no treatment for low-risk prostate cancer have a 98% survival rate. What has been accomplished? It is time to rethink our approach to this disease.

curs between the time the cancer is detected by PSA and the time there would be physical evidence of the disease.5,6 Radical prostatectomy was per-

formed nearly 60,000 times last year.7 Approximately 80% of surgeons performed fewer than 10 procedures per

Richard J. Boxer , MD

continued on page 42

We are here, where you need us most We are committed to the discovery and development of innovative immunotherapeutic approaches aimed at helping patients fight cancers, such as advanced melanoma.

Together, we can make a difference.

Concerning Data Annually, 30 million men are screened using PSA criteria. But two recent U.S. studies1,3 have thus far not shown any reduction in the death rate from prostate cancer. And European investigators reported4 that only 1 death could be prevented for every 1,400 men screened and 48 treated. Also, studies have shown that for patients with lowrisk prostate cancer, a 10-year delay ocEditor’s Note: For further perspectives on this topic, see “Is Prostate Cancer Being Overdiagnosed and Overtreated? The Controversy Continues,” which appeared in the October issue of The ASCO Post and is available online at ASCOPost.com. ©2010 Bristol-Myers Squibb. All rights reserved. 731US10AB00706 4/10

The ASCO Post | NOVEMBER 2010

PAGE 42

Opinion

Unnecessary Treatment for Prostate Cancer continued from page 41

year, and 25% of men who underwent surgery had a surgeon who performed only a single such procedure in a year.

This paucity of experience has been found to translate into poorer outcomes,8 higher complication rates, and a higher risk of postoperative incontinence and impotence. At least 30% of men given curative treatment for prostate cancer experience negative quality-of-life consequences.

In 2009, radiation therapy was used to treat approximately 85,000 patients with prostate cancer (55,000 by external-beam radiation therapy and 30,000 by brachytherapy), the majority with low-risk disease. Radiation therapy and surgery are associated with equivalent 10-year outcome data, but radiotherapy avoids the potential risks associated with anesthesia. Nevertheless, this modality has not produced a significant reduction in the death rate in patients with low-risk prostate cancer.

Relative Treatment Outcomes Active surveillance or “watchful waiting” offers an option for some men with low-risk prostate cancer,9 in avoiding the potential adverse quality-of-life consequences from treatment. In several large studies of active surveillance, only 2% to 5% of patients had tumor progression and 16% to 25% had a significant rise in PSA.10 This approach has resulted in very few men requiring further therapy, no change in mortality, and of course no complications from surgery or radiation therapy.

Thus, no treatment has the same effect on outcome as aggressive therapy.

Yet NCI’s Surveillance, Epidemiology and End Results (SEER) data demonstrate that over the past 20 years, marked increases in the use of radiation therapy and radical prostatectomy (compared to no therapy) have been observed. This may be because more men are being screened for elevated PSA. In addition, improvements in both surgical and radiation therapy and overmarketing by the health-care industry have given the public the perception that the treatments today have a greater success rate and fewer complications.

In support of surgical treatment, Holmberg and colleagues reported a randomized Swedish trial designed to determine whether radical prostatectomy reduces the risk of death due to prostate cancer. They observed a statistically significant difference in the

risk of death due to prostate cancer after radical prostatectomy, as compared with watchful waiting, but no significant difference between the two groups in the overall survival rate.11

to their death, and those with Gleason 6 or less be left untreated? Perhaps.

What is absolutely certain is that there are tens of thousands of men who are needlessly or inappropriately treated

Watchful waiting has resulted in very few men requiring further therapy, no change in mortality, and of course no complications from surgery or radiation therapy.

Finding Treatment Criteria It has been widely reported that prostate cancer deaths have been reduced recently, but this is a reflection of the increased number of men diagnosed because of PSA screening.

Actually, it is the proportion of men with prostate cancer who die that has decreased. The percentage of men who die with prostate cancer has declined because the number of men who have been diagnosed through screening has massively increased. In other words, the numerator (deaths) has stayed the same while the denominator (incidence) has risen. In 1975, 1993, and 2005, respectively, approximately 90, 240, and 170 American men per 100,000 were diagnosed with prostate cancer. The number of Americans per 100,000 dying of prostate cancer today is actually higher (~25) than it was in 1930 (~18).12 Wholesale screening results in earlier detection and treatment of a disease that would never cause harm. This is not progress; it is overtreatment13 due to overscreening.

Histologic Grade Determines Treatment The histologic grade should determine whether the patient is treated.

A Gleason grade totaling 6 or less for the primary and secondary areas commonly indicates that the disease will not cause the patient’s death. However, when the pattern results in a score of 7 or greater, the cancer has a much more aggressive course. For every one-level increase in histologic grade of either the primary or secondary pattern, there is a reduction in survival of 20% to 50% in every age range over 5, 10, and 15 years. These data are substantially true regardless of treatment.14 Does this imply that the patient’s survival is determined at the time of the diagnosis? Should patients who are diagnosed with a Gleason score of 7 to 10 be treated but have a higher expectation of prostate cancer leading

(any treatment, wrong treatment, or treatment by an inexperienced doctor), either because they have low-risk prostate cancer, an expected survival of less than 10 years, or advanced disease.

Need for Research Billions of dollars are expended annually in overscreening, overdiagnosis, and treatment of tens of thousands of American men,15 resulting in loss of quality of life. Only a tiny fraction of desperately needed money is focused on research.

Recent studies in genetics at the University of Michigan,16 Memorial SloanKettering,17 Texas Southwestern,18 and Harvard19 have identified DNA signatures that are more prevalent in aggressive tumors. This type of critical basic research could lead to an understanding of which patients should be observed and which should be offered curative therapy.

Basic research must be expanded to determine which patients need treatment; medical decision-making must be based upon evidence and outcomes; and men should be treated by experienced doctors only if there is the likelihood that prostate cancer may cause their death.

■

References 1. Welch HG, Albertsen PC: Prostate cancer diagnosis and treatment after the introduction of prostate-specific antigen screening: 1986-2005. J Natl Cancer Inst 101:1325-1329, 2009.

2. Whitmore WF Jr: Natural history of low-stage prostate cancer and impact of early detection. Urol Clin North Am 17:689-697, 1990.

3. Andriole GL, Crawford ED, Grubb RL 3rd, et al: Mortality results from a randomized prostate-cancer screening trial. N Engl J Med 360:1310-1319, 2009.

4. Schröder F, Hugosson J, Roobol SJ, et al: Screening and prostate-cancer mortality in a randomized European study. N Engl J Med 360:1320-1328, 2009.

5. Draisma G, Boer R, Otto SJ, et al: Lead times and over detection due to PSA screening: Estimates from the European Randomized Study of Screening for Pros-

tate Cancer. J Natl Cancer Inst 95:868878, 2003.

6. Tornblom M, Eriksson H, Franzen S, et al: Lead time associated screening for prostate cancer. Int J Cancer 108:122-129, 2004.

7. Blum RH, Scholz M: Invasion of the Prostate Snatchers. New York, Other Press, 2010.

8. Savage CJ, Vickers A: Low annual caseloads in US surgeons conducting radical prostatectomy. J Urol 182:2677–2679, 2009.

9. Klotz L: Active surveillance for favorable risk prostate cancer: What are the results, and how safe is it? Los Angeles, Prostate Cancer Research Institute. Available at http://www.prostate-cancer.org/ education/localdis/klotz_activesurveillance.html.

10. NCI Cancer Bulletin, January 12, 2010. Available at http://www.cancer. gov/aboutnci/ncicancerbulletin/archive/2010/011210/page2. Accessed October 4, 2010.

11. Holmberg L, Bill-Axelson A, Helgesen F, et al: A randomized trial comparing radical prostatectomy with watchful waiting in early prostate cancer. N Engl J Med 347:781-789, 2002.

12. Jemal A, Siegel R, Jiaquan Xu, et al: Cancer statistics, 2010. CA Cancer J Clin 60:277-300, 2010.

13. National Comprehensive Cancer Network: NCCN Clinical Practice Guidelines in Oncology: Prostate cancer.

V.3.2010. Available at www.nccn.org. Accessed October 4, 2010.

14. Albertsen PC, Hanley JA, Gleason DF, et al: Competing risk analysis of men aged 55 to 74 years at diagnosis managed conservatively for clinically localized prostate cancer. JAMA 280:975-980, 1998.

15. Saigal CS, Litwin MS: The economic costs of early stage prostate cancer. Pharmacoeconomics 20:869-878, 2002.

16. Palanisamy N, Ateeq B, KalyanaSuldaram S, et al: Rearrangements of the RAF kinase pathway in prostate cancer, gastric cancer and melanoma. Nat Med 16:793-798, 2010.

17. Taylor BS, Schultz N, Hieronymous H, et al: Integrative genomic profiling of human prostate cancer. Cancer Cell 18:1122, 2010.

18. Kong Z, Xie D, Boike T, et al: Downregulation of human DAB2IP gene expression in prostate cancer cells results in resistance to ionizing radiation. Cancer Res 70:2829–2839, 2010.

19. Min J, Zaslavsky A, Fedele G, et al: An oncogene–tumor suppressor cascade drives metastatic prostate cancer by coordinately activating Ras and nuclear factorκB. Nat Med 16:286-294, 2010.

Dr. Boxer is Professor of Clinical Urology at the University of Miami and Clinical Professor at the University of Wisconsin, Madison, and the Medical College of Wisconsin.

ASCOPost.com | NOVEMBER 2010

PAGE 43

Letter to the Editor

Fixing Medical Malpractice

I

enjoyed reading Dr. Richard Boxer’s column on tort reform (The ASCO Post, October 2010, page 3). I agree with much of it. The way to eliminate frivolous lawsuits and other abuses without limiting patient’s and lawyer’s right to sue, is a system similar to that in Kansas.

After the lawsuit is filed, under court monitoring, the plaintiff and defendant appoint their own expert witness. The two then select a mutually acceptable expert witness. The three specialists in the field, review the patient’s records and determine the basis for malpractice. The three experts receive a statedefined flat reimbursement.

