TAP Vol 1 Issue 3

Adjuvant chemotherapy for NSCLC 32

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Ipilimumab for melanoma 35

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VOLUME 1, ISSUE 3

Anthracycline cardiotoxicity 41

AUGUST 2010 ASCOPost.com

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

Cover Feature

Physician as Patient: A Personal Perspective

PRIMA Study: Rituximab Maintenance in Responders to Chemoimmunotherapy Cuts Recurrence in Follicular Lymphoma

By Richard J. Boxer, MD

By Alice Goodman

R

ituximab (Rituxan) maintenance therapy reduced the risk of recurrence by 50% in patients with follicular lymphoma (FL) who responded to induction therapy with rituximab plus chemotherapy, according to an interim analysis of the Primary Rituximab and Maintenance (PRIMA) phase III study, which compared rituximab maintenance therapy vs observation alone. Maintenance therapy was well tolerated, with little toxicity.

New Standard of Care “Rituximab maintenance after induction with rituximab plus chemotherapy significantly improved outcomes for FL patients. This study provides evidence for a new standard of care for patients with FL who need treatment,” stated Gilles Salles, MD, who is Professor of Medicine at the University of Lyon

Use your smartphone to view the PRIMA study abstract presented at ASCO’s Annual Meeting.

See page 42 for more information about using 2D barcodes

in Lyon, France. These results were presented at the 2010 ASCO Annual Meeting.1 FL is the second most common type of lymphoma, and it is usually incurable despite treatment with rituximab plus chemotherapy (chemoimmunotherapy), Dr. Salles explained. FL is typically characterized by recurrence, and the length of remission is shorter with each recurrence. The PRIMA trial was initiated because previous studies suggested that rituximab continued on page 13

Pancreatic Cancer

Combination Therapy Improves Outcomes in Metastatic Pancreatic Adenocarcinoma

A

fter both giving and receiving care, the true meaning of health becomes evident. Besides the sacred oath that physicians take upon entering the medical profession, Hippocrates also wrote, “A wise man should consider that health is the greatest of human blessings, and learn how by his own thought to derive benefit from his illness.”1 We all face the reality of life and death, but few extend the understanding to both themselves and their patients. When I was in the throes of my life-threatening illness, a physician told me that my experiences were meaningless to others because unless it is personal, that knowledge will not change one’s insight. I hope that is not true for all.

For 30 years I have been caring for patients with every type of genitourinary disease, but particularly malignancies. In September 1995, I discovered a malignant melanoma on my right knee. It was quickly removed, then widely excised. That was just the beginning. continued on page 28

By Kathleen Louden

A

multiagent chemotherapy regimen should become the new standard front-line treatment of metastatic pancreatic adenocarcinoma, according to authors of a phase III trial presented at this year’s ASCO Annual Meeting.1 Compared with single-agent gemcitabine (Gemzar), the new treatment, FOLFIRINOX (fluorouracil [5-FU], leucovorin, irinotecan, and oxaliplatin),

FOLFIRINOX for Metastatic Pancreatic Cancer ■■ A combination of fluorouracil, leucovorin,

irinotecan, and oxaliplatin greatly improves survival in patients with metastatic pancreatic adenocarcinoma.

■■ This combination regimen is an option for

patients with metastatic disease and good performance status who have a normal or near-normal bilirubin level.

produced significantly better outcomes in chemotherapy-naive patients, including an 11.1-month median overall survival (OS), said lead researcher Thierry Conroy, MD, of Centre Alexis Vautrin in Vandoeuvre-les-Nancy, France.

MORE IN THIS ISSUE 2010 ASCO Annual Meeting Coverage Prostate cancer �������������������������������3, 11 Breast cancer ������������������������������������������ 5 Hematology ������������������������������������1, 13 Lung cancer ����������������������������������������� 14 Thierry Conroy, MD

Longest Survival “This is the first time that a phase III trial has shown an 11-month median survival for patients with metastatic pancreatic cancer,” Dr. Conroy said.

Patients who received only gemcitabine—the current standard of care—had a median OS of just 6.8 months, which Dr. Conroy said is similar to that reported in prior studies. OS was the primary endpoint for this multicenter study, known as the Prodige 4/ACCORD 11 trial. He presented the

Gastrointestinal cancer ���� 1, 12, 24, 25 A conversation with Dr. Owen O’Connor ������������������������������������ 4 Direct from ASCO ����������������������������19–23 JCO Spotlight: NSCLC ���������������������������� 32

continued on page 12

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ASCOPost.com | AUGUST 2010

PAGE 3

News Prostate Cancer

Combined Modality Therapy Extends Survival in Patients with High-risk Prostate Cancer

By Alice Goodman

T

he addition of radiation therapy to hormone therapy extends survival of men with locally advanced high-risk prostate cancer vs hormone therapy alone, according to a phase III trial reported at the 2010 ASCO Annual Meeting.1 These findings are especially important, because many urologists and oncologists question the use of radiotherapy in this setting, said the lead investigator.

“This study challenges oncologists’ perceptions about radiation therapy [in high-risk prostate cancer],” stated Padraig Warde, MBChB, who is Deputy Head of the See page 42 Radiation Medicine Program at the University of Toronto’s Princess Margaret Hospital. “These data confirm that radiation therapy should be considered as part of the package for men with high-risk prostate cancer.”

“This study firmly cements radiation therapy as an indispensable part of the treatment of men with locally advanced, high-risk prostate cancer,” agreed Jennifer C. Obel, MD, who moderated an official press conference at the meeting. Dr. Obel is a medical oncologist at the NorthShore University HealthSystem and Assistant Clinical Professor of Medicine, University of Chicago.

Study Data The study population included 1,205 patients with bulky local and/or high prostate-specific antigen and/or high Gleason score. “Such patients represent 15% to 25% of all cases of prostate cancer,” Dr. Warde told listeners.

Patients were randomized to continuous hormone therapy (androgen deprivation) alone or hormone therapy plus radiation to the prostate and surrounding lymph nodes. Radiation was given as 45 Gy to the pelvis (25 fractions over 5 weeks) with an additional 20 to 24 Gy to the prostate (10 to 12 fractions over 2 to 2.5 weeks).

In 1999 the protocol was amended to allow treatment to the prostate alone if the treating physician felt whole pelvic radiation was inappropriate for the patient.

Baseline demographic and disease characteristics were similar between arms 1 and 2. Mean age was about 70 years, and 81% of patients had a Gleason score of 7 or less, whereas 18% had a Gleason score of 8 to 10.

After 7 years, overall survival was 74% for men treated with both hormone therapy and radiation vs 66% for men treated with hormone therapy alone (P = .0331), representing a 23% reduction in risk of death with the addition of radiation. Seven-year diseasespecific survival was 90% vs 79% for the two arms, respectively (P = .001), representing a 43% reduction in the likelihood of dying from prostate cancer when radiation was added to hormone therapy.

Late severe toxicities were rare and occurred in 2.3% of each arm.

Optimal Regimen “Even though this trial was designed in 1993, we believe it is relevant today,” Dr. Warde noted.

He added that although combinedmodality therapy should be considered the standard of care in this setting, the optimal duration of hormone therapy

Intergroup Phase III Study ■■ A total of 1,205 patients with locally advanced high-risk prostate cancer were randomly assigned to continuous hormone therapy alone or hormone therapy plus radiation.

■■ After 7 years overall survival was 74% for men treated with combined-

modality therapy vs 66% for men treated with hormone therapy alone (P = .0331); 7-year disease-specific survival was 90% vs 79% for the two arms, respectively (P = .001).

■■ Combined-modality therapy should be considered the standard of care in locally advanced high-risk prostate cancer.

Expert Point of View

A

nthony V. D’Amico, MD, Professor of Radiation Oncology at Harvard Medical School, Boston, was formal discussant of the Intergroup trial. He said that the current trial, as well as a second study presented at the same session,1 showed that radiation added to hormone therapy improved important outcomes in men with clinically advanced prostate cancer. Interestingly, he pointed out that the improvement in survival is greater when hormonal Anthony V. D’Amico, MD therapy is added to radiation therapy than when radiation therapy is added to hormonal therapy.

Taking current studies into consideration, he said that management of locally advanced prostate cancer should be based on the patient’s life expectancy and competing risks, or comorbidities. Men with a life expectancy of more than 5 years may be candidates for combined hormone therapy and radiation, whereas older men with shorter life expectancies may be more appropriate for hormone therapy alone. In the latter group, however, hormonal therapy could lead to early death in men with cardiovascular disease, including congestive heart failure or myocardial infarction.

■

Reference 1. Mottet N, Peneau M, Maseron J, et al: Impact of radiotherapy combined with androgen deprivation versus ADT alone for local control in clinically advanced prostate cancer. 2010 ASCO Annual Meeting. Abstract 4505. Presented June 6, 2010.

needs to be defined. “It may not be necessary to use lifelong androgendeprivation therapy, as was used in this trial,” he said.

In addition, he commented that radiation dose and techniques have changed considerably over the years, and modern radiation may be even more beneficial.

■

Reference 1. Warde PR, Mason MD, Sydes MR, et al: Intergroup randomized phase III study of androgen deprivation therapy + radiation therapy in locally advanced prostate cancer (NCIC-CTG, SWOG, MRCUK, Int: T94-0110;NCT000026333).

2010 ASCO Annual Meeting. Abstract CRA4504. Presented June 6, 2010.

Inside The ASCO Post – Don't miss these important perspectives: Page 1 Dr. Richard Boxer has been treating patients with genitourinary cancers for over 30 years; a survivor of non-Hodgkin lymphoma, he reflects on how being a patient gave him special insight into his work as a physician.

Page 28 “Doctor, how long do I have left to live?”

Dr. Stanley Winokur offers his thoughts on answering difficult questions your patients may ask.

Plus: Page 4 Dr. Owen O’Connor discusses the progress made in the management of hematologic malignancies, fundamentally a result of the rapidly increasing understanding of the biology of diseases like lymphoma, multiple myeloma, and the acute myeloid leukemias.

Page 19 Direct from ASCO— Applications open for career development award; West Virginia oncologists plan statewide clinical trial network; ASCO revised edition of Self-Evaluation Program available.

Page 35 With treatment options for advanced melanoma so limited and the results of the ipilimumab studies so promising, patients may be asking how they can participate in the Compassionate Use Trial for Unresectable Melanoma with Ipilimumab. Dr. Stephen O’Day discusses the impact of recent news about ipilimumab on patients with melanoma.

The ASCO Post | AUGUST 2010

PAGE 4

Expert’s Corner

A Conversation with Owen O’Connor, MD, PhD The Next Advances in Blood Cancers

By Jo Cavallo in New York City, about the advances being made in blood cancers and what clinicians and patients can expect in the future—not just in terms of more effective treatments but in the potential for cures for these cancers as well.

Advances in Hematology

Owen O’Connor, MD, PhD

T

he past decade has seen a surge in the development of novel therapies to treat hematologic malignancies, including some of the most aggressive types of lymphoma, such as mantle cell lymphoma and T-cell lymphoma, as well as other incurable blood cancers like multiple myeloma and myelodysplastic syndromes. In some cases, terminal disorders have been transformed to manageable chronic illnesses. And the pace over the next 10 years of developing better targeted, more effective therapies tailored to each patient’s cancer promises to be even faster as scientists gain a better understanding of the molecular pathogenesis of these diseases.

The ASCO Post talked with Owen O’Connor, MD, PhD, Deputy Director of Clinical Research and Cancer Treatment and Director of the Division of Hematology and Medical Oncology at the NYU Cancer Institute and NYU Langone Medical Center

Talk about the advances being made in the understanding of the biology of lymphoma, multiple myeloma, and leukemia and how that understanding is resulting in more effective treatments and even cures for these cancers.

Dr. O’Connor: We’ve seen enormous progress across the board in most hematologic malignancies. All of that progress is fundamentally related to our rapidly increasing understanding of cancer biology and especially the biology of diseases like lymphoma and multiple myeloma, as well as the acute myeloid leukemias.

For example, we historically classified the lymphomas largely based on morphologic principles. What we historically characterized as only a half-dozen diseases in the case of nonHodgkin lymphoma, for example, we now characterize as over 60 different diseases. The majority of that increase can be attributed to our more sophisticated understanding of the differentiation and ontogeny of B and T cells and new techniques in immunohistochemistry. While molecular phenotyping is yet to really contribute to the identification of new subtypes, it’s becoming clear that molecular phenotyping using gene expression array and polymerase chain reaction is beginning to splinter

heterogeneous diseases like diffuse large B-cell lymphoma (DLBCL), for example. What we thought was one disease we now recognize as a multiplicity of different diseases that are associated with distinctly different prognostic features and vastly different outcomes.

Ultimately, the goal in developing this knowledge is to begin to tailor therapies to very distinct molecular phenotypes of disease in the hope that we can determine which patients are most likely to respond to specific therapies, so that they derive maximum benefit with the least toxicity.

Developments in Mantle Cell Lymphoma What has changed in the treatment of mantle cell lymphoma?

Dr. O’Connor: We’ve also seen enormous progress over the past 10 years in

survival with standard upfront CHOPbased chemotherapy [cyclophosphamide, doxorubicin, vincristine, and prednisone] was only about 18 months. Over the years, many studies have explored different chemotherapy regimens, including hyperCVAD [hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone, and other agents], followed by autologous stem cell transplant, hyperCVAD-R [hyperCVAD plus rituximab], and maxi-CHOP [dose-intensified CHOP] followed by autologous stem cell transplant.

With the more widespread use of these aggressive approaches in first remission, we are beginning to observe some of the best data we’ve ever seen for patients with MCL. Most of these studies are demonstrating that at 5 years, the overwhelming majority of these patient are alive with

Ultimately, the goal in developing this knowledge is to begin to tailor therapies to very distinct molecular phenotypes of disease in the hope that we can determine which patients are most likely to respond to specific therapies, so that they derive maximum benefit with the least toxicity. the treatment of mantle cell lymphoma (MCL). Historically, we quoted survival estimates of only about 3 years for patients with MCL. Prior to the availability of rituximab (Rituxan), progression-free

a meaningful quality of life. Even within the past year, there has been some suggestion that there may be a plateau on the overall survival curves, continued on page 15

The ASCO Post (ISSN 2154-3283) is published 12 times annually by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodical Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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Editorial Mission: The ASCO Post communicates timely information to a broad audience of oncology specialists, helping to advance the highest quality multidisciplinary cancer care. The ASCO Post publishes highly validated coverage of cancer research and policy news, patient care and clinical practice issues, and thoughtful commentary from leaders in the field and others with an interest in clinical oncology.