An official report is submitted to the judge and all parties within a month. This ends the years of delay (with its physical and emotional

toll), costs of discovery, depositions, and expert witnesses.

The patient has a right to sue. But by this process, all parties—including both lawyers, patient, defendant, and malpractice carriers—officially know the merits of the case. Lawyers will not

be going after irrelevant side issues that surface during the discovery process or sue third parties as part of their initial lawsuit to snare all who touched the patient/plaintiff.

I enjoyed the cartoon after the article. It is right on the mark. The real

beneficiaries of medical malpractice are the defense lawyers, who drag the case out ad infinitum, and always come out the winners.

— Gilbert A. Lawrence, MD, DMRT, FRCR Radiation Oncology, Faxton Hospital

■

ERBITUX Increased Overall Survival in Both: Squamous Cell Carcinoma of the Head and Neck (SCCHN) in Combination With RT in Locoregionally Advanced Disease

EGFR-Expressing Metastatic Colorectal Cancer (mCRC) after Irinotecan and Oxaliplatin Failure as a Single Agent

Contact The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief email: Editor@ASCOPost.com Cara H. Glynn, Director of Editorial email: Cara@harborsidepress.com Phone: 631.935.7654 Andrew Nash, Assoc. Director of Editorial email: Andrew@harborsidepress.com Phone: 631.935.7657

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Rates, reprints, or supplements

Leslie Dubin email: Leslie@harborsidepress.com Phone: 631.935.7660

Rights and Permissions email: Permissions@harborsidepress.com

Editorial Office Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

ERBITUX Indications Head and Neck Cancer ■ ERBITUX® (cetuximab), in combination with radiation therapy, is indicated for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck

Metastatic Colorectal Cancer ■ ERBITUX, as a single agent, is indicated for the treatment of EGFR-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. ERBITUX, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens ■ Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for ERBITUX in patients whose tumors had K-ras mutations in codon 12 or 13. Use of ERBITUX is not recommended for the treatment of colorectal cancer with these mutations

ERBITUX Boxed WARNINGS ■ Infusion Reactions: Serious infusion reactions occurred with the administration of ERBITUX in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. Immediately interrupt and permanently discontinue ERBITUX infusion for serious infusion reactions ■ Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after ERBITUX EGFR=epidermal growth factor receptor; RT=radiation therapy.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

SOLUTION FOR INTRAVENOUS INFUSION

The ASCO Post | NOVEMBER 2010

PAGE 44

News

NCCN Updates Breast Cancer Guidelines, Version 3.2010

T

he National Comprehensive Cancer Network (NCCN) Guidelines Panel for Breast Cancer affirmed its existing recommendation of bevacizumab (Avastin) in combination with paclitaxel as an appropriate therapeutic option for metastatic breast cancer.

The panel assigned the recommendation an evidence designation of 2A, meaning that it is based on lower level evidence and uniform agreement of the panel as to its appropriateness.

The Panel revised the related footnote; it now states: “Randomized

clinical trials in metastatic breast cancer document that the addition of bevacizumab to some first- or secondline chemotherapy agents modestly improves time to progression and response rates but does not improve overall survival. The time to progres-

sion impact may vary among cytotoxic agents and appears greatest with bevacizumab in combination with weekly paclitaxel.”

The complete updated versions of the NCCN Guidelines are available at NCCN.org.

■

ERBITUX Significantly Increased SCCHN

in Combination With RT in Locoregionally Advanced Disease Survival in Combination With RT (N=424)*1,2 ERBITUX (cetuximab) + RT (n=211)

Median overall survival 49.0 months

vs

RT alone (n=213)

vs

29.3 months

vs

45%

HR: 0.74; 95% CI: 0.57-0.97; P=0.03

3-year overall survival rate 55%

19.7

month improvement

P=0.05 RT=radiation therapy; HR=hazard ratio; CI=confidence interval.

* A multicenter, randomized (1:1), controlled clinical trial was conducted with ERBITUX + RT vs RT alone. The primary endpoint of the trial was duration

of locoregional control. Secondary endpoints included overall survival.1,2 Median follow-up=54 months.2

■ Primary endpoint: ERBITUX + RT (n=211) significantly improved median duration of locoregional control by 9.5 months (24.4 vs 14.9 months) vs RT alone (n=213) (log-rank P value=0.005; HR: 0.68 [95% CI: 0.52-0.89])1

ERBITUX Safety Information for SCCHN ■ The most serious adverse reactions associated with ERBITUX® (cetuximab) across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%).

The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ ERBITUX Plus Radiation Therapy and Cisplatin: The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events ■ Late Radiation Toxicities: The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively. The incidence of grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

ASCOPost.com | NOVEMBER 2010

PAGE 45

FDA Update

Oncology Drug News Orphan Drug Status Granted to Darinaparsin for PTCL ZIOPHARM Oncology, Inc, announced that the FDA has granted Orphan Drug Designation to darinaparsin (Zinapar) for the treatment of peripheral T-cell lymphoma (PTCL). The

Orphan Drug designation provides eligibility for a 7-year period of market exclusivity in the United States after product approval, an accelerated review process, accelerated approval where appropriate, grant funding, tax benefits, and an exemption from user fees.

ZIOPHARM reported favorable results from a phase II trial with IV darinaparsin in lymphoma, particularly PTCL, at the 2009 ASCO Annual Meeting. There are currently no FDAapproved therapies for the front-line treatment of advanced PTCL.

Overall Survival in Both: EGFR-Expressing mCRC

after Irinotecan and Oxaliplatin Failure as a Single Agent Median Overall Survival, All Patients (N=572)†1 6.14 months ERBITUX + BSC (n=287)

vs

34%

4.57 months BSC alone (n=285)

improvement

HR: 0.77; 95% CI: 0.64-0.92; P=0.0046

BSC=best supportive care. † NCIC CTG CO.17 was a multicenter, open-label, randomized (1:1) clinical trial conducted with ERBITUX plus BSC or BSC alone. The main outcome

measure of the trial was overall survival.1

■ The data presented above include patients with K-ras mutations because K-ras mutational status was not assessed at the time the study was conducted ■ Use of ERBITUX is not recommended for the treatment of colorectal cancer with K-ras mutations in codon 12 or 13 because retrospective subset analyses have not shown a treatment benefit for ERBITUX in these patients1

ERBITUX Safety Information for EGFR-Expressing mCRC ■ The most serious adverse reactions associated with ERBITUX across metastatic colorectal cancer studies were infusion reactions, dermatologic toxicity, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/ desquamation (12%), and other-gastrointestinal (10%) References: 1. ERBITUX® (cetuximab) [package insert]. Branchburg, NJ and Princeton, NJ: ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb; September 2010. 2. Bonner JA, Harari PM, Giralt J, et al. Radiotherapy plus cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med. 2006;354(6):567-578.

Please see Important Safety Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

SOLUTION FOR INTRAVENOUS INFUSION

Vandetanib Gets Priority Review in Advanced Medullary Thyroid Cancer AstraZeneca announced that the FDA has accepted regulatory submission for review of the investigational continued on page 46

The ASCO Post | NOVEMBER 2010

PAGE 46

FDA Update

Oncology Drug News continued from page 45

drug vandetanib (Zactima) in the treatment of patients with advanced medullary thyroid cancer. The FDA also granted priority review status for the new drug application and set a Prescription Drug User Fee Act (PDUFA) action date of January 7, 2011.

The submissions are supported by the results from the double-blind, placebo-controlled ZETA study evaluating the safety and efficacy of vandetanib in patients with advanced thyroid cancer.

ZETA was a phase III trial that randomly assigned 331 patients to oral once-daily vandetanib, 300 mg, or placebo. Treatment with vandetanib significantly ex-

tended progression-free survival, demonstrating a 54% reduction in the rate of progression compared to placebo (HR = 0.46, P = .0001). The objective response rate was 45% vs 13% (P < .0001). The most common adverse events (incidence > 25%) associated with vandetanib included diarrhea, rash, nausea, hypertension, and headache.

FDA Issues Final Rule on Safety Information during Clinical Trials The FDA issued a final rule that clarifies what safety information must be reported during clinical trials of investigational drugs and biologics. This final rule is expected to improve the quality of safety reports submitted to

Important Safety Information Including Boxed WARNINGS Infusion Reactions ■ Grade 3/4 infusion reactions occurred in approximately 3% of patients receiving ERBITUX® (cetuximab) in clinical trials, with fatal outcome reported in less than 1 in 1000 — Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of ERBITUX, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest — Immediately interrupt and permanently discontinue ERBITUX infusions for serious infusion reactions ■ Most (90%) of the severe infusion reactions were associated with the first infusion of ERBITUX despite premedication with antihistamines — Caution must be exercised with every ERBITUX infusion, as there were patients who experienced their first severe infusion reaction during later infusions — Monitor patients for 1 hour following ERBITUX infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Longer observation periods may be required in patients who require treatment for infusion reactions

Cardiopulmonary Arrest ■ Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and ERBITUX, as compared to none of 212 patients treated with radiation therapy alone. Fatal events occurred within 1 to 43 days after the last ERBITUX treatment — Carefully consider the use of ERBITUX in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure or arrhythmias in light of these risks — Closely monitor serum electrolytes including serum magnesium, potassium, and calcium during and after ERBITUX therapy

Pulmonary Toxicity ■ Interstitial lung disease (ILD), which was fatal in one case, occurred in 4 of 1570 (<0.5%) patients receiving ERBITUX in clinical trials. Interrupt ERBITUX for acute onset or worsening of pulmonary symptoms.

Permanently discontinue ERBITUX where ILD is confirmed

Dermatologic Toxicities ■ In clinical studies of ERBITUX, dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (eg, S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis, occurred in patients receiving ERBITUX therapy. Acneform rash occurred in 76-88% of 1373 patients receiving ERBITUX in clinical trials. Severe acneform rash occurred in 1-17% of patients — Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days — Monitor patients receiving ERBITUX for dermatologic toxicities and infectious sequelae — Sun exposure may exacerbate these effects

ERBITUX Plus Radiation Therapy and Cisplatin ■ The safety of ERBITUX in combination with radiation therapy and cisplatin has not been established — Death and serious cardiotoxicity were observed in a single-arm trial with ERBITUX, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced squamous cell carcinoma of the head and neck — Two of 21 patients died, one as a result of pneumonia and one of an unknown cause — Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events

ASCOPost.com | NOVEMBER 2010

PAGE 47

FDA Update

FDA, thereby enhancing the safety of patients in clinical trials. The final rule lays out clear, internationally harmonized standards so that critical safety information about new drugs will be accurately and rapidly reported to the agency, minimizing uninformative reports and enhancing reporting of meaning-

ful, interpretable information.

The new rule requires that certain safety information be reported to FDA within 15 days of becoming aware of an occurrence.

These reports include: ■■ findings from clinical or epidemiologic studies that suggest a significant risk to study participants

■■ serious suspected adverse reactions that occur at a rate higher than expected ■■ serious adverse events from bioavailability and bioequivalence studies The rule also provides examples of evidence that would suggest that an investigational product may be the cause of a safety problem. Under current reg-

Electrolyte Depletion ■ Hypomagnesemia occurred in 55% (199/365) of patients receiving ERBITUX® (cetuximab) and was severe (NCI CTC grades 3 & 4) in 6-17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of ERBITUX therapy — Monitor patients periodically for hypomagnesemia, hypocalcemia and hypokalemia, during, and for at least 8 weeks following the completion of, ERBITUX therapy — Replete electrolytes as necessary

Late Radiation Toxicities ■ The overall incidence of late radiation toxicities (any grade) was higher with ERBITUX in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65%/56%), larynx (52%/36%), subcutaneous tissue (49%/45%), mucous membranes (48%/39%), esophagus (44%/35%), and skin (42%/33%) in the ERBITUX and radiation versus radiation alone arms, respectively — The incidence of grade 3 or 4 late radiation toxicities were similar between the radiation therapy alone and the ERBITUX plus radiation therapy arms

Pregnancy and Nursing ■ In women of childbearing potential, appropriate contraceptive measures must be used during treatment with ERBITUX and for 6 months following the last dose of ERBITUX. ERBITUX may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. ERBITUX should only be used during pregnancy if the potential benefit justifies the potential risk to the fetus ■ It is not known whether ERBITUX is secreted in human milk. IgG antibodies, such as ERBITUX, can be excreted in human milk. Because of the potential for serious adverse reactions in nursing infants from ERBITUX, a decision should be made whether to discontinue nursing or to discontinue ERBITUX, taking into account the importance of ERBITUX to the mother. If nursing is interrupted, based on the mean half-life of cetuximab, nursing should not be resumed earlier than 60 days following the last dose of ERBITUX

Adverse Events ■ The most serious adverse reactions associated with ERBITUX across all studies were infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus ■ The most common adverse reactions associated with ERBITUX (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection ■ The most frequent adverse events seen in patients with carcinomas of the head and neck receiving ERBITUX in combination with radiation therapy (n=208) versus radiation alone (n=212) (incidence ≥50%) were acneform rash (87%/10%), radiation dermatitis (86%/90%), weight loss (84%/72%), and asthenia (56%/49%). The most common grade 3/4 adverse events for ERBITUX in combination with radiation therapy (≥10%) included: radiation dermatitis (23%), acneform rash (17%), and weight loss (11%) ■ The most frequent adverse events seen in patients with metastatic colorectal cancer (n=288) in the ERBITUX + best supportive care arm (incidence ≥50%) were fatigue (89%), rash/desquamation (89%), abdominal pain (59%), and pain-other (51%). The most common grade 3/4 adverse events (≥10%) included: fatigue (33%), pain-other (16%), dyspnea (16%), abdominal pain (14%), infection without neutropenia (13%), rash/desquamation (12%), and other-gastrointestinal (10%)

Please see brief summary of Full Prescribing Information including Boxed WARNINGS regarding infusion reactions and cardiopulmonary arrest on adjacent pages.

Please visit www.ERBITUX.com or call 1-888-ERBITUX (372-4889).

©2010, ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company, New York, NY 10014 and Bristol-Myers Squibb, Princeton, NJ, 08543, U.S.A. All rights reserved. ERBITUX® is a registered trademark of ImClone LLC, a wholly-owned subsidiary of Eli Lilly and Company.

693US10AB08605

10/10

SOLUTION FOR INTRAVENOUS INFUSION

ulations, drug sponsors often report all serious adverse events, even if there is little reason to believe the product caused the event. Such reporting complicates and delays the FDA’s ability to detect a safety signal. The examples address when a single event should be reported or when there is need to wait for more than one occurrence.

■

The ASCO Post | NOVEMBER 2010

PAGE 48

Appointments

Raja M. Flores, MD, Named Chief, Thoracic Surgery, at Mt. Sinai Medical Center Raja M. Flores, MD, a world-renowned surgeon with specialized expertise in mesothelioma, lung cancer, and esophageal cancer, has been named Chief of Thoracic Surgery at The Mount Sinai Medical Center and Director of

the Thoracic Surgical Oncology Program at Mount Sinai Cancer Center.

“We are excited to welcome Dr. Flores,” said Dennis S. Charney, MD, Dean of Mount Sinai School of Medicine and Executive Vice President for Aca-

Raja M. Flores, MD

demic Affairs of The Mount Sinai Medical Center. “As an expert in pleural mesothelioma cancer [Dr. Flores] conducted a landmark study that changed the surgical management of this disease.”

Dr. Flores helped pioneer the use of intraopera-

eRbITUx® (cetuximab) injection, for intravenous infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: seRIOUs INFUsION ReACTIONs and CARDIOPULMONARY ARResT Infusion Reactions: Serious infusion reactions occurred with the administration of Erbitux in approximately 3% of patients in clinical trials, with fatal outcome reported in less than 1 in 1000. [See Warnings and Precautions and Adverse Reactions.] Immediately interrupt and permanently discontinue Erbitux infusion for serious infusion reactions. [See Warnings and Precautions and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest: Cardiopulmonary arrest and/or sudden death occurred in 2% of 208 patients with squamous cell carcinoma of the head and neck treated with radiation therapy and Erbitux. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Warnings and Precautions.]

INDICATIONs AND UsAGe squamous Cell Carcinoma of the Head and Neck (sCCHN) Erbitux® (cetuximab) is indicated in combination with radiation therapy for the initial treatment of locally or regionally advanced squamous cell carcinoma of the head and neck. [See Clinical Studies (14.1) in Full Prescribing Information.]

Erbitux, as a single agent, is indicated for the treatment of patients with recurrent or metastatic squamous cell carcinoma of the head and neck for whom prior platinum-based therapy has failed. [See Clinical Studies (14.1) in Full Prescribing Information.]

Colorectal Cancer Erbitux, as a single agent, is indicated for the treatment of epidermal growth factor receptor (EGFR)-expressing metastatic colorectal cancer after failure of both irinotecan- and oxaliplatin-based regimens. Erbitux, as a single agent, is also indicated for the treatment of EGFR-expressing metastatic colorectal cancer in patients who are intolerant to irinotecan-based regimens. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Erbitux, in combination with irinotecan, is indicated for the treatment of EGFR-expressing metastatic colorectal carcinoma in patients who are refractory to irinotecan-based chemotherapy. The effectiveness of Erbitux in combination with irinotecan is based on objective response rates. Currently, no data are available that demonstrate an improvement in disease-related symptoms or increased survival with Erbitux in combination with irinotecan for the treatment of EGFR-expressing, metastatic colorectal carcinoma. [See Clinical Studies (14.2) in Full Prescribing Information and Warnings and Precautions.]

Retrospective subset analyses of metastatic or advanced colorectal cancer trials have not shown a treatment benefit for Erbitux in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Erbitux is not recommended for the treatment of colorectal cancer with these mutations [see Clinical Studies (14.2) and Clinical Pharmacology (12.1) in Full Prescribing Information].

CONTRAINDICATIONs None.

WARNINGs AND PReCAUTIONs Infusion Reactions Serious infusion reactions, requiring medical intervention and immediate, permanent discontinuation of Erbitux, included rapid onset of airway obstruction (bronchospasm, stridor, hoarseness), hypotension, shock, loss of consciousness, myocardial infarction, and/or cardiac arrest. Severe (NCI CTC Grades 3 and 4) infusion reactions occurred in 2–5% of 1373 patients in clinical trials, with fatal outcome in 1 patient.

Approximately 90% of severe infusion reactions occurred with the first infusion despite premedication with antihistamines.

Monitor patients for 1 hour following Erbitux infusions in a setting with resuscitation equipment and other agents necessary to treat anaphylaxis (eg, epinephrine, corticosteroids, intravenous antihistamines, bronchodilators, and oxygen). Monitor longer to confirm resolution of the event in patients requiring treatment for infusion reactions.

Immediately and permanently discontinue Erbitux in patients with serious infusion reactions. [See Boxed Warning and Dosage and Administration (2.4) in Full Prescribing Information.]

Cardiopulmonary Arrest Cardiopulmonary arrest and/or sudden death occurred in 4 (2%) of 208 patients treated with radiation therapy and Erbitux as compared to none of 212 patients treated with radiation therapy alone in a randomized, controlled trial in patients with SCCHN. Three patients with prior history of coronary artery disease died at home, with myocardial infarction as the presumed cause of death. One of these patients had arrhythmia and one had congestive heart failure. Death occurred 27, 32, and 43 days after the last dose of Erbitux. One patient with no prior history of coronary artery disease died one day after the last dose of Erbitux. Carefully consider use of Erbitux in combination with radiation therapy in head and neck cancer patients with a history of coronary artery disease, congestive heart failure, or arrhythmias in light of these risks. Closely monitor serum electrolytes, including serum magnesium, potassium, and calcium, during and after Erbitux. [See Boxed Warning and Warnings and Precautions.]