Circulation: The ASCO Post is sent free of charge to approximately 26,000 physicians and nurses, including all US-based ASCO members. Medical, surgical, pediatric, and gynecologic oncologists, hematologists, and hematologist/oncologists in the United States who are not members of ASCO will be eligible for a complimentary subscription. ASCO members outside of the United States receive complimentary access to The ASCO Post online at www.ASCOPost.com. Paid subscriptions to The ASCO Post are available for all other interested individuals. Domestic: $75 for the print or online edition; $125 for both editions. International: $125 for print or online edition; $175 for both editions. Contact subscriptions@harborsidepress.com.

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Disclaimer: The ideas and opinions expressed in The ASCO Post™ do not necessarily reflect those of Harborside Press, LLC, HSP News Service, LLC, or the American Society of Clinical Oncology, Inc. (ASCO®). The mention of any product, service, or therapy in this publication should not be construed as an endorsement of the products mentioned. It is the responsibility of the treating physician or other health-care provider, relying on independent experience and knowledge of the patient, to determine the appropriate treatment for the patient. Readers are advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each product or therapy to be administered to verify the dosage, method, and duration of administration, or contraindications. Readers are also encouraged to contact the manufacturer with questions about the features or limitations of any products. Harborside Press, HSP News Service, LLC, and ASCO® assume no responsibility for any injury or damage to persons or property arising out of or related to any use of material contained in this publication or to any errors or omissions.

ASCOPost.com | AUGUST 2010

PAGE 5

News Breast Cancer

High Discordance between Primary Breast Cancer and Recurrence Observed in Three Large Trials

Editorial Board

By Caroline Helwick

James O. Armitage, MD Editor-in-Chief

Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center

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

Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology

Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center

Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia

Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha

Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami

David Khayat, MD Salpetriere Hospital, Paris

Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Harold J. Burstein, MD Dana-Farber Cancer Institute

James L. Mulshine, MD Rush University Medical Center

Robert W. Carlson, MD Stanford University Medical Center

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic

Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center

Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center

Eduardo Cazap, MD, PhD Buenos Aires, Argentina 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

Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida

Harborside Press Publishing Staff

Conor Lynch Executive Editor Conor@harborsidepress.com

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Contributing Writers Charlotte Bath, Barbara Boughton, Jo Cavallo, Alice Goodman, Caroline Helwick, Kathleen Louden

Contributing Artists Portraits by Keith Witmer, Keith Witmer Illustrations Financial disclosure information available at ASCOPost.com.

D

iscordance in tumor characteristics between a primary breast cancer and sites of recurrence are common and point to the need to rebiopsy, three investigative groups reported at the 2010 ASCO Annual Meeting.

“Tumor characteristics and treatment options for recurrent breast cancer are assumed to be the same,” said Eitan Amir, MD, of Princess Margaret Hospital, Toronto, but his pooled analysis of two large prospective studies suggested that over one-third of tumors may be discordant with regard to hormone receptor status.1 Similar discordance rates were found in a large retrospective study from Sweden,2 as well as in a study of liver biopsies.3

Canadian Analysis “Discordance is important because it may be associated with poorer survival. We wanted to know if discordance is ‘real’ and whether it is important, irrespective of its underlying etiology,” said Dr. Amir, whose study represented the largest prospective analysis of receptor status in matched primary and recurrent breast cancer, he said.

Discordance was defined as a change in receptor status from positive to negative, or vice versa, and not a quantitative change in receptor expression.

The Canadian and British investigators analyzed tumors from 271 patients with recurrences diagnosed a median of 6.5 years after initial diagnosis. They found that 38.8% of receptors were discordant from the primary tumor, including 34.1% discordant for the progesterone receptor (PgR), 12.6% for the estrogen receptor (ER), and 5.4% for HER2 status. This resulted in a change of systemic treatment for 15.1% of patients, or one change for every 6.6 biopsies, Dr. Amir noted.

The most common reasons for discordance were change in HER2 status, gain of hormone receptor, or identification of benign disease or second malignancy.

“We found substantial discordance in receptors that were most common in hormone receptors, less common

in HER2 status, and least common (6.8%) in triple-negative tumors,” he said. The duration between primary and recurrence biopsies did not influence receptor discordance.

Eitan Amir, MD

Similar Findings from Karolinska Institute Eva Karlsson, MD, and colleagues from the Karolinska Institute in Stockholm retrospectively analyzed 1,095 breast cancer specimens and found that 27% changed from ER-positive to ERnegative and 8% changed from negative to positive. PgR status changed in 38% from positive to negative and in 5% from negative to positive.

Overall breast cancer survival was significantly associated with receptor status at relapse (P < .001). “Survival was worse for those with ER-negative relapsed tumors, compared to ERpositive, independent of the primary hormonal status,” she reported. Patients with a primary ER-positive tumor that turned See page 42 negative had nearly a 1.5-fold increased risk of local or systemic relapse and 2-fold risk of systemic relapse, compared to patients with stable ER. “Our study showed that in nearly every third patient with breast cancer, the hormone receptor status changed during tumor progression. This impacts survival, and means that treatment of metastatic disease is not optimum when based on primary tumor characteristics,” she commented. Dr. Karlsson added that, based on her own experience, a biopsy of “recurrence” sometimes reveals benign lesions or new primaries, which would require different treatment. continued on page 7

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T H E 5 - Y E A R S U R V I VA L R AT E I S 17 % F O R PAT I E N T S W I T H M E TA S TAT I C S O F T T I S S U E S A R C O M A , YET SIGNIFICANT THERAPEUTIC A D VA N C E M E N T S A R E L A G G I N G .1

NEW TREATMENTS ARE URGENTLY NEEDED.

Reference: 1. National Cancer Institute. Surveillance Epidemiology and End Results. seer.cancer.gov/statfacts/html/soft.html. Accessed March 19, 2010.

Copyright © 2010 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. 21003100(5)-ARI

ASCOPost.com | AUGUST 2010

PAGE 7

News

High Discordance Observed in Three Large Trials continued from page 5

Italian Study Focused on Liver Metastases European researchers described their retrospective study of 255 patients with primary tumor and liver metastases tissue samples. Changes in ER status were observed in 41 patients (16.0%), reported Marzia Adelia Locatelli, MD, of the European Institute of Oncology in Milan.

More patients changed from ERnegative to ER-positive (25.9%) than from positive to negative (11.2%).

Similar to the other two studies, even more—48.6%—changed PgR status, primarily from positive to negative (64.6%). HER2 was discordant in 13.9% overall, including 31.5% who changed from HER2-positive to HER2-negative and 5.9% from negative to positive.

The discordance between primary tumors and liver metastases led to a change in treatment for 12.1% of patients, Dr. Locatelli reported.

“There is emerging evidence that

tumor receptor status may change dynamically during the natural history of the disease,” she suggested. “When it is safe and easy to perform, a biopsy of the metastatic lesion should be considered in all patients, particularly when there is a long interval from the first diagnosis, since this is likely to impact treatment choice.”

■

References 1. Amir E, Clemons M, Freedman OC, et al: Tissue confirmation of disease recurrence in patients with breast cancer: Pooled analysis of two large prospective studies. 2010 ASCO Annual Meeting.

Abstract 1007. Presented June 8, 2010.

2. Karlsson E, Lindström LS, Wilking U, et al: Discordance in hormone receptor status in breast cancer during tumor progression. 2010 ASCO Annual Meeting. Abstract 1009. Presented June 8, 2010.

3. Locatelli MA, Curigliano G, Fumagalli L, et al: Should liver metastases of breast cancer be biopsied to improve treatment choice? 2010 ASCO Annual Meeting. Abstract CRA1008. Presented June 8, 2010.

Breast Cancer Discordance: Primary vs Recurrence ■■ Discordance rates as high as 39% were found between receptor status in primary tumors and sites of recurrence, in three large trials.

■■ The most common change was for progesterone receptor status to

change from positive to negative, and the least common was for the HER2 receptor status to change from negative to positive.

■■ Overall survival was associated with receptor status upon recurrence.

■■ Rebiopsy of sites of recurrence is recommended.

Expert Point of View

A

ndrea Richardson, MD, PhD, Assistant Professor of Medicine at Brigham and Women’s Hospital and the Dana-Farber Cancer Institute, Boston, provided commentary for these three studies at the Oral Metastatic Breast Cancer Session during the 2010 ASCO Annual Meeting.

The studies added validity to previous observations of discordance (averaging 29%) that came mainly from much smaller retrospective reviews of pathology reports. In spite of consistent findings, she said, “the management of metastatic breast cancer has not changed and is usually still based on primary tumor characteristics.”

The trials presented at ASCO found significantly higher discordance for progesterone receptors (PgR) than for estrogen receptors (ER); a low rate of gain in HER2 negativity; and a fairly high rate of management change as a result of discordance.

It is unclear whether the discordance represents a change in tumor biology or other factors. Dr. Richardson does not attribute it to differences in assay methodology or undersampling of tumor (ie, small sample size of recurrence), but acknowledges that fixation differences could play a role.

“Core biopsies are usually put immediately into fixative, but breast excisions and mastectomies may have several-hour delays before fixation. Also, bone biopsies often require decalcification and this can reduce the expression of ER and PgR” and lead to false-negative results for hormone receptor expression in the primary tumor, she noted.

Indeed, studies have shown a marked drop-off in the ability to detect ER and PgR after a delay in time to fixation, she added. “Be aware of this when you think about the use of adjuvant therapy,” she advised oncologists.

In addition, some of the discordance may relate to the differences in cutoff values used by different laboratories. Biologic heterogeneity is also a strong possibility, according to genomic studies showing varying characteristics within different areas of the same tumor. “A core biopsy may hit one area and miss another,” she pointed out, “and you can fail to detect a subpopulation with a different receptor expression.” Finally, treatment may alter receptor expression, causing a loss of ER after endocrine therapy or loss of HER2 expression after anti-HER2 targeted treatment.

Ultimately, she told oncologists, “The reason for discordance may not be important. Therapy is determined by receptor status and we need to treat the tumor that is present now, not the one that was there years before. Based on these studies, 12% to 15% of patients will need a change in treatment.”

Inside this issue of The ASCO Post ■■ Comprehensive coverage of the 2010 ASCO Annual Meeting

see pages 1, 5, 7, 11-14, 24-26, 30, 41

■■ Dr. Owen O’Connor discusses advances in hematologic cancers

see page 4

■■ ODAC recommends FDA revoke approval of bevacizumab for metastatic

breast cancer see page 31

■■ JCO Spotlight: Adjuvant chemotherapy for NSCLC

see page 32

■■ Important appointments to CMS, AMA, NCI

see page 42

■

ASCOPost.com | AUGUST 2010

PAGE 11

News Prostate Cancer

Denosumab Superior to Zoledronic Acid in Delaying Time to Skeletal Events in Castrate-resistant Prostate Cancer

By Alice Goodman

D

enosumab significantly increased the time to sustaining a skeletalrelated event (SRE) compared to zoledronic acid in men with castration-resistant (hormone-refractory) prostate cancer, in one of the largest trials conducted in this setting.1 The study’s primary endpoint was to show noninferiority of denosumab vs zoledronic acid, and the secondary endpoint was to demonstrate superiority, explained Karim Fizazi, MD, PhD, Head of the Department of Medical Oncology at Institut Gustave Roussy, Villejuif, France. “The study met both endpoints. Denosumab was superior to zoledronic acid in preventing or delaying the first SRE and in preventing or delaying multiple skeletal events,” he stated.

The FDA approved denosumab in June for the treatment of postmenopausal women with osteoporosis at high risk of fracture, but this monoclonal antibody remains investigational in men receiving hormone-deprivation therapy for prostate cancer. (On July 16, the FDA granted priority review designation to denosumab for the treatment of bone metastasese to reduce SREs in patients with cancer.)

The drug has substantial affinity and specificity for RANK ligand and is designed to interrupt the cascade of molecular events leading to bone metastasis. Unlike the bisphosphonate zoledronic acid, denosumab has no requirement for monitoring renal toxicity or dose adjustment and is associated with little risk of acute-phase reactions.

Study Background The phase III trial randomly assigned 950 patients to subcutaneous denosumab at 120 mg and 951 patients to intravenous zoledronic acid at 4 mg. All patients received oral calcium

and vitamin D supplementation. The study period was 2006 to 2008. The mean age of patients was 71 years. All patients had bone metastases, and 93% had good performance status.

Patients in both arms were treated for about 1 year. More than 20% of patients on the zoledronic acid arm required dose adjustment for creatinine clearance at baseline and 15%, during the study. An additional 15% of those treated with the bisphosphonate required doses withheld for serum creatinine increases on study. This did not occur on the denosumab arm.

Denosumab was superior to zoledronic acid for time to first SRE. An SRE was sustained by 36% in the denosumab arm vs 41% in the zoledronic acid arm (P = .0002). Denosumab achieved an 18% risk reduction vs zoledronic acid for time to first and subsequent on-study SREs. The median time to experiencing an SRE with denosumab was 20.7 months, compared with 17.1 months for men treated with zoledronic acid, and this difference was statistically significant (P = .008).

Types of first on-study SRE in all patients included radiation to the bone (20%), fracture (14.7%), spinal cord compression (3.3%), and surgery to the bone (0.3%).

However, no difference was seen between the two treatment arms for prostate-specific antigen (PSA) time course, cancer progression, or overall survival.

Adverse Events Approximately 20% of all patients required radiation to the bone for SRE. About 14.7% experienced pathologic bone fractures, 3.3% had spinal cord compression, and 0.3% required bone surgery.

The rates of overall adverse events were similar between the two arms: About 97% in each arm experienced

Denosumab in Castrate-resistant Prostate Cancer ■■ Denosumab prevented or delayed the time to first and multiple

SREs compared with zoledronic acid in men with castration-resistant prostate cancer.

■■ Denosumab does not require renal monitoring or dose adjustment.

■■ Side effects of hypocalcemia and osteonecrosis of the jaw need to be investigated further.

■■ Potential effect of denosumab in preventing the onset of bone metastases is under study.

adverse events, mainly caused by underlying cancer. These events included anemia, back pain, nausea, fatigue, and decreased appetite. The rates of infection were also similar. Acute-phase reactions (during the first 3 days of treatment) occurred in 8.4% of the denosumab group vs 17.8% of the zoledronic acid group. Hypocalcemia occurred in 12.8% and 5.8%, respectively.

Osteonecrosis of the jaw, a side effect of major concern with these drugs, occurred in 1.3% of the zoledronic acid group vs 2.3% in the denosumab group.

“The large majority of patients who experienced osteonecrosis of the jaw had risk factors. Less than 10% required bone resection,” Dr. Fizazi said.

Is Cost Justified?