Pulmonary Toxicity Interstitial lung disease (ILD), including 1 fatality, occurred in 4 of 1570 (<0.5%) patients receiving Erbitux in clinical trials. Interrupt Erbitux for acute onset or worsening of pulmonary symptoms. Permanently discontinue Erbitux for confirmed ILD. Dermatologic Toxicity Dermatologic toxicities, including acneform rash, skin drying and fissuring, paronychial inflammation, infectious sequelae (for example S. aureus sepsis, abscess formation, cellulitis, blepharitis, conjunctivitis, keratitis, cheilitis), and hypertrichosis occurred in patients receiving Erbitux therapy. Acneform rash occurred in 76–88% of 1373 patients receiving Erbitux in clinical trials. Severe acneform rash occurred in 1–17% of patients.

Acneform rash usually developed within the first two weeks of therapy and resolved in a majority of the patients after cessation of treatment, although in nearly half, the event continued beyond 28 days. Monitor patients receiving Erbitux for dermatologic toxicities and infectious sequelae. Instruct patients to limit sun exposure during Erbitux therapy. [See Dose Modifications (2.4) in Full Prescribing Information.]

Use of erbitux in Combination With Radiation and Cisplatin The safety of Erbitux in combination with radiation therapy and cisplatin has not been established. Death and serious cardiotoxicity were observed in a single-arm trial with Erbitux, radiation therapy, and cisplatin (100 mg/m2) in patients with locally advanced SCCHN. Two of 21 patients died, one as a result of pneumonia and one of an unknown cause. Four patients discontinued treatment due to adverse events. Two of these discontinuations were due to cardiac events.

Hypomagnesemia and electrolyte Abnormalities In patients evaluated during clinical trials, hypomagnesemia occurred in 55% of patients (199/365) receiving Erbitux and was severe (NCI CTC Grades 3 and 4) in 6–17%. The onset of hypomagnesemia and accompanying electrolyte abnormalities occurred days to months after initiation of Erbitux. Periodically monitor patients for hypomagnesemia, hypocalcemia, and hypokalemia, during and for at least 8 weeks following the completion of Erbitux. Replete electrolytes as necessary.

tive chemotherapy for mesothelioma.

He has participated in and led a number of major studies and he is also a leading international educator on VATS lobectomy. Dr. Flores established the current program for this procedure at Memorial Sloan-Kettering Cancer Center, where he previously worked as Associate Professor of Cardiothoracic Surgery.

epidermal Growth Factor Receptor (eGFR) expression and Response Because expression of EGFR has been detected in nearly all SCCHN tumor specimens, patients enrolled in the head and neck cancer clinical studies were not required to have immunohistochemical evidence of EGFR tumor expression prior to study entry.

Patients enrolled in the colorectal cancer clinical studies were required to have immunohistochemical evidence of EGFR tumor expression. Primary tumor or tumor from a metastatic site was tested with the DakoCytomation EGFR pharmDx™ test kit. Specimens were scored based on the percentage of cells expressing EGFR and intensity (barely/faint, weak-to-moderate, and strong). Response rate did not correlate with either the percentage of positive cells or the intensity of EGFR expression.

ADveRse ReACTIONs The following adverse reactions are discussed in greater detail in other sections of the label: • Infusion reactions [See Boxed Warning and Warnings and Precautions.]

• Cardiopulmonary arrest [See Boxed Warning and Warnings and Precautions.]

• Pulmonary toxicity [See Warnings and Precautions.]

• Dermatologic toxicity [See Warnings and Precautions.]

• Hypomagnesemia and Electrolyte Abnormalities [See Warnings and Precautions.]

The most common adverse reactions with Erbitux (cetuximab) (incidence ≥25%) are cutaneous adverse reactions (including rash, pruritus, and nail changes), headache, diarrhea, and infection.

The most serious adverse reactions with Erbitux are infusion reactions, cardiopulmonary arrest, dermatologic toxicity and radiation dermatitis, sepsis, renal failure, interstitial lung disease, and pulmonary embolus.

Across all studies, Erbitux was discontinued in 3–10% of patients because of adverse reactions.

Clinical Trials experience Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice.

The data below reflect exposure to Erbitux in 1373 patients with colorectal cancer or SCCHN in randomized Phase 3 (Studies 1 and 3) or Phase 2 (Studies 2 and 4) trials treated at the recommended dose and schedule for a median of 7 to 14 weeks. [See Clinical Studies (14) in Full Prescribing Information.]

Infusion reactions: Infusion reactions, which included pyrexia, chills, rigors, dyspnea, bronchospasm, angioedema, urticaria, hypertension, and hypotension occurred in 15–21% of patients across studies. Grades 3 and 4 infusion reactions occurred in 2–5% of patients; infusion reactions were fatal in 1 patient.

Infections: The incidence of infection was variable across studies, ranging from 13–35%. Sepsis occurred in 1–4% of patients.

Renal: Renal failure occurred in 1% of patients with colorectal cancer.

Squamous Cell Carcinoma of the Head and Neck Table 1 contains selected adverse events in 420 patients receiving radiation therapy either alone or with Erbitux for locally or regionally advanced SCCHN in Study 1. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly). Patients received a median of 8 infusions (range 1–11).

Table 1:

Incidence of selected Adverse events (≥10%) in Patients with Locoregionally Advanced sCCHN erbitux plus Radiation Radiation Therapy Alone (n=208) (n=212) body system Grades Grades Grades Grades Preferred Term 1–4 3 and 4 1–4 3 and 4 % of Patients body as a Whole Asthenia 56 4 49 5 Fever1 29 1 13 1 Headache 19 <1 8 <1 15 3 2 0 Infusion Reaction2 Infection 13 1 9 1 1 16 0 5 0 Chills Digestive Nausea 49 2 37 2 Emesis 29 2 23 4 Diarrhea 19 2 13 1 Dyspepsia 14 0 9 1 Metabolic/Nutritional Weight Loss 84 11 72 7 Dehydration 25 6 19 8 43 2 21 1 Alanine Transaminase, high3 38 1 24 1 Aspartate Transaminase, high3 3 33 <1 24 0 Alkaline Phosphatase, high Respiratory Pharyngitis 26 3 19 4 skin/Appendages 4 87 17 10 1 Acneform Rash Radiation Dermatitis 86 23 90 18 Application Site Reaction 18 0 12 1 Pruritus 16 0 4 0 1 2

3 4

Includes cases also reported as infusion reaction.

Infusion reaction is defined as any event described at any time during the clinical study as “allergic reaction” or “anaphylactoid reaction”, or any event occurring on the first day of dosing described as “allergic reaction”, “anaphylactoid reaction”, “fever”, “chills”, “chills and fever”, or “dyspnea”.

Based on laboratory measurements, not on reported adverse events, the number of subjects with tested samples varied from 205–206 for Erbitux plus Radiation arm; 209–210 for Radiation alone.

Acneform rash is defined as any event described as “acne”, “rash”, “maculopapular rash”, “pustular rash”, “dry skin”, or “exfoliative dermatitis”.

The incidence and severity of mucositis, stomatitis, and xerostomia were similar in both arms of the study.

Late Radiation Toxicity The overall incidence of late radiation toxicities (any grade) was higher in Erbitux in combination with radiation therapy compared with radiation therapy alone. The following sites were affected: salivary glands (65% versus 56%), larynx (52% versus 36%), subcutaneous tissue (49% versus 45%), mucous membrane (48% versus 39%), esophagus (44% versus 35%), skin (42% versus 33%). The incidence of Grade 3 or 4 late radiation toxicities was similar between the radiation therapy alone and the Erbitux plus radiation treatment groups.

ASCOPost.com | NOVEMBER 2010

PAGE 49

Appointments

Dr. Edward Chu Assumes Role of Deputy Director, University of Pittsburgh Cancer Institute Edward Chu, MD, an internationally renowned expert in the biology and treatment of colorectal cancer, has been named Chief of the Division of Hematology/Oncology at the University of Pittsburgh School of Medicine

and Deputy Director of the University of Pittsburgh Cancer Institute (UPCI).

“We are thrilled to have such an accomplished cancer investigator join us,” said Nancy E. Davidson, MD, Director of UPCI and UPMC Cancer Centers. “Under Dr. Chu’s leadership, we anticipate the Division of Hematology/Oncology, as well as

Colorectal Cancer Table 2 contains selected adverse events in 562 patients receiving best supportive care (BSC) alone or with Erbitux (cetuximab) monotherapy for metastatic colorectal cancer in Study 3. Erbitux was administered at the recommended dose and schedule (400 mg/m2 initial dose, followed by 250 mg/m2 weekly).

Table 2:

Incidence of selected Adverse events Occurring in ≥10% of Patients with Advanced Colorectal Carcinoma1 Treated with erbitux Monotherapy erbitux plus bsC bsC alone (n=288) (n=274) body system Any Grades Any Grades Preferred Term Grades2 3 and 4 Grades 3 and 4 % of Patients Dermatology Rash/Desquamation 89 12 16 <1 Dry Skin 49 0 11 0 Pruritus 40 2 8 0 Other-Dermatology 27 1 6 1 Nail Changes 21 0 4 0 body as a Whole Fatigue 89 33 76 26 Fever 30 1 18 <1 3 Infusion Reactions 20 5 Rigors, Chills 13 <1 4 0 Pain Abdominal Pain 59 14 52 16 Pain-Other 51 16 34 7 Headache 33 4 11 0 Bone Pain 15 3 7 2 Pulmonary Dyspnea 48 16 43 12 Cough 29 2 19 1 Gastrointestinal Constipation 46 4 38 5 Diarrhea 39 2 20 2 Vomiting 37 6 29 6 Stomatitis 25 1 10 <1 Other-Gastrointestinal 23 10 18 8 11 0 4 0 Mouth Dryness Infection Infection without neutropenia 35 13 17 6 Neurology Insomnia 30 1 15 1 Confusion 15 6 9 2 Anxiety 14 2 8 1 Depression 13 1 6 <1

Adverse reactions occurring more frequently in Erbitux-treated patients compared with controls.

Adverse events were graded using the NCI CTC, V 2.0.

3 Infusion reaction is defined as any event (chills, rigors, dyspnea, tachycardia, bronchospasm, chest tightness, swelling, urticaria, hypotension, flushing, rash, hypertension, nausea, angioedema, pain, pruritus, sweating, tremors, shaking, cough, visual disturbances, or other) recorded by the investigator as infusionrelated.

BSC = best supportive care 1 2

The most frequently reported adverse events in 354 patients treated with Erbitux plus irinotecan in clinical trials were acneform rash (88%), asthenia/malaise (73%), diarrhea (72%), and nausea (55%). The most common Grades 3–4 adverse events included diarrhea (22%), leukopenia (17%), asthenia/malaise (16%), and acneform rash (14%).

Immunogenicity As with all therapeutic proteins, there is potential for immunogenicity. Immunogenic responses to cetuximab were assessed using either a double antigen radiometric assay or an ELISA assay. Due to limitations in assay performance and sampling timing, the incidence of antibody development in patients receiving Erbitux has not been adequately determined. Non-neutralizing anti-cetuximab antibodies were detected in 5% (49 of 1001) of evaluable patients without apparent effect on the safety or antitumor activity of Erbitux.

The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Erbitux with the incidence of antibodies to other products may be misleading.

Postmarketing experience The following adverse reaction has been identified during post-approval use of Erbitux. Because this reaction was reported from a population of uncertain size, it was not always possible to reliably estimate its frequency or establish a causal relationship to drug exposure.

• Aseptic meningitis DRUG INTeRACTIONs A drug interaction study was performed in which Erbitux was administered in combination with irinotecan. There was no evidence of any pharmacokinetic interactions between Erbitux and irinotecan.

UPCI, will play an even greater national and international leadership role in cancer research and cancer treatment. Ed is the consummate clinician-scientist, constantly striving to improve our understanding of how cancer drugs work so that he can improve care for the patient.”

Dr. Chu is well recognized for his

Use IN sPeCIFIC POPULATIONs Pregnancy Pregnancy Category C There are no adequate and well-controlled studies of Erbitux (cetuximab) in pregnant women. Based on animal models, EGFR has been implicated in the control of prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, Erbitux may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Erbitux should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Pregnant cynomolgus monkeys were treated weekly with 0.4 to 4 times the recommended human dose of cetuximab (based on body surface area) during the period of organogenesis (gestation day [GD] 20–48).

Cetuximab was detected in the amniotic fluid and in the serum of embryos from treated dams at GD 49. No fetal malformations or other teratogenic effects occurred in offspring. However, significant increases in embryolethality and abortions occurred at doses of approximately 1.6 to 4 times the recommended human dose of cetuximab (based on total body surface area).

Nursing Mothers It is not known whether Erbitux is secreted in human milk. IgG antibodies, such as Erbitux, can be excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from Erbitux, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of cetuximab [see Clinical Pharmacology (12.3) in Full Prescribing Information], nursing should not be resumed earlier than 60 days following the last dose of Erbitux.

Pediatric Use The safety and effectiveness of Erbitux in pediatric patients have not been established. The pharmacokinetics of cetuximab have not been studied in pediatric populations.

Geriatric Use Of the 1062 patients who received Erbitux with irinotecan or Erbitux monotherapy in five studies of advanced colorectal cancer, 363 patients were 65 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients.

Clinical studies of Erbitux conducted in patients with head and neck cancer did not include sufficient number of subjects aged 65 and over to determine whether they respond differently from younger subjects. Of the 208 patients with head and neck cancer who received Erbitux with radiation therapy, 45 patients were 65 years of age or older.

OveRDOsAGe The maximum single dose of Erbitux administered is 1000 mg/m2 in one patient. No adverse events were reported for this patient.

NONCLINICAL TOxICOLOGY Carcinogenesis, Mutagenesis, Impairment of Fertility Long-term animal studies have not been performed to test cetuximab for carcinogenic potential, and no mutagenic or clastogenic potential of cetuximab was observed in the Salmonella-Escherichia coli (Ames) assay or in the in vivo rat micronucleus test. Menstrual cyclicity was impaired in female cynomolgus monkeys receiving weekly doses of 0.4 to 4 times the human dose of cetuximab (based on total body surface area).

Cetuximab-treated animals exhibited increased incidences of irregular or absent cycles, as compared to control animals. These effects were initially noted beginning week 25 of cetuximab treatment and continued through the 6-week recovery period. In this same study, there were no effects of cetuximab treatment on measured male fertility parameters (ie, serum testosterone levels and analysis of sperm counts, viability, and motility) as compared to control male monkeys. It is not known if cetuximab can impair fertility in humans.

Animal Pharmacology and/or Toxicology In cynomolgus monkeys, cetuximab, when administered at doses of approximately 0.4 to 4 times the weekly human exposure (based on total body surface area), resulted in dermatologic findings, including inflammation at the injection site and desquamation of the external integument. At the highest dose level, the epithelial mucosa of the nasal passage, esophagus, and tongue were similarly affected, and degenerative changes in the renal tubular epithelium occurred. Deaths due to sepsis were observed in 50% (5/10) of the animals at the highest dose level beginning after approximately 13 weeks of treatment.

PATIeNT COUNseLING INFORMATION Advise patients: • To report signs and symptoms of infusion reactions such as fever, chills, or breathing problems.

• Of the potential risks of using Erbitux during pregnancy or nursing and of the need to use adequate contraception in both males and females during and for 6 months following the last dose of Erbitux therapy.

• That nursing is not recommended during, and for 2 months following the last dose of Erbitux therapy.

• To limit sun exposure (use sunscreen, wear hats) while receiving and for 2 months following the last dose of Erbitux.

Erbitux® is a registered trademark of ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company.

Manufactured by ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, Branchburg, NJ 08876 USA Distributed and marketed by Bristol-Myers Squibb Company, Princeton, NJ 08543 USA Co-marketed by Eli Lilly and Company, Indianapolis, IN 46285 USA

Copyright © 2004–2010 ImClone LLC a wholly-owned subsidiary of Eli Lilly and Company, and Bristol-Myers Squibb Company. All rights reserved.

1236886A7

ER-B0001A-09-10

Rev September 2010

contributions in understanding the action of antimetabolites in cancer therapy. Before coming to UPCI, Dr. Chu served as a Professor of Medicine and Pharmacology at Yale University School of Medicine, Chief of the Section of Medical Oncology, and Deputy Director of the Yale Cancer Center.

“I am e x t re m e l y excited and honored to take on my new roles at UPCI and the University of PittsEdward Chu, MD burgh,” said Dr. Chu. “As the leading institution in western Pennsylvania for the delivery of cancer care, the conduct of cancer research and the education of future generations of oncologists, UPCI plays a critically important role in the fight against cancer. I look forward to working closely with Dr. Davidson and her leadership team at UPCI as we work to improve the lives of our cancer patients.”

Dr. Chu received his MD degree from Brown University. He then completed an internal medicine residency and served as Chief Medical Resident at the Roger Williams Hospital of Brown University. In 1987, he began training in medical oncology at the NCI, where he extended his interest in cancer pharmacology and gastrointestinal oncology, and he served as a tenured senior clinical investigator in the NCI-Navy Medical Oncology Branch at the NCI in Maryland.

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Call for Papers The ASCO Post invites readers to share their thoughts and opinions on matters of interest to the oncology community (500 words recommended). All submissions will be acknowledged and considered for publication.

Write to: Editor@ASCOPost.com for more information or to submit your commentary.

The ASCO Post | NOVEMBER 2010

PAGE 50

In the News

Palliative Care Can Improve Quality of Life and Extend Survival

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

A

palliative care study published in The New England Journal of Medicine1 is “an example of research that shifts a long-held paradigm that has limited access to palliative care to patients who were predictably and clearly dying,” according to the accompanying editorial by Amy S. Kelley, MD, MSHS, and Diane E. Meier, MD.2 The study reported that patients with metastatic non–small cell lung cancer (NSCLC) who received palliative care in addition to standard oncologic care had not only improved quality of life, but longer lives than patients who received only standard oncologic care.

Diane E. Meier, MD

Rigorous Study Listed as one of the top-viewed articles on the journal’s website, the palliative care report was also covered

by the medical and consumer media.

“This study got the kind of attention it did not only because it was published in The New England Journal of Medicine.

It was a rigorous, randomized prospective study, which is difficult to conduct in this patient population,” Dr. Meier noted. She is Director of both the Hertzberg Palliative Care Institute at Mount Sinai School of Medicine and the Center to Advance Palliative Care in New York. The “significant gain in longevity was much more beneficial than anyone had a right to hope,” she added.

Median survival for study participants randomly assigned to early palliative care integrated with standard oncologic care was 11.6 months, compared with 8.9 months for patients receiving standard oncologic care alone (P = .02). Judged by all measures, quality of life was significantly better for patients receiving palliative care, who also had lower rates of depression. (A summary of the study findings appeared in the August issue of The ASCO Post and can be found at www.

ASCOPost.com.)

Patients in the early palliative care group were also more likely to have a resuscitation preference documented in their outpatient electronic medical records, which the study authors considered “an essential step in clarifying and ensuring respect for patients’ wishes about their care at the end of life.”

Dr. Meier agreed. “It is part of the quality indicators for a palliative care program—that people’s goals are discussed,” she said. “There is no bias as to what the patient’s goals should be. There is simply the understanding that care plans should be

Links to Palliative Care Training Options

T

raining in palliative care is currently available from several sources.

“We know that teaching is effective,” noted Diane E. Meier, MD, “that it changes behavior for the better, because we have outcome studies.” She provided the following links: ■■ Stanford School of Medicine’s Cancer Palliation Education Network: http://ecampus.stanford.edu/ ■■ Oncotalk: http://www.oncotalk.info/ ■■ Medical College of Wisconsin’s End of Life/Palliative Education Resource Center: http://www.eperc.mcw.edu/EPERC/Training ■■ Harvard Medical School’s Center for Palliative Care: http://www. hms.harvard.edu/pallcare/pcep.htm

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Expect Questions

D

espite recent findings, patients and families may react negatively to the prospect of palliative care, thinking that it represents the end of treatment and of hope. These questions and answers can help physicians respond to those concerns.