Ian Tannock, MD, of Princess Margaret Hospital, Toronto, Canada, raised some important issues, commenting from the audience. “The study shows a difference in time to SRE [including radiation to the bone].

Denosumab costs a lot of money, yet there is no difference in overall survival, the endpoint we really care about. If fractures are not clinically evident, is a delay in time to SRE an important endpoint for improving these men’s lives?”

Similarly, formal discussant of the trial, Robert E. Coleman, MD, Profes-

Coming in the September 2010 issue of ■■ Reports from Best of ASCO ■■ A Conversation with Dr. Joseph Bailes on Medicare and Reimbursement ■■ Gene Profiling in Colorectal Cancer ■■ Important Columns, Features, and Clinical Departments

Be sure to visit The ASCO Post online at www.ASCOPost.com.

sor of Medical Oncology at the University of Sheffield, UK, noted, “This study showed an improvement from 17.1 to 20.7 months (or a risk reduction of 18%) in time to first SRE in patients not on the bisphosphonate, but disease-free survival and progression were unaffected.”

Issues that remain to be addressed with denosumab include benefits in specific subgroups, impact on quality of life, optimum duraSee page 42 tion of therapy, and whether denosumab can prevent or delay bone metastasis, he continued.

“The cluster of events including hypocalcemia and oral health with denosumab need further study,” Dr. Coleman added. “Denosumab could be considered for preventing bone loss, it should be considered for preventing skeletal morbidity, and we await data on whether it will prevent bone metastasis.”

The study was supported by Amgen.

■

Reference 1. Fizazi K, Carducci MA, Smith MR, et al: A randomized phase III trial of denosumab versus zoledronic acid in patients with bone metastases from castration-resistant prostate cancer. 2010 ASCO Annual Meeting. Abstract LBA4507. Presented June 6, 2010.

The ASCO Post | AUGUST 2010

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News

Metastatic Pancreatic Adenocarcinoma continued from page 1

final results in 342 adult patients during the Gastrointestinal (Noncolorectal) Cancer Oral Abstract Session of the Annual Meeting.

“We recommend FOLFIRINOX as the new international standard of care for patients with metastatic pancreatic cancer,” Dr. Conroy said.

He added that the regimen should be standard only for patients with a normal or near-normal bilirubin level and a high performance status (0–1) based on criteria from the Eastern Cooperative Oncology Group (ECOG), as was the case for their patients.

cluded “very concerning” toxicity.

“Our enthusiasm over the benefit of this regimen must by tempered by its attendant side effects,” she said.

Dr. Conroy, however, said the regimen’s toxicity was manageable.

FOLFIRINOX caused significantly higher rates of grade 3/4 neutropenia (45.7% vs 18.7% for gemcitabine), grade 3/4 febrile neutropenia (5.4 % vs

or FOLFIRINOX every 2 weeks. The experimental regimen consisted of 85 mg/ m2 of oxaliplatin and 400 mg/m2 of leucovorin over the first 2 hours, 180 mg/ m2 of irinotecan in a 90-minute infusion, followed by a bolus of 5-FU (400 mg/ m2) on day 1, and a continuous, 46hour infusion of 5-FU at a dosage of 2,400 mg/m2. Chemotherapy was recommended for 6 months.

This is groundbreaking work.

It provides more evidence that gemcitabine does not need to be the anchor drug.

– Margaret A. Tempero, MD

Good News The study results were good news for physicians, who, according to Dr. Conroy, have few good options to treat patients with this incurable disease.

The discussant, Margaret A. Tempero, MD, Professor of Medicine at the University of California, San Francisco, commented, “We have had very little good news in a long, long time.”

She added, “This is groundbreaking work. It provides more evidence that gemcitabine does not need to be the anchor drug.”

However, Dr. Tempero said she See page 42 is unsure whether FOLFIRINOX should become the new international standard of care for high-performance–status patients with this cancer, for reasons that in-

0.6%, respectively), and grade 3/4 thrombocytopenia (9.1% vs 2.4%), he reported.

The experimental arm also had significantly higher rates of the following grade 3/4 adverse events: peripheral neuropathy, vomiting, fatigue, and diarrhea.

Groups Well Balanced The investigators reported no major differences in patient characteristics between treatment arms (n = 171 in each), but the gemcitabine arm had slightly more lung metastases, according to Dr. Conroy.

In this intent-to-treat analysis, the investigators randomly assigned participants to receive either single-agent gemcitabine weekly (1,000 mg/m2 IV over 30 minutes, weekly with 1 week off after week 7, then weekly for 3 weeks every 28 days)

Only about 9% of gemcitabinetreated patients had a confirmed partial response rate, but more than 31% of patients receiving FOLFIRINOX did, Dr. Conroy said.

Median progression-free survival was reportedly 6.4 months in the FOLFIRINOX group and 3.3 months in the gemcitabine group. The difference was highly significant, as was the more than 4-month difference in median OS, the authors’ statistical analysis showed (both P < .0001).

At 1 year, 48.4% of patients in the FOLFIRINOX arm were still alive compared with 20.6% in the other arm, according to Dr. Conroy. Over a median follow-up of 26.6 months, 273 patients died.

Adjuvant Setting The investigators plan to study the FOLFIRINOX combination in an adjuvant setting, a move that Dr. Tempero welcomed.

“This needs to be advanced to the adjuvant setting, where we can accept a regimen with more toxicity,” she said.

Dr. Tempero called the study well stratified with a highly selected patient population. However, she pointed out that the patient population had an unusually low rate of primary tumors in the head of the pancreas— approximately one-third of patients, rather than the usual 50% to 60%. Because primary tumors in the body and tail of the pancreas rarely cause biliary obstruction, fewer patients than average may have had biliary stents in place, she noted.

“Most of my patients have biliary stents, and I would be very reluctant to put them on a regimen with this degree of neutropenia,” Dr. Tempero commented. She added that patients who receive FOLFIRINOX must have access to a capable biliary team and should receive good supportive care.

■

Reference 1. Conroy T, Desseigne F, Ychou M, et al: Randomized phase III trial comparing FOLFIRINOX (F: 5FU/leucovorin [LV], irinotecan [I], and oxaliplatin [O]) versus gemcitabine (G) as first-line treatment for metastatic pancreatic adenocarcinoma (MPA): Preplanned interim analysis results of the PRODIGE 4/ ACCORD 11 trial. 2010 ASCO Annual Meeting. Abstract 4010. Presented June 7, 2010.

ASCOPost.com | AUGUST 2010

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News

PRIMA Study continued from page 1

maintenance might benefit patients with relapsed or previously untreated FL. The study enrolled 1,217 patients with untreated FL and high tumor burden, primarily stage III or IV, who were age 18 or older and in need of immediate treatment. Patients were initially treated with rituximab plus CHOP (75%), CVP (22%), or FCM (3%).* Responders to initial therapy (n = 1,018) were randomized to observation alone or maintenance rituximab infusions every 2 months for 2 years.

“More patients had a complete response or unconfirmed complete response in the group treated with rituximab maintenance therapy,” Dr. Salles said.

Rituximab maintenance therapy was well tolerated. Grade 3 and 4 events were more frequent in the maintenance arm (23% vs 16%, respectively) and grade 2 infections were also more frequent (37% vs 22%, respectively). Quality of life was similar in both arms.

“Very few patients withdrew from the trial for toxicity-related reasons—10 in the rituximab arm and 1 in the observation arm,” Dr. Salles noted.

Survival Benefit?

This study, conducted by the Groupe d’Etude des Lymphomes de l’Adulte (GELA)-sponsored intergroup, suggests that lymphoma is a chronic disease that is likely to need chronic therapy, said Andrew Zelenetz, MD, PhD George W. Sledge, Jr, MD ASCO President George W. Sledge, Jr, MD. Study Results “It is not clear yet whether imAt a median follow-up of 25 months, proved progression-free survival in which was the first preplanned interim this trial will translate to improved analysis, the rate of progression-free overall survival, but this study is an survival (PFS) was 82% in the rituximportant step in this direction,” Dr. imab maintenance therapy arm vs 66% Sledge stated. of those in the observation arm, which Andrew Zelenetz, MD, PhD, was a highly significant difference commented, “This is an important (P < .0001). and potentially practice-changing “This means that the recurrence rate study. However, longer follow-up is was 18% with rituximab maintenance needed to determine if there is surand 34% with observation alone,” Dr. vival benefit, because there is risk Salles stated. for long-term toxicity.” Dr. Zelenetz A consistent benefit was observed is Chief of the Lymphoma Service for rituximab maintenance therapy at Memorial Sloan-Kettering Cancer for secondary endpoints. The risk of Center in New York. requiring a new round of lymphoHe pointed out that in a retrospecma treatment was reduced by 39% tive study, he and his colleagues found (P < .0003 vs observation). Benefits of that about 39% of patients treated rituximab maintenance therapy were with rituximab developed hypogamobserved across all subgroups, includmaglobulinemia and 10% of patients ing age, disease severity, and type of inrequired treatment with IV immune duction chemotherapy received. globulin for recurrent infections. During the maintenance period, no signifi*CHOP = cyclophosphamide, doxorucant differences in the median levels of bicin, vincristine, prednisone; CVP = cythree classes of immunoglobulin were clophosphamide, vincristine, prednisone; observed between patients on obserFCM = fludarabine, cyclophosphamide, vation and those receiving rituximab mitoxantrone. maintenance.

■

Expert Point of View

T

he prognosis for follicular lymphoma has improved greatly during the past decade, largely as a result of the availability of rituximab (Rituxan) in both untreated and relapsed situations. Several large randomized studies have shown statistically improved failure-free and even overall survival in untreated patients treated with rituximab added to various chemotherapy combinations.

The remaining controversy regarding rituxRichard I. Fisher, MD imab use is the question of where maintenance rituximab should be used. Improvement in progression-free survival (PFS) has been documented after initial therapy with single-agent rituximab alone or with CVP (cyclophosphamide, vincristine, and prednisone) and after R-chemotherapy combinations in patients with relapsed disease.

However, it has been unclear whether rituximab maintenance is indicated in previously untreated patients after initial therapy with R-chemotherapy. The PRIMA study presented at the 2010 ASCO Annual Meeting addresses this. Untreated patients with high-tumor-burden follicular lymphoma received R-CVP (rituximab plus CVP), R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone), or R-FCM (rituximab plus fludarabine, cyclophosphamide, and mitoxantrone). Each center selected the initial treatment that all patients at that center would receive. Responding patients were then randomly assigned to either maintenance rituximab, one dose every 8 weeks for 2 years, or observation.

Answering the Maintence Question The study enrolled 1,200 patients, and then randomized 900 patients to answer the maintenance question. At 2 years, PFS was 82% vs 66% (HR = 0.50, P < .0001). Furthermore, the benefit favored maintenance therapy in all subsets except the R-FCM arm, where the numbers were quite small.

The most impressive data were those following R-CHOP, since over 75% of the patients received this initial treatment. No major increase in severe toxicity was noted in the maintenance arm. Survival data are not available at this point of relatively early follow-up.

Thus, should maintenance rituximab be routinely used following R-chemotherapy in untreated follicular lymphoma? One could argue that overall survival benefit has not yet been demonstrated, that follow-up is only 2 years, that quality-of-life data have not yet been presented, etc. However, in the context of all the positive data for maintenance rituximab in all other situations, it appears reasonable to draw the following conclusion: Maintenance rituximab therapy is currently indicated following all treatment programs in rituximab-sensitive patients.

Richard I. Fisher, MD Director, James P. Wilmot Cancer Center Director, University of Rochester Medical Faculty Group Senior Associate Dean for Clinical Affairs, School of Medicine and Dentistry Vice President, University of Rochester Medical Center Rochester, New York

■

Reference 1. Salles GA, Seymour JF, Feugier P, et al: Rituximab maintenance for 2 years in patients with untreated high tumor burden

follicular lymphoma after response to immunochemotherapy. 2010 ASCO Annual Meeting. Abstract 8004. Presented June 5, 2010.

The ASCO Post | AUGUST 2010

PAGE 14

News Lung Cancer

Multiple Benefits Shown for Early Palliative Care in Metastatic NSCLC

By Caroline Helwick

P

alliative care initiated upon diagnosis helped patients with metastatic non–small cell lung cancer (NSCLC) not only have better quality of life (QOL) but also live longer, in a phase III randomized trial comparing early palliative care to standard cancer care. Jennifer S. Temel, MD, of Massachusetts General Hospital, Boston, presented the study at the 2010 ASCO Annual Meeting.1 “Compared with standard oncology care, integrated palliative care led to improvements in QOL, lower rates of depression, less aggressive care at the end of life, greater documentation of resuscitation preferences, and higher survival rates,” Dr. Temel reported.

Study Design In the study, 150 patients with newly diagnosed metastatic NSCLC were randomly assigned to early palliative

care integrated with standard oncology care, which included palliative care visits at least monthly, or to standard care, which included palliative care visits only when requested by the patient, family, or oncologist.

QOL was determined by measuring symptoms and functional/physical well-being according to the Functional Assessment of Cancer Therapy (FACT)-Lung questionnaire (Lung Cancer Symptom Index and Trial Outcome Index), and psychological distress according to the Hospital Anxiety and Depression Scale (HADS) and the Patient Health Questionnaire-9 (PHQ-9). Change in the FACT-Lung Trial Outcome Index was the primary endpoint.

At 12 weeks, 100% of the palliative care arm had received at least one palliative care visit, and 65% had four or more visits. In the standard care arm,

Early Palliative Care in NSCLC ■■ A total of 150 patients with newly diagnosed metastatic NSCLC were randomly assigned to early palliative care integrated with standard oncology care.

■■ Fewer patients randomized to palliative care received aggressive care (33.3% vs 53.6%; P = .05).

■■ Patients randomly assigned to early palliative care lived significantly

longer than those randomly assigned to standard oncology care (11.6 vs 8.0 months; P = .02).

■■ QOL was significantly better for patients in the palliative care arm, as judged by all measures.

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Initiation of palliative care at diagnosis improves quality of life, psychological wellbeing, end-of-life care, and even survival.

4% of patients had two visits, 9% had one visit, and no patient had more than two palliative care visits.

Key Results Fewer patients randomized to palliative care received aggressive care (33.3% vs 53.6%; P = .05). Nevertheless, they lived significantly longer (11.6 vs 8.0 months; P = .02), Dr. Temel reported.

Aggressive care was defined as no use of hospice, use of hospice for 3 days or less, or chemotherapy administered within 14 days of death.

Patients in the standard care arm averaged 4 days of hospice, compared to 11 days for the palliative care arm.

Patients in the palliative care arm were more likely to have documented their resuscitation preferences (53% vs 28%; P = .05).

QOL was significantly better for

patients in the palliative care arm, as judged by all measures. The mean FACT-Lung score was 98.0 for the palliative care arm vs 91.5 for the standard care arm (P = .03), the mean Lung Cancer Symptom score was 21.0 vs 19.3 (P = .04), and the mean Trial Outcome Index score was 59.0 vs 53.0 (P = .009). Patients receiving palliative care also had lower rates of depression on the HADS (15.8% vs 38.3%; P = .01) and the PHQ-9 (3.5% vs 17%; P = .02). While patients in the palliative care arm improved over baseline in virtually all QOL measures, those receiving standard care declined.

Raffit Hassan, MD, of the National Cancer Institute, noted that this is the first randomized study of early palliative care in patients with newly diagnosed advanced NSCLC. “It shows that palliative care and active cancer therapy can go hand in hand,” he said, “and that initiation of palliative care at diagnosis improves quality of life, psychological well-being, endof-life care, and even survival.”

■

Reference 1. Temel JS, Greer J, Gallagher E, et al: Effect of early palliative care (PC) on quality of life (QOL), aggressive care at the end-of-life (EOL), and survival in stage IV NSCLC patients: Results of a phase III randomized trial. 2010 ASCO Annual Meeting. Abstract 7509. Presented June 7, 2010.

ASCOPost.com | AUGUST 2010

PAGE 15

Expert’s Corner

The Next Advances in Blood Cancers continued from page 4

which has led some in the lymphoma community to suggest that we may be seeing the beginnings of a curative approach to MCL. If true, this would be a remarkable development.

To think that within a decade, the

simple relocation of autologous stem cell transplants from the relapsed or refractory setting to first remission, coupled with a cytarabine-containing induction regimen, could produce this sort of benefit is a testament to our ability to conduct quality clinical trials for rare diseases.

What is really exciting and increas-

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL (dasatinib) in clinical studies. The median duration of treatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar to those with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retention events such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such as diarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), and dyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions included pleural effusion (11%), gastrointestinal bleeding (7%), febrile neutropenia (6%), infection (5%), pyrexia (4%), pneumonia (3%), diarrhea (3%), nausea (2%), vomiting (2%), and colitis (2%).

Additional Data From Clinical Trials The following adverse reactions were reported in patients in the SPRYCEL clinical studies at a frequency of ≥10%, 1%–<10%, 0.1%–<1%, or <0.1%. These events are included on the basis of clinical relevance.

Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis.

General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance.

Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome.

Respiratory, Thoracic, and Mediastinal Disorders: ≥10% – cough; 1%–<10% – lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome.

Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack.

Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell.

Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular inflammation, muscular weakness, musculoskeletal stiffness; 0.1%–<1% – rhabdomyolysis; <0.1% – tendonitis.

Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased.

Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection, sepsis (including fatal outcomes).

Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances, hyperuricemia; <0.1% – hypoalbuminemia.

Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia), myocardial infarction; <0.1% – cor pulmonale, myocarditis, acute coronary syndrome.

Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis.

Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis.

Psychiatric Disorders: 1%–<10% – insomnia, depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased.

Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular.

Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion.

Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo.

Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis.

Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria.

Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome.

Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum).

DRUG INTERACTIONS Drugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mg SPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax and AUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 may increase exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, close monitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of a potent CYP3A4 inhibitor cannot be avoided [see Dosage and Administration (2.1) in Full Prescribing Information].

Drugs That May Decrease Dasatinib Plasma Concentrations CYP3A4 Inducers: When a single morning dose of SPRYCEL was administered following 8 days of continuous evening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinib were decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential should be considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered [see Dosage and Administration (2.1) in Full Prescribing Information].

Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL.

ingly clear in MCL is that the disease is even more complex and heterogeneous than DLBCL. Based on recent data using gene expression profiling and immunohistochemical staining, various groups have been able to demonstrate that you can risk-stratify patients with MCL based on the gene cellular proliferation signature. The subtypes of

H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL (dasatinib) therapy.

Drugs That May Have Their Plasma Concentration Altered By Dasatinib CYP3A4 Substrates: Single-dose data from a study of 54 healthy subjects indicate that the mean Cmax and AUC of simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin was administered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known to have a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl, pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should be administered with caution in patients receiving SPRYCEL. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category D SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and wellcontrolled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised of the potential hazard to the fetus and to avoid becoming pregnant. If SPRYCEL is used during pregnancy, or if the patient becomes pregnant while taking SPRYCEL, the patient should be apprised of the potential hazard to the fetus.

In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In both rats and rabbits, the lowest doses of dasatinib tested (rat: 2.5 mg/kg/day [15 mg/m2/day] and rabbit: 0.5 mg/kg/day [6 mg/m2/day]) resulted in embryo-fetal toxicities. These doses produced maternal AUCs of 105 ng•hr/mL (0.3-fold the human AUC in females at a dose of 70 mg twice daily) and 44 ng•hr/mL (0.1-fold the human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations at multiple sites (scapula, humerus, femur, radius, ribs, clavicle), reduced ossification (sternum; thoracic, lumbar, and sacral vertebrae; forepaw phalanges; pelvis; and hyoid body), edema, and microhepatia.

Nursing Mothers It is unknown whether SPRYCEL is 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 SPRYCEL, 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.

Pediatric Use The safety and efficacy of SPRYCEL in patients less than 18 years of age have not been established.

Geriatric Use Of the 2182 patients in clinical studies of SPRYCEL, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients.

While the safety profile of SPRYCEL in the geriatric population was similar to that in the younger population, patients aged 65 years and older are more likely to experience fluid retention events and dyspnea.

Hepatic Impairment The effect of hepatic impairment on the pharmacokinetics of dasatinib was evaluated in healthy volunteers with normal liver function and patients with moderate (Child-Pugh class B) and severe (Child-Pugh class C) hepatic impairment. Compared to the healthy volunteers with normal hepatic function, the dose normalized pharmacokinetic parameters were decreased in the patients with hepatic impairment.

No dosage adjustment is necessary in patients with hepatic impairment [see Clinical Pharmacology (12.3) in Full Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepatic impairment.

Renal Impairment There are currently no clinical studies with SPRYCEL in patients with impaired renal function. Less than 4% of dasatinib and its metabolites are excreted via the kidney.

OVERDOSAGE Experience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mg per day for 1 week was reported in two patients and both developed severe myelosuppression and bleeding.

Since SPRYCEL is associated with severe myelosuppression [see Warnings and Precautions and Adverse Reactions], patients who ingested more than the recommended dosage should be closely monitored for myelosuppression and appropriate supportive treatment given.

Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricular necrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. There was a tendency for increased systolic and diastolic blood pressure in monkeys at single doses ≥10 mg/kg (120 mg/m2).

SPRYCEL® is a registered trademark of Bristol-Myers Squibb Company. Other brands listed are the trademarks of their respective owners and are not trademarks of Bristol-Myers Squibb Company.

Manufactured by: Bristol-Myers Squibb Company Princeton, NJ 08543 USA

1237674A6

DS-B0001A-06-09

Rev June 2009

MCL with an enrichment of genes involved in cell-cycle dysregulation appear to be associated with the most unfavorable outcome, whereas patients with slower-growing types of MCL with fewer cell-cycle dysregulated genes have a more favorable outcome.

So what’s coming in MCL in the near future will be the risk stratification in patients with highly proliferative disease vs lesser proliferative disease, with differential treatment of these patients. One might presume that a reasonable treatment for patients with aggressive, highly proliferative MCL will be a combination of an induction chemotherapy regimen followed by autologous stem cell transplant. In contrast, a simple watch-and-wait approach or perhaps rituximab monotherapy may be reasonable for patients with less proliferative disease. It will be exciting to take these first steps toward the tailoring of treatment for patients with MCL and DLBCL.

Novel Therapeutic Options for Multiple Myeloma Will you be able to use risk stratification for patients with multiple myeloma?

Dr. O’Connor: In diseases like myeloma, we’re making very strong inroads into defining adverse biologic features of the disease and then using that information to redefine specific treatment regimens based on the biologic risk. In multiple myeloma, we’ve had no less than a culture shock with all the new drugs being used for treatment, including proteasome inhibitors, such as bortezomib (Velcade); immunomodulatory drugs (IMiDs), including thalidomide (Thalomid) and lenalidomide (Revlimid); the investigational agent pomalidomide, an IMiD derivative that’s even more potent than lenalidomide; and novel combinations of agents like histone deacetylase inhibitors and proteasome inhibitors. Myeloma is a great example of how we moved away from an emphasis on the nonspecific and cytotoxic chemotherapy approach and, in some cases, even transplant.

A number of studies have begun to clarify which subtypes of multiple myeloma are likely to respond to these agents. Many of these new drugs and combinations appear to override the adverse cytogenetic features of myeloma. In fact, combinations of these drugs—for example, lenalidomide, bortezomib, plus steroids—are changing the face of upfront therapy for mycontinued on page 16

The ASCO Post | AUGUST 2010

PAGE 16

Expert’s Corner

The Next Advances in Blood Cancers continued from page 15

eloma, relegating chemotherapy to the treatment of later-stage disease.

Perhaps what is most interesting in myeloma in terms of the evolution of standard practices is that over the past 10 years we’ve seen a slow, gradual transition away from a dependency on autologous stem cell transplants. The advent of all these new agents and their ability to obtain very high rates of overall response—and complete remissions that seem to be remarkably durable—has created an opportunity for us to begin managing these diseases for extended periods of time.

Long-term Management With so many incurable cancers being turned into chronic diseases, how do patients cope long-term with drug toxicities and the possibility that they may never be cured of their cancer?

Dr. O’Connor: When I think about evolving trends in the management of many cancers, not just blood cancers, I try to recognize that the paradigms unfolding in oncology have really been the paradigms that we’ve relied on in all of medicine for the past 50 years. What diseases in hospitalized patients do we actually cure? Other than infectious diseases, we’re not curing patients with diabetes, Alzheimer’s disease, chronic heart disease, chronic obstructive pulmonary disease, or renal insufficiency—we’re managing them. And I think that both the medical community and the lay population have developed this concept that cancer is different from all those other diseases. Many believe that if you don’t cure these cancers, then

“Hey, Doc, have you seen the picture of my three grandchildren?” When patients realize that managing a disease does not mean disturbing their quality of life, then cure becomes less important.

Turning cancer into a chronic disease demands the use of therapies that are well tolerated for extended periods of time. Again, because of our improved understanding of cancer biology, our ability to develop drugs that selectively target the biology of the tumor has become greater. That has afforded us new opportunities to treat patients over extended periods of time with drugs that don’t have cumulative toxicity.

Remaining Obstacles It seems that the advances being made in more effective targeted therapies are happening at a quickening pace. What could hinder continued success?

Dr. O’Connor: That pace is going to get even brisker. But what’s becoming very limiting in our translation of observations from the laboratory to the clinic is no longer our ability to identify the biology of a specific cancer and it’s no longer our ability to identify a new agent to treat that cancer—it’s our ability to get patients into clinical trials. Both medical practitioners and patients need to become better educated about the important role clinical trials play in our ability to move agents forward from development to patient practice.

A host of different barriers hinder clinical trial enrollment. Cost and insurance-related issues are probably the most important of these problems, but others exist as well. Many patients have significant fears about the possibility that they’re getting a placebo,

Both medical practitioners and patients need to become better educated about the important role clinical trials play in our ability to move agents forward from development to patient practice. patients have a poor quality of life. But slowly, with the birth of all these new agents, both scientists and lay people have been shifting their thinking about how best to manage these diseases.

Cure is no longer the only victory.

Just ask your patients. “Hey, Doc, keep me alive so I can see my daughter get married; that’s all I want,” one patient told me. Now that same patient asks me,

even though in oncology we rarely if ever use a placebo. They also have concerns about the safety of the new drugs being studied and often draw parallels between animal experiments and treatment on an experimental protocol.

Therefore, we really need a concentrated educational effort in different communities, especially where minorities are overrepresented, in light of ethnic differ-

FDA-approved Targeted Drugs for Multiple Myeloma Generic (Brand) Name

Approved Dosage(s)

Bortezomib (Velcade)

1.3 mg/m2 IV. FDA approved, May 13, 2003.

Lenalidomide (Revlimid)

25 mg/d po on d1–21 of 28-d cycle, with dexamethasone, 40 mg/d, on d 1–4, 9–12, and 17–20 of each 28-d cycle for first 4 cycles, then d 1–4 every 28 d; adjust dosage for thrombocytopenia or neutropenia. FDA approved, December 27, 2005.

Thalidomide (Thalomid)

200 mg/d po, with dexamethasone, 40 mg/d po, on d 1–4, 9–12, and 17–20 every 28 d, discontinue or adjust dosage for severe adverse reactions. FDA approved, July 16, 1998.

ences in drug toxicity and response. As we begin to evolve greater reliance on the role of pharmacogenomics, it will be critical to develop therapies in discrete patient populations so we can understand issues related to new drug toxicities and efficacy in ethnically diverse populations.

Looking Ahead What is needed to help further the development of new therapies?

Dr. O’Connor: Three rapidly emerging areas are critical to the innovative development of new ideas in cancer biology and treatment.

1. One area is chemical biology, as we try to forge collaborations with chemists who can now generate a multiplicity of novel chemical entities that are able to selectively affect the biology of interest. Historically, the interface between chemists and clinicians or physician scientists has been remarkably limited. However, with the growth of targets and the ability to generate new chemical entities to hit those targets, we need more dynamic crosstalk between chemists and biologists so that they can work quickly to identify optimal lead compounds to take into the laboratory in the proper diseasespecific context.

2. The second critical area involves how we evaluate these drugs. We are in desperate need of new models of all types of human cancers. Enormous initiatives at the National Cancer Institute and National Institutes of Health, many championed by Dr. Harold Varmus, are using genetically engineered mouse models and trying to recapitulate many different types of cancers by engineering specific lesions in specific tissues. These murine models are critical in prioritizing which drugs to move forward, and are really pharmacologic tools used to sort out how best to use the new drugs.

When you look at many drugs that have been developed in preclini-

cal models, including mouse models, and consider how those drugs were then translated to the clinic, it can be aggravating to see that how we give the drugs to the animals does not resemble how we give the drugs to our patients. It seems counterintuitive to develop a therapeutic strategy that’s effective in a preclinical model and then alter that strategy as we try to translate it to patients, usually for the sake of convenience. We need to understand more about both the genetics of a tumor and the pharmacologic disposition of agents as we make the transition from one species to another.