Does a referral to palliative care mean treatment is not effective?

No. Patients can and do receive palliative care while continuing active treatment.

Why begin palliative care if active treatment is still working?

As reported in The New England Journal of Medicine article,1 palliative care can improve quality of life and extend survival. In that study, the survival benefit for patients randomly assigned to early palliative care integrated with standard oncologic care was 2.7 months. Diane E. Meier, MD, noted that these patients were getting aggressive treatment for non–small cell lung cancer and palliative care from the point of diagnosis, and many of them were leading active lives, working full time, and caring for children at home.

“These were not patients who would be ready for or even eligible for hospice care,” she said.

What’s the difference between palliative care and hospice care?

Palliative care focuses on improving quality of life at any time during an illness. While receiving palliative care, patients may continue active treatments including chemotherapy and radiation. Hospice provides palliative care at the end of life, defined by U.S. government regulations as ≤ 6 months expected survival, and patients must usually stop active treatments. “We say all hospice is palliative care, but not all palliative care is hospice,” Dr. Meier explained.

“Most people with advanced chronic disease continue to benefit from disease-modifying treatment until very close to the end of their life,” Dr. Meier said. “That is why hospice tends to be used only for a few weeks, as opposed to 6 months—prior to those few weeks, people are still benefiting from treatment. So the palliative care movement grew to fill that gap” and allow patients “to continue getting treatment that is helping them.”

■

driven first and foremost by achievable patient and family goals. Hence the importance of inquiring about and then documenting them, which increases the likelihood that the care will be consistent with what the patient wants.”

Getting Data to Doctors “An increasing body of research suggests that a team focusing on quality of life for patient and family not only improves quality of life but lengthens it,” 3-5 Dr. Meier reported. “There are studies showing that cancer patients referred to hospice live substantially longer—1 or 2 months more—than cancer patients not referred to hospice.

These are big gains in life expectancy, equivalent to average gains associated with best cancer care.”

It is important to “get these data into the hands of the oncologist,” Dr. Meier said. “Patients and families take their guidance from their physicians.”

Palliative care discussions with patients should take into account patient and family goals. These conversations with patients and families should be considered “a procedure,” Dr. Meier said, citing a recent article in The New Yorker6 that quoted Susan D. Block, MD, Chair of the Department of Psychosocial Oncology and Palliative Care at Dana-Farber Cancer Institute in Boston. In that article, Dr. Block stated, “A family meeting is a procedure, and it requires no less skill than performing an operation.”

And it requires training, Dr. Meier added. “Just as you would not send in a doctor who hadn’t been trained to do an appendectomy, you shouldn’t send in a doctor who hasn’t been trained to conduct a goals-of-care conversation.”

Palliative care discussions with patients and family require “a very different skill set than your typical specialist has,” she continued. “Spe-

ASCOPost.com | NOVEMBER 2010

PAGE 51

In the News

cialists typically see themselves as physicians with expertise in a disease or a set of diseases.” But palliative care discussions require a broader understanding of the human beings who have these diseases, “finding out about who they are, what their understanding of See page 52 their disease is, and of its implications, its prognosis, and given what time they have left, their highest priorities.”

Physicians need to “make sure the patient understands that he or she has options, including palliative care delivered concurrently with cancer treatment” Dr. Meier said. “Chemotherapy or radiation may be one of the options, but only one. Maybe a person would rather be home with his grandchildren than in the hospital participating in a phase I trial or coming to the hospital every day for radiation. That means we need to step back from what we are wedded to— the procedures and treatments we have been trained to rely upon. So it is a pretty fundamental shift in selfconcept for doctors,” she added.

Changing Training “It is not right to expect physicians to do things that they never got any training for or were never exposed to, and we can’t improve quality in this regard without changing the training process,” Dr. Meier noted.

“Year after year, we are continuing to graduate physicians and nurses who have not had training in symptom management, communication about goals, and managing care outside the hospital, because such training isn’t mandated as a condition of accreditation or licensing for medical schools or residencies. That needs to change.” Adding palliative care to the medical school curriculum should ensure that graduates “demonstrate competency in the management of pain, the identification and treatment of depression, and the conduct of a family meeting about goals of care,” Dr. Meier said.

“Some of my colleagues and I are trying to drive different policy levers to create both carrots and sticks for palliative care,” Dr. Meier said. She would like to see the Joint Commission recognize hospitals that develop high-quality palliative care programs, she said. “My hope is that ultimately, it will become an accreditation requirement.”

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References 1. Temel JS, Greer JA, Muzikansky A, et al: Early palliative care for patients with metastatic non–small-cell lung cancer. N Engl J Med 363:733-742, 2010.

2. Kelley AS, Meier DE: Palliative care—a shifting paradigm. N Engl J Med 363:781-782, 2010.

3. Bakitas M, Lyons KD, Hegel MT,

et al: Effects of a palliative care intervention on clinical outcomes in patients with advanced cancer: The Project ENABLE II randomized controlled trial. JAMA 302:741-749, 2009.

4. Connor SR, Pyenson B, Fitch K, et al: Comparing hospice and nonhospice patient survival among patients who die within a three-year window. J Pain Symp-

tom Manage 33:238-246, 2007.

5. Pyenson B, Connor S, Fitch K, Kinzbrunner B: Medicare cost in matched hospice and nonhospice cohorts. J Pain Symptom Manage 28:200-210, 2004.

6. Gawande A: Letting go. What should medicine do when it can’t save your life? The New Yorker, August 2, 2010.

(Stimulating Targeted Antigenic Responses To NSCLC)

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

The ASCO Post | NOVEMBER 2010

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In the Literature

PANCREATIC CANCER Treatment Alternatives Validated for Patients with Pancreatic Cancer “Gemcitabine did not result in improved overall survival compared with fluorouracil plus folinic acid [leucovorin] in patients with resected pancreatic cancer,” concluded European Study Group for Pancreatic Cancer (ESPAC) investigators in a JAMA article on the ESPAC-3 trial version 2. (The trial was modified to remove the observation group after an earlier trial provided definitive survival benefits for chemotherapy.) All 1,088 patients in ESPAC-3 had undergone complete resection for pancreatic ductal adenocarcinoma and were randomly assigned to receive fluorouracil plus leucovorin (n = 551) or gemcitabine (n = 537) for 6 months.

Median survival was 23.0 months for patients treated with fluorouracil plus leucovorin and 23.6 months for patients treated with gemcitabine. The investigators reported “no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.” A higher proportion (14%) of patients receiving fluorouracil plus leucovorin had serious treatmentrelated adverse events, compared with those receiving gemcitabine (7.5%).

Past and Present ESPAC Trials The ESPAC-4 trial, currently in progress, is comparing combination chemotherapy with gemcitabine plus capecitabine (Xeloda) to the use of

capecitabine alone.

“ESPAC-3 and ESPAC-1 firmly establish the value of adjuvant chemotherapy alone in the treatment of resected pancreatic cancer,” according to an accompanying editorial by Eileen M. O’Reilly, MD, of Memorial Sloan-Kettering Cancer Center and Weill Medical College of Cornell University, New York.

She noted that while a “consensus exists that gemcitabine remains the preferred treatment” given other trial results, “for patients unable to tolerate gemcitabine there is now a clearly validated alternative with fluorouracil and leucovorin.” Additional options being explored as adjuvant chemotherapy for resected pancreatic adenocarcinoma include adding erlotinib (Tarceva) to gemcitabine and FOLFIRINOX (fluorouracil [bolus and infusion], leucovorin, irinotecan, oxaliplatin).

“Other directions deserving further evaluation,” Dr. O’Reilly wrote, “include the role of neoadjuvant or preoperative therapy for patients with resectable pancreatic adenocarcinoma.”

Neoptolemos JP, et al: JAMA 304:10731081, 2010.

O’Reilly EM: JAMA, 304:1124-1125, 2010.

NEUROBLASTOMA High Survival Rates Maintained with Reduced Chemotherapy Infants and children with intermediate-risk neuroblastoma had high survival rates with substantially reduced

chemotherapy, according to a phase III study reported in The New England Journal of Medicine. The study enrollment consisted of 479 patients with intermediate-risk neuroblastoma, as defined by the Children’s Oncology Group, including 270 patients with stage 3 disease, 178 with stage 4 disease, and 31 with stage 4S disease. The 323 patients who had tumors with favorable biologic features received four cycles of chemotherapy, and the 141 patients who had tumors with unfavorable disease received eight cycles of chemotherapy with carboplatin, etoposide, cyclophosphamide, and doxorubicin administered at 3-week intervals.

The combination chemotherapy was followed by surgical excision of the primary tumor “to achieve a complete response or a very good response according to the International Neuroblastoma Response Criteria,” the investigators stated. Patients who were younger than 60 days and who were enrolled in the study after 1999 (enrollment was from 1997 to 2005) also received granulocyte colony-stimulating factor (G-CSF, Neupogen) after each chemotherapy. For older patients, G-CSF was optional.

Key Data “The 3-year estimate (±SE) of overall survival for the entire group was 96±1%, with an overall survival rate of 98±1% among patients who had tumors with favorable biologic features and 93±2% among patients who had tumors with unfavorable

biologic features,” the researchers reported. These outcomes were similar to those achieved in the Children’s Cancer Study Group (CCG)-3881 trial, but with a 40% reduction in duration of therapy for those receiving eight cycles and a 70% reduction in therapy for those receiving four cycles.

“In addition, as compared with previous clinical trials involving patients with intermediate-risk neuroblastoma, total cumulative doses of anthracyclines, topoisomerase II inhibitors, and platinum agents were reduced to minimize both acute and long-term toxic effects on hearing, the heart, and the kidneys,” the authors noted.