3. The third area that’s beginning to provide enormous new insights in treatment is systems biology. We’ve spent the past 10 to 20 years understanding gene-expression profiling and the spectrum of genes turned on or off under different disease-specific contexts. Those experiences have given us enormous insights into disease subclassifications and the heterogeneity of disorders such as DLBCL and MCL. The concept that all of the genetic signaling in the cell is actually organized in a hierarchical structure means that this information flows through primary, secondary, and tertiary signaling hubs. Like people, some genes have a message that’s important for everyone to hear, whereas others have messages of lesser importance. Understanding this hierarchy and where the primary signaling hubs are is the purview of the systems biologist.

These concepts are beginning to form the platform for a new way to think about drug discovery and development: Target a cadre of primary hubs, cut off the underlying root of the pathogenetic cause of these cancers, and hopefully, circumnavigate the emergence of acquired drug resistance.

If we can integrate these three areas into a concentrated, focused area of innovative drug discovery and development, our progress over the next 10 years will exceed all we have seen in the past 50.

■

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.

ALREADY ACTIVE

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% 2% 4% Vaginal Bleeding

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 | AUGUST 2010

PAGE 19

Direct from ASCO

Applications Open for Career Development Award Deadline: September 21, 2010 ffective July 1, The ASCO Cancer Foundation (TACF) is accepting applications for Career Development Awards (CDAs) for the 3-year period July 1, 2011, to June 30, 2014. The $200,000 award will be paid in three annual increments to the awardee’s institution. Since its inception in 1992, the CDA program has awarded research grants to over 180 recipients, totaling more than $32 million.

The Foundation encourages qualifying individuals at institutions across the country to apply for these grants.

Submissions in all oncology subspecialties are welcome.

Kathleen Cooney, MD

Noting that obtaining federal funding is becoming more difficult for investigators, Kathleen Cooney, MD, Chair of the Foundation’s Grants Selection Committee said, “These grants are critical in helping to groom future medical oncologists. More investigators are turning to private foundations for research support, and an increasing number of organizations such as ASCO are emphasizing early-stage career awards.”

Asked what advice she would give applicants, Dr. Cooney suggested that individuals start preparing the appli-

cation early. “Seek advice from prior awardees and experienced faculty members.” She noted that the clarity of presentation in the application materials is also critical. “Reviewers are reading a large number of abstracts and applications, and it’s important for the applicant’s ideas to be clear,” Dr. Cooney said.

81 75

After initial review by TACF staff for completeness and eligibility, applications are distributed to members of the Grants Selections Committee for peer review. Dr. Cooney explained that the committee comprises more than 40 individuals, who represent all disciplines related to the proposed clinical research projects, such as surgeons, radiation oncologists, medical oncologists, and geneticists. Biostatisticians and laboratory scientists “who are well integrated into cancer centers” are also included on the committee.

The peer review process has two rounds. In the first round, the committee chair and the Foundation’s scientific reviewer assign each application to two committee members chosen on the basis of the type of science being proposed. This determination is made using the “focus areas” designated on the application as well as the application abstract. In addition to the primary and secondary reviewers, a biostatistician also reviews applications.

Reviewers use a modified version of the National Institutes of Health (NIH) scoring system to score the applications. TACF also has its own

■■ Be in the first 3 years of a full-time faculty appointment as a physician in a clinical department

■■ Be able to conduct investigator-initiated clinical research ■■ Be an active ASCO member (may submit membership application with grant application)

■■ During the award period, spend more than 50% of his or her time in research

■■ Have a mentor from his or her institution ■■ Do not have another career development award (such as a K23 or

83 79

72 64

58

57

45

Applicants

42

39

Recipients

Application Review Process

Eligibility Criteria

K08 award)

CDA Applicants and Recipients, 2000-2010

Individuals

E

22

6

2000

8

2001

11

2002

14

15

14

13

12

2003 2004 2005 2006 2007 Year Grant Funding Begins

2008

2009

13

15

2010

Fig. 1: CDA Applicants and Recipients, 2000-2010.

“strengths and weaknesses” checklist that is used in conjunction with the score. The committee looks closely at the career development aspects of the application, according to Dr. Cooney. She added, “Much of the emphasis in reviewing applications is on asking questions such as ‘Is the applicant qualified and well prepared for a career in academic oncology? Is the science appropriate, considering the individual’s training and experience? Will completion of the proposed research move the applicant along in an academic career toward his or her stated goal?”

While the science of the proposed research is certainly critical, other elements are also important, such as selection of a mentor and the training environment.”

After the first round of review, the reviewers present their view of the application to the full Grants Selections Committee at a face-to-face meeting, and open discussion follows. Every member of the committee (except those with a conflict of interest) scores the application in this second round. The final score from the entire committee determines which applications are funded.

Trends in CDA Applications Dr. Cooney commented that in her 5-year tenure on the Grants Selection Committee, as well as in her service on NIH study sections, she has seen a remarkable growth in the number of translational research projects. “Many cancer treatment

programs are moving toward use of agents that target specific biologic pathways. This requires the assessment of biomarkers and tissue endpoints, so the grants are by necessity becoming more translational. There is also the need for more statistical input because of the sophistication of clinical trial designs.”

A strong mentor is a requirement for CDA grants, reflecting the emphasis on this in the current academic community. “Another trend [in grant applications] is having a mentoring team in which a variety of individuals with different intellectual or training expertise contribute to mentoring a junior faculty member.”

Dr. Cooney said.

The Foundation will announce the CDA grant recipients in April 2011.

For more information and to download application templates, go to www.ascocancerfoundation.org/cda.

■

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

To Apply Applications open for Career Development Award and Young Investigator Award.

Deadline: September 21, 2010 For additional information and to apply online, visit www.ascocancer foundation.org/TACF/grants.

The ASCO Post | AUGUST 2010

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Direct from ASCO

Improving Colorectal Cancer Outcomes the Goal of Career Development Award Recipient

George J. Chang, MD

I

n his application for a 2008 Career Development Award (CDA), colorectal oncology surgeon George J. Chang, MD, MS, outlined a research project to develop a Markov decision model for optimizing rectal cancer therapy. Dr. Chang, an Assistant Professor at The University of Texas M. D. Anderson Cancer Center in Houston, was 1 of 13 recipients in 2008 of the 3-year, $200,000 award given by The ASCO Cancer Foundation.

“A Markov model is a mathematical tool for simulating outcomes after different treatment scenarios,” Dr. Chang explains, adding that the model has been commonly used in business forecasting.

Explaining that his overall research

agenda is to improve outcomes in colorectal cancer, Dr. Chang says that the CDA he received has led to many other opportunities that support this work. “The Career Development Award has provided resources for research, education, and career development and provided opportunities for collaboration. It’s helped me engage new areas of work and carry on existing work,” he said.

Creating the Model As part of the preparation for creating the decision model for rectal cancer therapy, Dr. Chang and his colleagues used data from more than 23,000 patients in the Surveillance, Epidemiology, and End Results (SEER) registry to analyze survival outcomes of patients who had preoperative or postoperative radiotherapy for rectal cancer. The study, published in Cancer, found that patients with persistent lymph node–positive disease after preoperative radiotherapy have impaired survival expectancy, and the authors recommended targeting this group for novel treatment strategies.1 To refine the decision model, Dr.

Chang is developing a prospective registry of health state utilities and quality of life in patients following multidisciplinary curative treatment for rectal cancer. In addition, he will soon launch a prospective single-arm phase II clinical trial at M. D. Anderson to obtain additional data about treatment outcome and survivorship in patients undergoing toxicity-optimized treatment for rectal cancer. Controlling for a number of factors such as the quality of surgery and the chemotherapy administered, the clinical trial will measure the quality of life in a population of patients who do not receive radiotherapy. “This will give us robust data to optimize our models,” Dr. Chang said. He added, “These are the kinds of things that the CDA has definitely helped us to do.”

Dr. Chang says that the decision model will permit simulation of different treatment strategies in order to measure their effects on the quality of life over a lifetime. “We can determine quality-adjusted life expectancy, and the net effect of treatment-related trade-offs, to inform decision-making about current therapy and future clini-

cal investigations,” he explained.

In related work, Dr. Chang and his colleagues have developed a model that provides important prognostic information for survivors of colon cancer. Using SEER data, they analyzed more than 83,000 patients diagnosed with colon adenocarcinoma between 1988 and 2000 to determine riskadjusted conditional survival probabilities. As a result of this work— published in the Journal of Clinical Oncology—an online calculator for conditional survival has been made available to clinicians (www.mdanderson.org/coloncalculator).2

■

References 1. Chang GJ, Rodriguez-Bigas MA, Eng C, et al: Lymph node status after neoadjuvant radiotherapy for rectal cancer is a biologic predictor of outcome. Cancer 115:5432-5440, 2009.

2. Chang GJ, Hu CY, Eng C, Skibber JM, et al: Practical application of a calculator for conditional survival in colon cancer. J Clin Oncol 27:5938-5943, 2009. © 2010. American Society of Clinical Oncology. All Rights Reserved.

West Virginia Oncologists Plan Statewide Clinical Trial Network ASCO Affiliate Grant Helps State Lay Groundwork

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lthough the West Virginia Oncology Society (WVOS) is barely 2 years old, its members have undertaken an ambitious plan to establish a statewide clinical trial network. In June the society received a $10,000 grant from ASCO’s State Affiliate Grant Program to help lay the groundwork for the network.

First-year Focus In this first year of setting up a clinical trial network, the focus is on educating cancer care providers in the state about clinical trial requirements and gaining support for the network.

In collaboration with West Virginia University, the society has also received a $35,000 grant from Susan G. Komen for the Cure to support these initial activities.

West Virginia has the third-highest state death rate from cancer. “A goal of the society is to expand access to state-

of-the-art clinical trials for patients in West Virginia,” said WVOS President John Azar, MD, a medical oncologist in solo practice in Fairmont, West Virginia. “The opportunity to participate in clinical trials is not available at all clinical sites in our state.” Dr. Azar estimates that the state has between 70 and 100 oncologists, many in rural practices of one or two. “The only way to have a statewide clinical network and be cost-effective is to band together,” he said.

The society is off to a good start.

Dr. Azar estimates that about 95% of oncologists in West Virginia have joined WVOS. A pilot clinical trial network begun in January 2009 at four sites had enrolled 40 patients by the end of April 2010. Once the statewide clinical trial network is set up, the challenge will be to gain broad participation.

“This is something major, and we

need to have 95% on board with the project,” Dr. Azar said. “The only way to make progress in oncology is to put people on clinical trial. We feel that this is a noble thing, and we are very excited about it.”

The only way to have a statewide clinical network and be cost-effective is to band together.

– John Azar, MD

To learn more about establishing a network, the members of a small ad hoc committee reviewed clinical trial networks that had been established in three states—Florida, Kentucky,

and New Mexico—asking questions about administration, funding, patient screening, staff requirements, and government subsidies. The information obtained and the challenges addressed in each state are helping the WVOS develop its own network.

Training Weekend Planned Providing education about clinical trials for physicians, nurses, and administrators is the next step on the society’s to-do list. A task force of about 12 WVOS members is planning the training, a 2- or 3-day weekend program to be held in a central location in West Virginia. “We have to learn a lot about data management, ethical considerations, budgets, and administration of clinical trials,” Dr. Azar said.

A combination of local experts and out-of-state consultants will be used as faculty. Task force members have continued on page 22

ASCOPost.com | AUGUST 2010

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Direct from ASCO

Molecular Markers Meeting Focuses on Clinical Application From Discovery to Clinical Practice: October 18–20

David R. Gandara, MD

D

esigned to promote interaction among participants, the ASCONCI-EORTC Annual Meeting on Molecular Markers in Cancer, to be held October 18–20 in Hollywood, Florida, will bring together clinicians, pathologists, statisticians, researchers in basic and translational science, and industry representatives—the multidisciplinary audience needed to put emerging science into practice. The

educational content has something for everyone, according to David R. Gandara, MD, Chair of the Organizing Committee. “For practicing oncologists, many of the laboratory findings about molecular markers are being put right into their daily clinic.

The basic scientist will learn about the latest technology and data, and the translational researcher will learn how to apply those new findings.”

Dr. Gandara noted that the Organizing Committee placed particular emphasis on practical, clinical applications. “Clinicians will learn how to incorporate a personalized approach to biomarker use, to know how to treat a particular patient,” he said.

Within the overall emphasis on practical applications of biomarkers, the meeting focuses on immunotherapy biomarkers and DNA repair.

Meeting site: The Westin Diplomat, Hollywood, Florida Early discounted registration deadline: September 8 With its setting on the Atlantic Ocean, the Westin Diplomat Hotel in Hollywood, Florida, provides a relaxed and balmy setting for the meeting.

International but Intimate First held in 2000, the meeting is now jointly planned by ASCO, the European Organisation for Research and Treatment of Cancer, and the National Cancer Institute. “The purpose is to bring together experts from around the world in one setting,” Dr. Gandara said. Each year the setting alternates between Europe and the United States. When it is held in the United States, ASCO coordinates it.

“The meeting really has two parts,” Dr. Gandara said. “One part is the educational sessions, led by professionals from multiple disciplines. But another significant part is the interaction that takes place—the audience with the faculty, the faculty with faculty, and the audience with the audience.” Because the meeting does not have concurrent general sessions, attendees are all together in every session, enhancing the networking opportunities and comfortable interaction.

When asked how he feels about this year’s meeting, Dr. Gandara said, “I feel like a proud father. We think we have an outstanding faculty, and it is a good feeling to be able to bring together these top people.”

Limited-size Tutorial Accompanies Meeting

By car, the hotel is 30 minutes north of Miami International Airport and 15 minutes south of Fort Lauderdale/Hollywood International Airport

To register, go to www.molecularcameeting.org.

Complementing the meeting, the 1½-day “Diagnostic Development Tutorial: From Hypothesis to Product” is open to selected early-career oncologists, biostatisticians, and industry and regulatory representatives.

The tutorial will address issues critical

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

to understanding the advances, development, limitations, and validation of molecular markers. Working in small teams with faculty members, participants will create molecular marker development plans based on specific clinical scenarios.

The tutorial will be held October 17–18 in the same hotel as the meeting. Individuals from academic institutions who are within 8 years of training may apply to participate in the tutorial and receive a travel grant.

A registration request form is available online at www.molecularcameeting.org for individuals from industry interested in applying.

■

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

Board Preparation, Practice Assessment Possible with ASCO Tool

A

SCO has released a revised edition of the ASCO Self-Evaluation Program (ASCO-SEP®), designed to help oncologists assess their knowledge of the field.

The 22 chapters of the comprehensive publication review the latest evidence covering the complete range of oncology topics. Updated by experts in each field, the chapters cover all major cancer types as well as underlying biology, pharmacology, clinical strategies, and research

design. Three new chapters in the second edition address multiple myeloma, end-of-life care, and statistics and clinical trials.

Closing the Gap between Cancer Care and Current Evidence ASCO launched the first edition of the program in 2008 to create an evidence-based resource for practice as well as a tool for oncologists to assess their level of knowledge in vari-

ous areas. The initiative responded to a 2005 survey conducted by the National Cancer Institute, which had shown that oncologists believe a gap exists between the cancer care patients receive and the care indicated by current evidence.

Planned regular revisions allow users to stay up-to-date with the latest scientific evidence regarding care of patients with cancer. Each updated edition will also provide a current resource for information on drug

therapies, standard lab values, and survivorship strategies.

The self-assessment questions in ASCO-SEP ® are useful for fellows preparing for initial board certification as well as practitioners moving through the maintenance-of-certification process. The questions directly correspond to the exam blueprint used for both initial certification and maintenance of certification. All questions explain in detail the ratiocontinued on page 22

The ASCO Post | AUGUST 2010

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Direct from ASCO

Clinical Trial Network continued from page 20

had conversations with companies who have offered to provide a clinical trial training module. Physicians, nurses, administrators, data managers, and statisticians are expected to be involved in the educational program.

The funding from the ASCO and Komen grants is supporting the educational and organizational activities targeted in this initial year of establishing the network. Once the network is established as a nonprofit organization, fundraising to initiate the clinical trial network will begin

in earnest. Dr. Azar estimates that $200,000 to $300,000 will be needed in start-up costs. “We are looking for funding from institutions within the state,” he said.

■

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

Board Preparation continued from page 21

nale for the correct answer and provide links to relevant references for further reading.

The print version of ASCO-SEP® contains 165 self-assessment questions. The online version has a bank of questions incorporating those in the print publication plus 90 additional ones, for a total of 255 practice questions. The online version uses a timed approach for answering the questions, whereas the hard-copy publication is designed to facilitate self-pacing.

Up to 45.5 category 1 continuing medical education (CME) credits are available with the print publication, and an additional 10 CME credits accompany the online question bank.

The print and online versions may be purchased together at more than a 20% discount over buying them separately. ASCO-SEP® may be ordered at www.ASCO.org/ascosep.

■

(Stimulating Targeted Antigenic Responses To NSCLC)

What’s Covered in ASCO-SEP®?

Chapters in the 2nd Edition ■■ Epidemiology and Prevention ■■ Molecular Biology ■■ Clinical Pharmacology ■■ Biologic Therapy ■■ Statistics and Clinical Trials ■■ Breast Cancer ■■ Lung Cancer ■■ Head and Neck Cancer ■■ Gastrointestinal Cancers ■■ Genitourinary Cancers ■■ Gynecologic Cancers ■■ Malignant Melanoma ■■ Sarcoma ■■ AIDS and Cancer ■■ Central Nervous System Tumors ■■ Leukemias ■■ Lymphomas ■■ Multiple Myeloma ■■ Hematopoietic Cell Transplantation ■■ Cancer in the Elderly ■■ Symptom Management ■■ Palliative and End-of-life Care

EMD Serono, Inc. is an affiliate of Merck KGaA, Darmstadt, Germany

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

ASCOPost.com | AUGUST 2010

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Direct from ASCO

ASCO Offers Big Tent for Oncology Professionals

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s the collective voice for professionals working to improve cancer prevention, diagnosis, and treatment, ASCO offers membership to individuals in oncology-related professions, including physicians, oncology nurses, nurse practitioners, physician assistants, practice management professionals, researchers, and other health specialists. ASCO’s programs, products, and services are specifically designed with this wide array of professionals in mind.

Examples of Member Benefits

■■ Scientific Exchange and Networking—ASCO’s meetings, publications, and programs offer ways for members to stay connected and learn from each other, fostering the multidisciplinary approach so essential in cancer prevention, treatment, and research. ASCO meetings are prime examples of opportunities offered for interdisciplinary learning and networking, but ASCO also offers nonmeeting opportunities to exchange information and network with other professionals. An example? The Oncology EHR social networking site (ehr. ascoexchange.org) serves as a

platform for oncologists and different vendors of electronic health records (EHR) to discuss the advancements, usability, and challenges that emerge in using EHR in oncology offices. In addition to blogging, users can build up their personal profile page and incorporate widgets and RSS feeds on their page as well.

■■ Practice Improvement and Efficiency—ASCO offers many publications and tools to enhance the efficiency of health-care delivery and support practice management activities. For example, ASCO’s Coding & Reimbursement Services offer ASCO members help in navigating oncology-related coding, billing, and reimbursement questions. The service is an ASCO member benefit and provided free of charge to ASCO members and their practices.

■■ Improving Quality of Care— ASCO’s Quality Oncology Practice Initiative (QOPI®) is one of ASCO’s member benefits that specifically targets its mission to improve cancer care. A self-evaluation and improvement program, QOPI features a national data collection program that gives participating practices information to

compare their performance with those of peers and nationally recognized practice guidelines. The new QOPI Certification Program builds on the success of QOPI to meet oncologists’ evolving needs.

This voluntary program provides practices with additional quality improvement targets, as well as a demonstrable designation of achievement on oncologist-approved quality measures.

■■ Education—ASCO meetings, educational tools, and publications provide education in every aspect of cancer research, prevention, and care. Members receive significant discounts when registering for meetings or purchasing ASCO products.

■■ Advocacy—ASCO makes sure the interest of patients with cancer, cancer researchers, and cancer care providers are heard by policymakers and the public. ASCO submits testimony to Congress, urges members of Congress to act on key issues, and provides comments on proposed regulations, such as those of the FDA or the Centers for Medicare & Medicaid Services. As an example of ASCO’s advocacy efforts, in May ASCO representatives met with

members of Congress to support $35.2 billion in funding for the National Institutes of Health in the next fiscal year.

■■ Patient Education—In addition to providing doctor-approved cancer information directly to patients via the Internet, ASCO’s patient information website, Cancer.Net, provides booklets, fact sheets, and other materials in English and Spanish to help patients learn about their diagnosis.

One of the newest publications is the booklet Managing the Cost of Cancer Care, which gives practical tips on financial planning before, during, and after treatment. Oncology providers can feel confident that their patients are receiving current, oncologist-approved information. Members can order these materials for a reduced rate by visiting www.cancer.net.

■■ Over 28,000 oncology professionals worldwide take advantage of member benefits such as these.

To learn more about member benefits, visit benefits.asco.org; to join, go to www.asco.org and click on “Join ASCO.”

■

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

Still Possible to ‘Attend’ 2010 Annual Meeting Sessions—Virtually ASCO products deliver videos and slides from presentations

V

ideo and slides of educational sessions from the ASCO 2010 Annual Meeting are now available electronically using the Virtual Meeting, a product that allows users to watch and listen to the presentations over the Internet.

The Virtual Meeting player provides access to all nonticketed sessions and selected ticketed sessions from the meeting, including plenary sessions, education sessions and discussions, clinical science symposia, special sessions, and abstract and poster presentations.

The Virtual Meeting features user-friendly access to and sorting of the content in number of ways. For example, when the user selects “Developmental Therapeutics Track,” the education sessions, four clinical

science symposia, and six poster and oral abstract sessions related to this topic are immediately listed, with sorting available by session title or session type.

All of the content of the Annual Meeting is searchable by speaker, session name, abstract number, or key word. The Virtual Meeting also

features the opportunity to see related videos or browse a list of mostviewed videos.

Podcast Offers Second Format Option Presentations from the 2010 Annual Meeting are also available as a series of audio and video podcasts.

Subscribers to ASCO’s Podcast have full access to all captured presentations from the meeting and can listen to and watch the files on a computer or a portable media player.

ASCO’s Podcast allows downloading to MP3 and MP4 players, iPod, iPhone, or CD. Once downloaded, sessions are available without Internet access.

As with the Virtual Meeting, sessions are fully searchable by speaker, session name, abstract number, or keyword. Technical support is available by both phone and email.

To subscribe to either the Virtual Meeting or Podcast, visit www.asco. org and click on “Multimedia.”

■

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

The ASCO Post | AUGUST 2010

PAGE 24

News Colon Cancer

Gene Expression Similar for Stages II and III Colon Cancer

By Kathleen Louden

A

n analysis of pathologic markers and gene expression by stage in colon cancer indicates that between stage II and III disease, the vast majority of cancer-related genes studied show a “remarkable similarity,” accord-

ing to authors of the study, presented at the 2010 ASCO Annual Meeting.

During the Gastrointestinal Cancer Oral Abstract Session June 6, lead author Michael O’Connell, MD, Associate Chairman of the National Surgi-

cal Adjuvant Breast and Bowel Project (NSABP), presented the findings of the NSABP study.1 Dr. O’Connell said the results shed further light on the “possibility there’s a fundamental difference in biology between stage II and III co-

2010 Breast Cancer Symposium

IntegratIng emergIng ScIence Into clInIcal PractIce

OCTOBeR 1-3, 2010 GAylORd NATiONAl HOTel SuBuRBAN WASHiNGTON, dC (NATiONAl HARBOR, Md)

Registration and Housing Now Open Join us for two and a half days of the most comprehensive discussions on multidisciplinary breast cancer research and treatment. Designed as an interactive and specialized meeting, the Symposium will highlight clinically relevant and translational science with supporting education sessions. Education sessions will feature a variety of topics including biology of metastases, cosmetic outcome with breast surgery, controversies in radiation therapy, and many more.

Highlights of this year’s Symposium include: • Enhanced discussion-based sessions with faculty speakers from top cancer institutions • Case presentations using audience response technology to maximize audience participation • General Poster Sessions • Systemic Management and Local-regional Management Poster Discussion Sessions • 2010 Gianni Bonadonna Breast Cancer Award and Lecture • Fellows, Residents, and Junior Faculty Special Events including Poster Walks and a Networking Breakfast Session

Register early for best rates.

Housing and Early Registration Deadline: August 25, 2010 at 11:59 (EDT) To register and reserve housing, visit: www.breastcasymposium.org Abstract Submission Deadline: June 11, 2010 at 11:59 PM (EDT)

lon cancer,” which was one explanation for clinical trial results published by the ACCENT Group in 2009.

Michael O’Connell, MD

Objectives of the new study were to examine stage II and III colon cancers for pathologic markers and expression of 375 cancer-related genes, including the 12-gene colon cancer recurrence score, and to determine the distribution of markers and their relationship to clinical outcome. Previous research of the recurrence score (Oncotype DX Colon Cancer Assay, Genomic Health, Redwood City, California) has shown that it predicts recurrence after surgery in patients with stage II colon cancer.

The investigators examined 644 patients with stage II cancer and at least 12 lymph nodes assessed as well as 844 patients with stage III cancer across four independent development studies (NSABP C-01/C-02, C-04, and C-06, and a study by the Cleveland Clinic).

Of these patients, 1,035 underwent surgery only, whereas the others also received chemotherapy.

Pathologic Markers As expected, nodal status strongly predicted disease recurrence, Dr. O’Connell said. Patients with stage II cancer were more likely to have mis-

Genetics of Colon Cancer ■■ Stage II and stage III colon

cancer are very similar for expression of 375 cancerrelated genes, suggesting they are not unique tumor phenotypes.

■■ The 12-gene recurrence

This activity has been approved for AMA PRA Category 1 Credit.™

Primary Supporter of the 2010 Breast Cancer Symposium

TARG E T I NG

C A NC E R

C A RE

score, previously validated in stage II colon cancer, appears to be stage-independent and should be tested to see if it also predicts recurrence risk in patients with stage III colon cancer.

ASCOPost.com | AUGUST 2010

PAGE 25

News

14

Small absolute differences in mean expression of individual genes in stage II vs III: - Median = 0.09 CT - Maximum = 0.58 CT

12

Stage II CT

10 8

Only 5 of 375 genes had significant (P < .05) differences in all 4 studies

6 4 2

2

4

6

8

10

12

14

CT Stage III Fig. 1: Mean expression of cancer-related genes shows a high correlation between stage II and stage III colon cancer. CT = concordance of mean expression. Courtesy of Michael O’Connell, MD.

match repair (MMR) deficiency than those with stage III disease (17.2% vs 12%, respectively). They also were more likely to have mucinous tumor histology (19.5% vs 14.2%).

Analysis of an interaction between stage and grade showed that high tumor grade was associated with a favorable prognosis in stage II but an unfavorable prognosis in stage III, Dr. O’Connell reported.

Gene Expression The researchers quantified gene expression using reverse transcription– polymerase chain reaction (RT-PCR).

Nearly all of the 375 genes studied

appeared to be stage-independent (Fig. 1), with only 45 showing some evidence of interaction with tumor stage. However, Dr. O’Connell said that 37 of these are likely to be falsepositive findings. Only 5 of the 375 genes (1.4%) showed statistically significant differences in mean expression by stage in all four studies.

Genes that showed stage-specific differences in mean expression included FABP4 and SI (related to cancer cell metabolism), STMY3 (invasiveness), and EFNB2 and Maspin (tumor-host interactions). Additionally, MMRassociated genes demonstrated an interaction of gene expression and stage,

which he called “provocative, given the stage-specific association of MMR deficiency with recurrence.”

Dr. O’Connell said further study is needed to determine the clinical relevance of the markers that differ between stages II and III. He added, “We cannot rule out stage-specific differences in other molecular markers that were not assessed.”

The researchers found no evidence of an interaction between the recurrence score and tumor stage. According to Genomic Health, this finding

suggests that recurrence score may also predict recurrence risk in stage III colon cancer. Studies are in progress to evaluate this possibility.

■

Reference 1. O’Connell MJ, Lavery IC, Gray RG, et al: Comparison of molecular and pathologic features of stage II and stage III colon cancer in four large studies conducted for development of the 12-gene colon cancer recurrence score. 2010 ASCO Annual Meeting. Abstract 3503. Presented June 6, 2010.

Expert Point of View

T

his study suggests that stage II and III colon cancer are not unique phenotypes but rather represent different time points in a common natural history of colorectal cancer,” said discussant Charles Fuchs, MD, MPH, Associate Professor of Medicine, Harvard Medical School, and Director of the Center for Gastrointestinal Cancer at the Dana-Farber Cancer Institute, Boston. He said the researchers must confirm Charles Fuchs, MD, MPH these findings and analyze more biomarkers.

“The data do not yet directly inform clinical management of stage II or III colon cancer,” Dr. Fuchs said.

Dr. Fuchs disclosed a financial relationship with Genomic Health. Dr. O’Connell reported no relevant financial relationships, but some of his coauthors are employees of Genomic Health.