Summary “In conclusion, using risk stratification based on clinical and genetic data, we substantially reduced both the doses and duration of therapy for intermediate-risk neuroblastoma and maintained very high survival rates,” the authors stated. “These data, along with the low rate of treatment-related deaths (1.7%) and low incidence of secondary leukemia (three cases), provide support for further dose reduction in this population, and assessment of chromosomal deletions and segmental aberrations may provide more specific criteria for determining the duration of therapy in individual patients.”

Using 2D Barcodes The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Getting the Application There are three ways to download the ScanLife application:

1 2

3

Simply text the word “scan” to 43588.

Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

Visit the application store for your smartphone (such as the iTunes Store or the Android Market).

Scanning 2D codes When you see a code you would like to scan, start the ScanLife application. The screen will look similar to camera mode. Position your phone so that you can see the barcode and that the code fills about half your screen. If one of the soft keys displays the word “Click,” you will need to click that key or the center key to scan. Otherwise, the code will scan automatically.

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Baker DL, et al: N Engl J Med 363:13131323, 2010.

© Leo Cullum/The New Yorker Collection/www.cartoonbank.com

ASCOPost.com | NOVEMBER 2010

PAGE 53

Awards

Oncology on Canvas: Expressions of a Cancer Journey Award Winners Announced

F

ollowing her lung cancer diagnosis, a woman who had spent nearly 30 years in nursing felt as if her life had been “cut up, rearranged, and become a different picture.” An amateur artist, Annette Zalewski, of Peoria, Arizona, sought to express her cancer journey on canvas by using a cut-up painting technique. Her mixed media entry, “Wild Water,” took first place (Fig. 1) among the more than 600 submissions to the fourth biennial Oncology On Canvas: Expressions of a Cancer Journey Art Competition and Exhibition.

The 2010 competition’s 24 winning entries were announced at an awards presentation held recently at historic Union Station in Washington, DC (Figs. 2 and 3). Artwork from the 2010 competition will tour cancer centers, hospitals, and patient

advocacy events nationwide beginning in January 2011.

Lilly Oncology On Canvas is presented by Lilly Oncology and the National Coalition for Cancer Survivorship. The biennial competition invites residents of the United States and Puerto Rico who have been touched by cancer—patients, family members, friends, caregivers, and healthcare providers—to express, through art and narrative, the life-affirming changes that give their cancer journeys meaning. Winners’ prizes consist of donations made in their name to the cancer-related charities of their choice.

To Learn More For further information, an exhibit schedule, and more, visit www.

LillyOncologyOnCanvas.com.

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Fig. 1: 1st Place. Wild Water, by Annette Zalewski, Peoria, Arizona. “My life after a diagnosis of lung cancer feels like it has been cut up, rearranged, and become a different picture. The treatments and side effects, like the rocks in the turbulent water, can make me feel bruised, battered, and worn out.

When scan results show improvement or stability, I can coast smoothly for a while, but any negative change leads to another bumpy ride down the falls. Yet as the rushing water continues on its path, I plan to continue surviving and weaving a beautiful life.”

Mrs. Zalewski designated the Lung Cancer Alliance as the recipient of her $10,000 first-place award.

Fig. 2: 2nd Place. Breathing Room, by Victoria Kelly, Baldwin, Michigan. “Lung cancer. Inoperable.

Radiation. Chemotherapy. Those were terrifying words. After 20 years of not smoking, I tried to come to terms with my diagnosis. As my treatment progressed, I thought, “Why couldn’t I be one of the survivors?” As an artist who works with fabrics, I needed to visualize what was happening inside my body. So I made this collage of my lungs, surrounded by hope in the form of leaves and flowers. Today, after 4½ years, I am grateful to be cancer-free…thanks to my wise and caring doctors and staff whose research and knowledge saved my life.”

Ms. Kelly chose the LUNGevity Foundation as the recipient of her $5,000 prize. The foundation funds promising research into the early detection and successful treatment of lung cancer.

Fig. 3: 3rd Place. No Words, by Juliana Carvatt, Clinton, New Jersey. I was 21 when cancer disrupted my life. I was in college, in love, and unstoppable. But in the months following my diagnosis and treatment, I lost my hair, my invincibility, and the boy I thought I would marry. I held on to the hope I would pick up the pieces of myself when it was all over. But I couldn’t. I kept my cancer a secret. Ultimately, I realized I needed to tell my story and wrote it all down; 150 pages later, I found I had finally untangled myself from cancer’s grip. I said goodbye; goodbye past, goodbye pain, goodbye cancer. I’ve won and that means that you lose. I am finally free!

Ms. Carvatt selected First Descents to receive her prize of $2,500. The organization works to help young adults cope with the emotional effects of cancer by experiencing outdoor adventure therapy through kayaking, rock climbing, and other outdoor adventure sports.

The ASCO Post | NOVEMBER 2010

PAGE 54

TAP Caucus Pro/Con

Is Maintenance Chemotherapy Appropriate for Metastatic Non–Small Cell Lung Cancer?

Maybe More Really Is Better

Maintenance Is Not for Everybody

By Joan H. Schiller, MD

By Thomas Stinchcombe, MD

A

Joan H. Schiller, MD

dvanced non–small cell lung cancer (NSCLC) is one of the few solid tumors for which multiple clinical trials have randomly assigned patients to treatment vs no treatment. These studies have shown that platinum-based chemotherapy improves survival, compared to best supportive care, in patients with good performance status.1,2 Since then (somewhat remarkably, given the nihilistic attitude toward NSCLC), both second-line (docetaxel, erlotinib [Tarceva], and pemetrexed) and third-line (erlotinib) therapies have also been shown to improve survival.

Interpretations of ‘More’ Therapy If chemotherapy can impact the natural history of this disease, why not give more of it? Until recently, most randomized studies have failed to show a definitive improvement in survival with “more” first-line chemotherapy. Although most trials have shown an improvement in progression-free survival, that improvement unfortunately has often been accompanied by an increase in side effects. More recently, however, several randomized studies have suggested that “more” is indeed “better.”3-5

Although we hope that the advent of targeted therapies will result in more effective and less toxic drugs, we should continue to use any weapon in our armamentarium to make cancer a chronic disease.

Why the conflicting results? There are several ways to give “more” chemotherapy to patients who have responded or stabilized after four to six cycles of first-line chemotherapy. These approaches include (a) continuing first-line chemotherapy until disease progression; (b) continuing first-line chemotherapy, but limiting it to a specified number of cycles; or (c) switching to a different regimen after a defined number of cycles of first-line chemotherapy. Various terms have been used to describe these different scenarios, but one convention, as used by the National Comprehensive Cancer Network (NCCN), is to call options (a) and (b) “continuation maintenance” and to call (c) “switch maintenance.”

Survival Findings Regardless of the terminology, before maintenance chemotherapy can be adopted as part of routine practice in advanced NSCLC, it is critically important to show a survival benefit, given the toxicities associated with chemotherapy in a disease with such a poor prognosis. Presumably, an improvement in progression-free survival without an improvement in overall survival suggests that both the first and second regimens are active, and that it does not matter when the second regimen is administered—at disease progression or immediately following the first regimen. The question of sequence has been tested extensively in other malignancies such as colorectal carcinoma and breast cancer, where it has been argued that if progression-free survival is improved without a corresponding improvement in overall survival, the timing of consolidation or second-line therapy really does not matter, and that the second regimen can be delayed until disease progression.

The issue of maintenance chemotherapy has now been tested in several advanced NSCLC trials. A trial reported by Fidias et al administered four cycles of gemcitabine and carboplatin, and patients without progression were randomly assigned to immediately receive an additional six cycles of docetaxel, or to continued on page 55

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he treatment of non–small cell lung cancer (NSCLC) continues to evolve, and there has been increasing interest in extending the duration of first-line chemotherapy. Several trials have investigated the initiation of a new agent after four cycles of platinum-based therapy (often referred to as “switch” maintenance). The FDA has approved pemetrexed as maintenance therapy for patients with non-squamous histology, and erlotinib 1,2 Thomas Stinchcombe, MD (Tarceva) as maintenance therapy. Thus, these agents are treatment options; however, the data from these trials should be analyzed carefully, and the strategy should be considered in the context of current treatment paradigms for NSCLC.

Maintenance Eligibility and Toxicity Only a select proportion of patients with NSCLC are eligible for maintenance therapy. Among patients who were started on platinum-based doubleagent chemotherapy in recent trials, only 45% to 55% were eligible for random assignment to maintenance therapy.2,3 Of the patients assigned to the placebo arm in the erlotinib and pemetrexed trials, only about two-thirds received second-line therapy, and there was significant heterogeneity in the type of second-line therapy administered. Moreover, many patients received secondline therapy that has not been validated in phase III trials. This raises a question about the benefit of maintenance therapy compared to the same therapy administered at the time of disease progression.

The difficulty with maintenance therapy is that it requires a patient for whom the goals of therapy are palliative and overall survival remains modest to undergo continuous treatment.

In a phase III trial of immediate vs delayed docetaxel after four cycles of platinum-based double-agent chemotherapy, survival among patients in the immediate docetaxel arm and the delayed docetaxel arm (for patients who actually received docetaxel) was an identical 12.5 months.3 This suggests that an important factor in patient survival is that the patient actually received second-line therapy.

Although the rate of grade ≥ 3 toxicities observed in maintenance trials has been low, grade 1 and 2 toxicities associated with maintenance therapy can have a cumulative impact on a patient’s quality of life. It is also important to note that the phase III trials of maintenance pemetrexed, erlotinib, and docetaxel compared to placebo or delayed docetaxel maintenance therapy did not show an improvement in patients’ quality of life.

Current Paradigms Another critical question is whether maintenance therapy applies to our current paradigms. For instance, patients in the trial of maintenance pemetrexed received first-line therapy with platinum-based double-agent chemotherapy that did not contain pemetrexed or bevacizumab (Avastin). Thus, phase III trial data demonstrating a benefit of maintenance pemetrexed after first-line treatment with pemetrexed is not available. For patients receiving bevacizumab, the curcontinued on page 55

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TAP Caucus

Maybe More Really Is Better continued from page 54

“standard of care”—no additional therapy until disease progression, at which point they received docetaxel.3 Median progression-free survival for immediate docetaxel (5.7������������������������� ������������������������ months) was significantly longer (P = .0001) than for delayed docetaxel (2.7 months). Additionally, the investigators found a trend toward improved overall survival for immediate docetaxel (12.3 months) compared to delayed docetaxel (9.7 months) that did not quite reach statistical significance (P = .0853).