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Colorectal Cancer

Can Bevacizumab Monotherapy Substitute for Multiagent Maintenance in Metastatic Colorectal Cancer?

By Kathleen Louden

S

ingle-agent bevacizumab (Avastin) may be an appropriate option for maintenance therapy in patients with metastatic colorectal cancer, instead of continuing treatment with bevacizumab and chemotherapy, according to a phase III study presented at the 2010 ASCO Annual Meeting.

However, the data remain to be confirmed, and the investigators’ conclusions were strongly debated at this Gastrointestinal Cancer Oral Abstract Session.

Lead author Josep Tabernero, MD, presented the findings of the Maintenance in Colorectal Cancer (MACRO) trial, conducted by the Spanish Cooperative Group for the Treatment of Digestive Tumors.1 Dr. Tabernero, Chairman of the Medical Oncology Department at Vall d’Hebron University Hospital in Barcelona, Spain, said the optimal

duration of treatment of metastatic colorectal cancer after maximal response is still under debate.

Using a noninferiority design, he and his colleagues compared maintenance treatment with single-agent bevacizumab vs that with bevacizumab plus continued standard chemotherapy. The aim of using bevacizumab alone was to “avoid cumulative toxicity without reducing the efficacy of treatment,” Dr. Tabernero said.

“Noninferiority cannot be confirmed [yet for bevacizumab alone], but we can reliably exclude a detriment of larger than 3 weeks in median progression-free survival,” he said, noting that longer follow-up is needed.

The investigators compared the two regimens after administering six cycles of induction che-

Bevacizumab Monotherapy for Colorectal Cancer ■■ Maintenance therapy for metastatic colorectal cancer, with single-agent

bevacizumab may have similar progression-free and overall survival rates to bevacizumab and chemotherapy.

■■ To date no significant differences in OS, ORR, and safety have been noted.

■■ More data are needed to determine if bevacizumab monotherapy is not inferior.

motherapy—a classic regimen of capecitabine (Xeloda) plus oxaliplatin (XELOX)—and bevacizumab.

Treatment continued until disease progression, toxicity, or withdrawal from the study. Dosages for induction therapy were 7.5 mg/kg of IV bevacizumab on day 1, 1,000 mg/ m2 of oral capecitabine twice daily on days 1 to 14, plus 130 mg/m2 of IV oxaliplatin on day 1 every 3 weeks

for six cycles.

Of the 480 patients enrolled in the study, 239 were randomly assigned to receive bevacizumab plus chemotherapy maintenance (arm 1) and 241 received the experimental treatment, bevacizumab alone (arm 2). Patient characteristics did not differ significantly for the two groups, Dr. Tabernero reported. The median duration of continued on page 26

The ASCO Post | AUGUST 2010

PAGE 26

News

Bevacizumab Monotherapy in Metastatic Colorectal Ca

1.00

XELOX-BEV 239 161 (67%) 78 (33%) 10.49 (9.3–11.9)

No.of patients Events Censored Median (95% CI) HR = 1.11 (0.89–1.37)

0.75

Progression-free survival

one more cycle of maintenance treatment than did the control arm (medicontinued from page 25 an of four vs three, respectively). follow-up was 21.1 months for arm 1 In terms of safety, another secand 20.4 for arm 2. ondary endpoint, the investigators observed no major differences between arms. As expected, more patients in arm 1 had grade 3 or 4 adverse events (53.8% vs 47.9% in arm 2), Dr. Tabernero said. Four patients in arm 1 and eight patients in arm 2 had adverse events leading to death.

Josep Tabernero, MD Alan Venook, MD Of note, only one patient in the bevacizumab-only Progression-free survival (PFS), arm had a gastrointestinal perforation, the primary endpoint, was a median of compared with two patients in the 10.4 months in arm 1 vs 9.7 months in control arm. arm 2 (Fig. 1). The difference was not Conclusions Questioned statistically significant.

Discussant Alan Venook, MD, Secondary Endpoints Similar Professor of Clinical Medicine at the Between Regimens University of California, San FranThe secondary endpoints of overall cisco, questioned the authors’ consurvival (OS) and objective response clusion that they can reliably exclude rate also showed no significant differa detriment of larger than 3 weeks of ences between the treatment arms, acPFS. Instead, based on a statistician’s cording to the authors. Median OS in review of the authors’ data (HR = arm 1 was 23.4 months and in arm 2 1.11; 95% CI = 0.89–1.37; median was 21.7 months. The confirmed rePFS = 10 months), he believes the sponse rate was 46% in arm 1 and 49% excess hazard in the experimental arm in arm 2. is approximately 3.7 months. He said The experimental arm completed this does not indicate noninferiority.

s/a BEV 241 174 (74%) 67 (24%) 9.7 (8.5–10.6)

0.50

0.25

0.00

Patients at risk 1 239 2 241

0

204 199

158 160

108 102

71 58

49 40

3

6

8

12

15

27 27

13 17

7 11

4 8

2 6

1 4

0 1

18

21

24

27

30

33

36

Time (months)

Fig. 1: Progression-free survival. Yellow curve indicates arm 1 (capecitabine, oxaliplatin, and bevaciTreatment 1: XELOX-BEV 2: s/a BEV zumab); red curve, arm 2 (bevacizumab alone). s/a BEV = single-agent bevacizumab; = 20.4 (0-38)XELOX-BEV mo Follow-up 21.1 (0-40) mo median (range) capecitabine, oxaliplatin, bevacizumab.

Courtesy of Josep Tabernero, MD.

In response, Dr. Tabernero told The ASCO Post, “We can rule out a difference of more than 3 weeks on the median [PFS], but the 95% CI could include a maximum of 3 months.”

However, Dr. Venook told the presentation attendees, “Based on overall survival, PFS is not terribly relevant in this analysis, because patients live the same length of time.”

He did agree with Dr. Tabernero’s comment that further studies of single-agent bevacizumab after standard chemotherapy for metastatic colorectal cancer are warranted.

A member of the audience commented that bevacizumab is an ex-

pensive maintenance treatment, and the study should have included a notreatment arm after induction chemotherapy concluded.

■

Reference 1. Tabernero J, Aranda E, Gomez A, et al: Phase III study of first-line XELOX plus bevacizumab (BEV) for 6 cycles followed

by XELOX plus BEV or single-agent (s/a) BEV as maintenance therapy in patients (pts) with metastatic colorectal cancer (mCRC): The MACRO Trial (Spanish Cooperative Group for the Treatment of Digestive Tumors [TTD]). 2010 ASCO Annual Meeting. Abstract 3501. Presented June 6, 2010.

The ASCO Post’s TAP Caucus June 2010: Should oncologists participate in physician-assisted suicide?

July 2010: Should oncologists own imaging services?

View the debates by visiting ASCOPost.com.

Coming in Future Issues:

PAGE 73

ASCO Post.c om

Suicide

d Physician-assiste

Is partial breast irradiation acceptable care in patients receiving breast-conserving treatment?

Should patients with low-risk early-stage Hodgkin lymphoma receive radiotherapy?

We encourage you to share your opinions on these and other important issues in oncology. Send your thoughts to Editor-in-Chief, Dr. James Armitage, at Editor@ASCOPost.com. Your letters will be published in future issues of The ASCO Post.

TAP Caucus

| JUNE 2010

n-aided Dying

Physicia In Support of acker, MD

By Nancy Crump

“physiuse the phrase hy do I no longer ”? It is simply inaccian-assisted suicide d to distinguish the emerge curate. The phrase asia, which suggests lack of practice from euthan the patient. But “physicianof part tation probchoice on the ” has its own conno assisted suicide ian-aided lems.

Washington, physic In Oregon and al Death with ed by nearly identic dying is regulat specifically to A) that pertain Dignity Acts (DWD achiev ing a peaceful death. t in cker, MD e Nancy Crumpa physician suppor g in a suicide, becaus assistin e regulat DWDA does not es In both states, the medical practic that is still a crime. e” to describe similar medical treatment the word “suicid aw or withhold We do not use physicians to pres to choose to withdr like allowing patient Current medical practice allows food while sciousness death. that will cause patient into uncon that sedates the ing death. scribe medication withheld, thus hasten and hydration is

W

d Suicide Is Physician-assiste ective, and Ineff Unnecessary, gerous Increasingly Dan

By Kevin Olson,

d medications I have prescribe nts A for a few patie under the DWD are ect those who because I resp experiencing ibly dying and poss be able to not may I suffering that ameliorate. istic Distinction word “suicide” demeans people The More Than a Lingu ent deaths. Peonot just linguistic.

MD

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| JU LY 2010

Should Oncolo gists O Phys wn

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By Rober Physicia t M. Lan gdon, MD Imagin ns Should Not g Cent Own

By Charle ers s L. Ben nett, MD T he ability of an ,

PAG E 53

TAP Ca

suicide physician-assisted or reliy opposition to oncology PhD, MP operate from purely ethical practic P, and E.W (PAS) stems less tic concerns with hig its own imagin . Lingle, more from pragma perspecg center e to own and her qua PhD lity, pro gious ideology and and con care. My sistent care better efficien vides patients y of this kind of about the deliver ters pro ing hematology/ vide imp . Physician-own cy, lower costs, full-time practic and as the tive comes as a roved qua years ed imagin wor 16 past k the wit an for lity h g hysicians e oncologists oncology physici to reading oncologic radiolo through collabo cenof 40 private practic had many should group gist rati a scan of ve not s who are leader s from ge has can ensure dedicated The PAS challen own ima own their Robert ng imquality thro a cancer view. for the past 10. includi M. niza Oregon Lan ging cen The tions suc gdon, MD uences in Period. ters. h as the ugh accreditation se centers beneficial conseq the end of life, End of The pra palliative care at with org ies and ma cticing onc American Co The Un story. proved focus on n ranks among alleg ited Sta utilization (Orego als, these ke special reques with on-site rad ologist can imm e of Radiology. manspe the Kevin Olson, MD in improved hospice se tes nds iologists ts rad mo ed training and experti the end of to review ediately consult characteris iologists are attu in regard to issu on health re of its GDP Charles es in this regard), improv the patient by those near L. Benn the nation’s leaders a reduced fear of painful death and other tics to meet Res ned to providing under question. ett, MD, other cou care than any PhD, MPP However, three main During clin ’s studand ponse Eva accurate criteria set ntry, and d death via PAS. and agement of pain, e, larg in hastene tum luat a ical sha pat fort e and inc tha ion or re is risi triient mig who pursue not always effectiv E.W. Ling reasing ng. Suppor t ration fromh in the trial. The Criteria in Sol measurements life—even for those tion to PAS: It is not needed, it is nent of . le, PhD ers ma system y id and ze affi of tTum deliver hea opposi ima of liate our hea ors (RE ging cen x medical care issues drive my tween $58 lth-care costs— regulatory req CIST) ter to ima d facility provid an increasingly comple uirements system point lth-care es ging cen The effi it is dangerous in annually billion and $34 and unnecessar to the as an imp ter for pro for reduction ciency y 0 is cedures.

When ship of out derived from phy billion annually. costs at that—acc ortant compoof an on within This it is rarely used.

Another ounting a multidi cancer because cology Not Needed That tories, day patient facilitie sicians’ additio estimate for befor patients with “100-10-2-1” rule. imaging sciplina s, inc nal center is -surgery PAS is not needed s for PAS, I use the ry frees facilities, luding diagno income that resu that $8 billion is extra in the panic of becenter frequency of request stic ima the option (often and pro lts from tan or asked about the about process ask din legal who gin din Co the ced ow g centers ary. nflict of individuals ure labo g cancer 10 begin to pursue , testing neris, for every 100 ratories.

Interest al diagnosis), only h completely with allows eas laboratermin Co throug a of nfli ed an follow 2 ct-of-intere d Ov only y access ing inform inter- stag Empirical ption. Of those 10, for the dying process st concer eruse of Fac ing and of obtaining a prescri a prescription (often because ptions,wh tumor respthe imaging pro powerfu studies in medic ns affect the ent ilities obtain two who get prescri en there l. the process and d death). For the are questio onse on therap cedure to consist tories, imaThey consistent ine concerning ire economy, not need for a hastene y. It also ently asse ns of rela ly con venes without the pro ss accura pse, pro excess in ging equipment show that when flict of interest just health care Full-spe use it. gression, vides a rapid te . one will actually the use , pharma ctrum physici are par com or

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Care a new ma par The effi lignancy. ison ciency of Under One iduals who ask freestandin Roof an onc For every 100 indiv of receiv g cancer center ology imaging ing the center -assisted suicide, Pat is ext about physician of ients mo full spectrum of raordinary. The patwithin a multid isci outpatien nly the legal process ies as welcom t oncolo ient has the con plinary l as a me come into the only 10 pursue only gy ven ima on and dic care und ience al oncolo active ging cen ription, programs, treatment or dur gy visit and trea ter for all of the er a single roof. obtaining a presc ing ir imagin all in a tment on w through andspecifi single faci follow-up in g studcall 2 of those 10 follo support the same day, whether der the y the radiologist lity. Because ription. the multid groups and sur same roo and me obtain a presc vivors dical ment f, the isci

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by Mark is immin far one ca Chassin, The distinction manner of their tes: cess alm MD, the n get. in the timing and suicide are opposi to ost current who wish a choice and those who would commit or misuse 2always represe President but does not wish nts ple using the DWDA is generally physically healthy ). to live. tic Testing Although reg overuse of the of the Joint Co person is dying but wishes mmission, se facilitie ulatory ■ The suicidal deaths Facility DWDA uses the DWDA app who ones. resp s this exPer (as loved roa person onses plin formanc hip oppose and rad ches in a tim patient live. The tragedy to iation onc ary physicians benefits . s bring shock and inofma workable to overutilization e Standards including Indepe d to underuse PAS ely manner. the — ny from olo part as ■ Typical suicide are supported by family and friends are allows Thi faci gist or even ption ndent Dia open design s is litie s— under our law donine Oregon meaningf , 3it is not clear received a prescri bring closure and in a min s, where the asse in contradistinct collaboration meet unoccur my patients have and violent. Dying in practic ed to prevent me gnosul. and asse 30,000 deaths that ion to ssment often impulsive Although a few of par- imum of one Safety e that the ani ■ Suicides are are emand Leg used it. Of the roughly of a PAS treatment. Most who se standar ngful day in adv , radiology, and outpatient situ ssul death. part . DWDA deaths process, none has as Co dignity al futility of atio occur ds anc nv A and Iss loss planning for a peacef sca r second are ns enience e of the ue my and to 60 deaths patient’s nning needs to expression of despai cite loss of autono each year, only 40 long-term concern reflectss primary and Cost the con s.