Another study compared pemetrexed to placebo in the “switch maintenance” setting.4 Here the investigators observed an improvement in both overall survival (13.4 vs 10.6 months; HR = 0.79; 95% CI = 0.65–0.95; P = .012) and progression-free survival (4.3 months [95% CI = 4.1–4.7] vs 2.6 months [1.7–2.8]; HR = 0.50; 95% < .0001). In addiCI = 0.42–0.61; P ������������������ tion, a study evaluating maintenance erlotinib vs placebo in patients with stable or responding disease after four cycles of platinum-based chemotherapy observed a significant improvement in overall survival (median = 12.0 vs 11.0 months; HR = 0.81; 95% CI = 0.70–0.95; P = .0088.)5

Underlying Mechanism Why might “more” chemotherapy prove effective in this setting? Is it the result of introducing a non–cross-resistant therapy? Or is it simply because many patients randomly assigned to receive delayed treatment on progression never actually received it? For example, in the

Maintenance Is Not for Everybody continued from page 54

rent standard practice is to initiate bevacizumab therapy with platinum-based chemotherapy, and then in the absence of disease progression, continue singleagent bevacizumab. Phase III data of maintenance therapy with bevacizumab and pemetrexed is not available, and a phase III trial of bevacizumab and erlotinib compared to bevacizumab and placebo did not reveal a statistically significant improvement in overall survival.4 Patients with epidermal growth factor receptor (EGFR) mutation experienced the greatest improvement in progression-free survival with maintenance erlotinib.

Increasingly, however, patients with an EGFR mutation are receiving

Fidias trial, although 145 (95%) of 153 patients randomly assigned to immediate docetaxel received at least one cycle of chemotherapy, only 98 (63%) of the 156 patients randomly assigned to the delayed arm actually went on to receive docetaxel at progression. Among the 58 patients who did not receive delayed docetaxel, 30 discontinued treatment because of disease progression or death.

improved both progression-free survival (HR = 0.75; 95% CI = 0.69–0.81; P < .00001) and overall survival (HR = 0.92; 95% CI = 0.86–0.99; P = .03).6

make cancer a chronic disease. “Switch maintenance” chemotherapy with more tolerable drugs for NSCLC may be a small step toward getting us there.

Toxicity Considerations

References 1. Chemotherapy in non-small cell lung cancer: A meta-analysis using updated data on individual patients from 52 randomised clinical trials. Non-small Cell Lung Cancer Collaborative Group. BMJ 311:899-909, 1995.

2. Spiro SG, Rudd RM, Souhami RL, et al: Chemotherapy versus supportive care in advanced non-small cell lung cancer: Improved survival without detriment to quality of life.

Thorax 59:828-836, 2004.

3. Fidias PM, Dakhil SR, Lyss AP, et al: Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 27:591-598, 2009.

4. Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 374:1432-1440, 2009.

5. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung cancer: A multicentre, randomised, placebo-controlled phase 3 study. Lancet Oncol 11:521-529, 2010.

6. Soon YY, Stockler MR, Askie LM, et al: Duration of chemotherapy for advanced non-small-cell lung cancer: A systematic review and meta-analysis of randomized trials. J Clin Oncol 27:3277-3283, 2009.

Toxicities of chemotherapy are always of concern, particularly when given to patients who have a disease with a dismal prognosis. However, five of the

With the advent of more tolerable drugs, patients with lung cancer may now have the opportunity to receive ‘more’ of an effective therapy.

Overall survival for the 98 patients in the delayed treatment arm who actually received docetaxel was 12.5 months— identical to the 12.5 months survival of the 145 patients in the immediate treatment arm. This discrepancy suggests that the trend toward improved survival in the immediate treatment arm was the result of more patients being able to receive an active drug. Thus, early treatment may be better, not because it does a better job of killing cancer cells in the first-line setting, but because it can be given before other complications of the disease render patients unable to receive it.

Regardless of the underlying mechanism, the most important thing is that it “works” (ie, improves survival).

Without a clear-cut survival advantage, it is hard to justify the added expense or toxicity. However, a recent metaanalysis of 13 randomized controlled trials involving over 3,000 patients found that extending chemotherapy

seven trials included in the meta-analysis noted no major differences in quality of life between the treatment and the control groups. Thus, although extended chemotherapy may not have improved quality of life, it did not appear to have a negative impact on it either. Nonetheless, additional studies are needed to determine which patients are more likely to benefit from the additional treatment.

Many oncologists have long argued that the goal of cancer treatment is to make cancer a “chronic disease,” and chronic diseases often require chronic therapy. For example, chronic hormonal therapy is standard of care for breast and prostate cancer. With the advent of more tolerable drugs, patients with lung cancer may now have the opportunity to receive “more” of an effective therapy. Although we hope that the advent of targeted therapies will result in more effective and less toxic drugs, we should continue to use any weapon in our armamentarium to

erlotinib as first-line therapy. Thus, there are significant segments of the NSCLC patient population who receive treatments where the maintenance therapy paradigms do not apply, or where we lack phase III data demonstrating benefit.

patients, treatment-free intervals remain an option. However, patients who elect to have a treatment-free interval should be counseled about the signs and symptoms of disease progression, monitored closely, and informed about the inherent risk of experiencing disease progression and not being a candidate for further therapy.

Palliative Goals, Modest Survival The difficulty with maintenance therapy is that it requires a patient for whom the goals of therapy are palliative and overall survival remains modest to undergo continuous treatment.

My personal practice is to consider maintenance therapy in patients who have not experienced significant toxicity related to first-line therapy, maintain a good performance status, and desire to continue therapy. For other

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References 1. Ciuleanu T, Brodowicz T, Zielinski C, et al: Maintenance pemetrexed plus best supportive care versus placebo plus best supportive care for non-small-cell lung cancer: A randomised, double-blind, phase 3 study. Lancet 374:1432-1440, 2009.

2. Cappuzzo F, Ciuleanu T, Stelmakh L, et al: Erlotinib as maintenance treatment in advanced non-small-cell lung can-

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Dr. Schiller is Professor and Chief of the Division of Hematology/Oncology and Deputy Director of the Simmons Comprehensive Cancer Center at the University of Texas Southwestern Medical Center, Dallas.

cer: A multicentre, randomised, placebocontrolled phase 3 study. Lancet Oncol 11:521-529, 2010.

3. Fidias PM, Dakhil SR, Lyss AP, et al: Phase III study of immediate compared with delayed docetaxel after front-line therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer. J Clin Oncol 27:591-598, 2009.

4. Kabbinavar FF, Miller VA, Johnson BE, et al: Overall survival (OS) in ATLAS, a phase IIIb trial comparing bevacizumab (B) therapy with or without erlotinib (E) after completion of chemotherapy (chemo) with B for first-line treatment of locally advanced, recurrent, or metastatic non-small cell lung cancer (NSCLC). J Clin Oncol 28(15S):Abstract 7526, 2010.

Dr. Stinchcombe is Associate Professor at the UNC Lineberger Comprehensive Cancer Center, Chapel Hill, North Carolina.

Antibody-drug conjugates (ADCs):

Can an ADC be greater than the sum of its parts?

Antibody-drug conjugates (ADCs) ADCs are a unique combination of a precise and targeted monoclonal antibody, a stable linker, and a potent cytotoxic and are designed to selectively kill cancer cells while minimizing effects on normal tissue.1-4

Monoclonal antibody

Stable linker

Cytotoxic

targets antigens that are preferentially or exclusively expressed on the surface of cancer cells and may retain anticancer activities1,3,5-7

conjugates cytotoxic to monoclonal antibody and is designed to allow ADC to remain inactive while in circulation1,2,7,8

incorporated into an ADC can be up to 1000-fold more potent than currently used chemotherapies2,5,7

These investigational ADCs have multiple proposed mechanisms of action, including monoclonal antibodyâ&#x20AC;&#x201C;mediated anticancer activities and targeted intracellular delivery of a potent cytotoxic.5-7 Preclinical studies show that these anticancer activities may include prevention of signaling, antibody-dependent cellular cytotoxicity, and induction of apoptosis.3,5,6

To learn more, visit the new ADC resource at www.ResearchADCs.com References: 1. Jaracz S, Chen J, Kuznetsova LV, Ojima I. Recent advances in tumor-targeting anticancer drug conjugates. Bioorg Med Chem. 2005;13:5043-5054. 2. Wu AM, Senter PD. Arming antibodies: prospects and challenges for immunoconjugates. Nat Biotechnol.

2005;23:1137-1146. 3. Ricart AD, Tolcher AW. Technology insight: cytotoxic drug immunoconjugates for cancer therapy. Nat Clin Pract Oncol. 2007;4:245-255. 4. Junutula JR, Raab H, Clark S, et al. Site-specific conjugation of a cytotoxic drug to an antibody improves the therapeutic index. Nat Biotechnol. 2008;26:925-932. 5. Carter PJ, Senter PD. Antibody-drug conjugates for cancer therapy. Cancer J. 2008;14:154-169. 6. Oflazoglu E, Stone IJ, Gordon K, et al. Potent anticarcinoma activity of the humanized anti-CD70 antibody h1F6 conjugated to the tubulin inhibitor auristatin via an uncleavable linker. Clin Cancer Res. 2008;14:6171-6180. 7. Chari RVJ. Targeted cancer therapy: conferring specificity to cytotoxic drugs. Acc Chem Res. 2008;41:98-107. 8. Sanderson RJ, Hering MA, James SF, et al.

In vivo drug-linker stability of an anti-CD30 dipeptide-linked auristatin immunoconjugate. Clin Cancer Res. 2005;11:843-852.

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