■ Suicide is an be visit. over the past 2 years . Fear of painful death wasThe venience patient a few of my patient ticipated in PAS healththe staff be a sign safety risks of , thebec the DWDA for powering acts. of workin tion for the request . Clearly CT scans. 4 safety. Recent ificant cau medications under dying and possibly experiencing omes g in a ded e inti as their major motiva s in the early years of the program ns,orand studies hav increase I have prescribed herit is possibl who are icated onc patients patient as the rate se of preventab Excessive use e reporte ividual74nee mately acquain these pain concer of edind I respect those watched as these concern in PAS ology of CT on page le can d on s of utilizat ted proced I did it because A third to ameliorate. I continu to address and relieve s to years of ures and ds, anxieties, and with each pat imaging center ion of out cers. These safe scanning appear the may not be able care system evolved them during month tand how provide targets in concern is lega approach ient and is that suffering that I clinical patient ima ty concer s to l that had eluded unders l— urg the und fully can contro situ ent phy to of coming erst ns will onl atio be individ sician-ow ging cen pro tient can cally. Mu gained a sense that I am not able continued on page 74 healthters ualized. n. Adjustment ands his ned y cer center. cedures withou ltip I reminded myself s The free t thromb increased le concerns rela care reform sett imaging centers increase. terminal illness. standing in timing osis, pul These procedure the patient eve ing facility can r hav monar syndrome an-aidrangementcosts to the Me ted to self-referra , and have bee are increasingly s inc dic n l, includ . The diag y emboli, per lude the prim ing to leave the , or physic und of physici s under the Me are program, ing conflic targets historiary icar nosis can out ian-assisted suicide ue and . Send resu dic ansomyour be confirm dial effusions, diagnosis of dee pasubject of physic incurable etim eracancer Violations owned imagin are program. Un lted in a ban t of interest and pubcomment on the p-vein and ofses ed within will for patients with freq on self-ref invites you to uenbet pre es unnecessary g centers der healthof Stark the outpat superior vena cav real issue in caring . Selected respon The ASCO Post very mo an cian cer erra but pro wil ost.com effi vem tific care s l l versial, visi ASCOP who ow arcient fash expand ien atio a ent to a reform, c/o TAPCaucus@ n imagin ons are increa ed dying, a contro in hospital-ba t facility withou ion. A ded n, this proces James Armitage, The ASCO Post. singly diffi ways yet to be oversight g centers 5,6 s can be t icated staff sed of thoughts to Dr. . determine cult to pre Competi in future issues that is kno streamlined and facility. In the d. vent am lished online and tio wledgeable perform ong phy A fourth n and Transp ed in siabout an individual be fair com concern involves arency continu ed on pag mists reco petitive practic competition. For e 54 es and tran markets gnize that to run spa the U.S. health-care rent pricing opt efficiently, the re must ions. Hea system doe lth-care s not me et the crit econoeria to catcontinu ed on pag

e 54

ucus

The ASCO Post | AUGUST 2010

PAGE 28

Lessons Learned

The Gift of Hope

By Stanley Winokur, MD

Lessons Learned presents reflections from practitioners who have gained a greater understanding of clinical practice (and life) through sometimes surprising experiences. Send us your own Lessons Learned for consideration; write to Editor@ASCOPost.com.

A

t some point in his or her career, every practicing oncologist has been asked this difficult question by a patient: “Doctor, how long do I have to live?” In my case, I’ve been asked that question hundreds of times. Sometimes the question about the patient’s survival comes from family members.

Because we’ve spent our early medical careers learning the life expectancy associated with specific cancers, our

Physician as Patient continued from page 1

Six weeks later, I developed left chest pain that was quickly evaluated.

A 20-cm non-Hodgkin lymphoma was subsequently removed from my abdomen along with my spleen and a portion of my pancreas. After seven courses of chemotherapy, a bone marrow biopsy revealed a minimal residual lymphoma.

After several consultations at major medical centers, I agreed with my truly astounding physicians and aggressively treated the disease with autologous stem cell rescue therapy.

Douglas MacArthur said that the two words that summarized all lost battles were “too late.” Just as in war, I thought that the treatment for my cancer must be more aggressive than the disease, or else the disease would win.

Eyes on the Prize To be as sick as a person can be and still believe that there is a chance not only for recovery, but also for cure is an extraordinary physical as well as philosophical experience. Profound exhaus-

impulse is to give patients and their family members an answer. Although we may be aware of the “average life expectancy” for an individual with a certain disease, in my experience, those statistics did not apply to my patients.

Of course, all patients hope that they will be cured of their cancer, or if that’s not possible, they at least hope to have a high quality of life for as long as they can. I once had a patient who taught me about the importance of hope. His name was Jack and he had gastric cancer with liver metastases.

Jack and I discussed the fact that there was no cure for his disease, and he said that he hoped for some quality time before the cancer progressed.

We have a responsibility to our patients to be honest, but we also have a responsibility to never take away their hope.

I started Jack on a regimen of chemotherapy, and after just two courses of treatment, he achieved a remarkable 70% shrinkage of the tumors in his liver, which resulted in a significant improvement in the quality of his life. At a follow-up office visit, I asked Jack if he had any questions about his prognosis.

He thought about it for a moment and then said, “No, doc, I’m very pleased with the result.” As I opened the office door, Jack said, “There is one question I’d like to ask, although it may seem silly.”

I said, “Go ahead and ask your question.”

“My subscription to Time magazine has run out,” Jack said. “If I buy a copy at the newsstand it will cost me $2 per issue, but if I get a 6-month subscription I can save $8. What do you think I should do?”

I looked at Jack, smiled, and said, “I know you will save a lot more money if you get a 1-year or even a 2-year subscription. No one knows how long any of us is going to live but if it were me, I would get a long-term subscription to the magazine.”

Jack’s face beamed with delight.

“Thanks, doc, that’s great to hear,” he said.

As I left the exam room, I thought about the power of hope. I had given Jack hope. We had never discussed

tion due to inadequate, restless sleep, anemia, and weight loss sapped my life.

I literally saw my life disappear day by day. When you are uncontrollably losing weight, you are losing your body… and your life.

However, I kept my optimistic eyes on the prize—the future good health and enjoyment of family, friends, and

Thus, by projecting a positive attitude toward patients, the doctor gives more than life-sustaining medicine; the doctor gives life-sustaining hope. The patient will identify with the doctor’s positive attitude immediately, and live by his or her words, in fact, live because of the words.

Hippocrates wrote, “For where there is love of man, there is also love of the art.

Not-So-Silly Question

In my experience, the patients or families that are the most appreciative of my efforts are the ones that I scientifically help the least. profession. Denial is only pathologic if it interferes with one’s life. I may have used denial to ignore the present and look toward the future. In fact, this mindset allowed me to ignore the potential fatality and the certain miseries. I was able to live at that time so that I could live in the future. The entire health-care team, including my family, promoted the feeling that I would recover. Their confidence and encouragement gave me the strength to endure.

For some patients, though conscious that their condition is perilous, recover their health simply through their contentment with the goodness of the physician.”2 In my experience, the patients or families that are the most appreciative of my efforts are the ones that I scientifically help the least. If the physician has no medications or surgery, there is only one thing left to give—oneself. The inner strength that transfers from physician to patient overcomes many deficiencies in science.

how long he had to live, but I had given him something to look forward to, and that was all he needed to hear.

Predicting Survival During my long career in medicine, I have seen many incurable malignancies, such as testicular cancer and some forms of leukemia, lymphoma, and breast cancer, become curable or at least treatable diseases. Who was I to presume to know how long Jack, or any of my patients, would live?

The longer I practiced medicine, the more I came to believe that neither I nor anyone else is able to predict how long anyone has to live. With the rapid advances we are witnessing in more effective targeted therapies and better diagnostic tools, many once-deadly cancers are being converted to chronic illnesses, and the possibility of cure is on the horizon.

We have a responsibility to our patients to be honest, but we also have a responsibility to never take away their hope.

■

Stanley Winokur, MD, is a retired oncologist who lives with his family in Singer Island, Florida. He is the author of Grandfathered In: A Memoir, a book about finding balance between having a career in medicine and having a family.

It would be dishonest if physicians were not realistic in the assessment of the prognosis, but confidence and positive attitude may improve the patient’s chance for life and future quality of life.

Clearly, it will not hurt.

Doctor-Patient Personal Time Personal time is the lifeblood of the doctor-patient relationship. We are all one diagnosis away from being on the other side of the doctor-patient relationship. The patient’s emotions and knowledge, and possibly his life hang on every word you say. By placing yourself in the patient’s position, your bedside manner, compassion, and empathy will improve and give both you and your patient greater satisfaction.

If it were not for the personal caregiver, a spouse, a friend, a child, or a sibling, there would be no survival. It is nearly impossible to endure a transplant or severe illness alone. The patient gets all the credit, but it must be shared. There is no quality of life without the survivor having the caregiver to share the survival. Thus, the care receiver and the caregiver are inexorably

ASCOPost.com | AUGUST 2010

PAGE 29

Perspective

Physician as Patient continued from page 28

linked forever.

The physician is also linked to the patient and brings the life force to the true meaning of the word “doctor.”

Though time will pass and I will be physically and mentally in a different state, my physician is with me. I am the embodiment of his art and science. I am proof that science, art, and acts of human kindness lead one from the grips of death to the ecstasy of life.

that, we owe them our livelihoods, but more importantly, our spiritual understanding of life and death.

■

References 1. Hippocrates: Regimen in health, bk IX. Cited in Kaplan J (ed): Bartlett’s Familiar Quotations: Expanded Multimedia Edition (CD-ROM), New York, Time Warner

Electronic Publishing, 2002.

2. Hippocrates: Precepts, chap 6. Cited in Kaplan J (ed): Bartlett’s Familiar Quotations: Expanded Multimedia Edition (CDROM), New York, Time Warner Electronic Publishing, 2002.

Dr. Boxer is Professor of Clinical Urology at the University of Miami and Clinical Professor at the University of Wisconsin, Madi-

son, and the Medical College of Wisconsin.

Dr. Boxer was a two-time finalist for U.S. Surgeon General (under both the William J. Clinton and George W. Bush administrations) and served on President Clinton’s Task Force on Health Reform. In addition, Dr. Boxer has served on the National Cancer Advisory Board, represented the United States at the World Health Organization, and was the Chair of the National Health Policy Council.

Tria l

Mutual Identification Some pass through a challenging time, others learn from it. Understanding life means grasping its meaning and appreciating that personal experiences impact on interpersonal relationships.

I always tried to be a compassionate physician, yet I wrapped myself in the protection of objectivity. Now, as I tell my patients about their illness, perhaps their malignancy, I identify with them physically and emotionally. More importantly, patients identify with me.

They sense that I would not order a test or a procedure without first understanding how it would affect them and possibly cause pain or discomfort.

However, they also know that these tests may mean—hopefully do mean— a passage to health again.

They also know that as soon as the tests are complete, I will tell them the results. Physicians who do not immediately report to the patient results of crucial blood tests, x-rays, or especially a biopsy, when anxiety and well-being are hanging on the results, have never waited for test results for themselves or their families. The simple human kindness of calling the patient the day of the test can save an enormous amount of anxiety.

Our Patients Are Our Professors I survive because of those who came before me. I live because of the research performed by others, often funded by the generosity of the American people. But the generosity is beyond their tax dollars supporting research; I live because others participated in clinical trials that may not have helped them. By volunteering for clinical research, they helped push back the unknown and shed light upon the darkness of the undiscovered.

Our patients are our professors.

They teach us every day about the disease processes we treat. But they also teach us about the subtleties of life and of illness. They teach us how to live with disease, and how to die with dignity. For

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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 | AUGUST 2010

PAGE 30

News

Gemcitabine/Carboplatin Has No Benefit Over Standard First-line Chemotherapy for Ovarian Cancer

By Kathleen Louden

W

omen with ovarian cancer do not survive longer if they receive firstline chemotherapy with gemcitabine (Gemzar) and carboplatin, compared with the standard of care, according to a phase III trial presented during the Gynecologic Cancer Oral Abstract Session at the 2010 ASCO Annual Meeting.

The final report for this multicenter trial found a similar progression-free survival (PFS) between the experimental treatment and the standard, paclitaxel plus carboplatin.1

of a positive PFS result (the primary endpoint) in the experimental arm, according to the abstract. The study’s lead researcher, Michael Teneriello, MD, a gynecologic oncologist with US Oncology, The Woodlands, Texas, presented the intent-to-treat data in 831 patients.

In explaining the rationale for this study, Dr. Teneriello said phase II trials had shown the combination of gemcitabine and cisplatin to be active as first-line chemotherapy for patients with platinum-sensitive ovarian cancer. This trial compared gemcitabine plus carboplatin with standard chemotherapy, and aimed to determine if monthly paclitaxel consolidation therapy would improve survival for patients achieving a complete Ronald Buckanovich, MD, PhD Michael Teneriello, MD response to induction The results demonstrate that pachemotherapy, he said. clitaxel/carboplatin therapy remains The investigators randomly asthe standard of care for front-line signed patients with stage IC through treatment of ovarian cancer, said the IV ovarian cancer to receive one of abstract’s discussant, Ronald Buckatwo treatments postoperatively. One novich, MD, PhD, Assistant Professor regimen was 1,000 mg/m2 of gemcitabine on days 1 and 8 of each 21of Internal Medicine and Obstetrics/ day cycle plus carboplatin (area under Gynecology, University of Michigan the curve [AUC] 5) on day 1 (n = Health System, Ann Arbor.

417). The other regimen consisted of “For patients who do not tolerate 175 mg/m2 of paclitaxel plus carbotaxanes, gemcitabine plus carboplatin platin (AUC 6) on day 1 (n = 414). treatment is a legitimate alternative,” Patient characteristics were similar in Dr. Buckanovich said. each group, Dr. Teneriello reported.

Trial Stopped Early Patients with a complete clinical In August 2009, the trial was response after 6 cycles of chemotherstopped early, after an ad hoc futilapy could elect to continue paclitaxel ity analysis showed a low probability treatment (135 mg/m2) every 28 days

Table 1: Comparison of Regimens for Survival in Patients with Ovarian Cancer Gemcitabine + Carboplatin

Paclitaxel + Carboplatin

P

Progression-free survival (PFS)

20.0

22.2

NS

PFS after paclitaxel consolidation therapy

27.2

30.6

NS

Overall survival (OS)

43.8

57.3

.01

OS after paclitaxel consolidation therapy

65.6

51.4

.04

Median Survival (mo)

NS = not significant.

Gemcitabine/Carboplatin for First-line Treatment of Ovarian Cancer?

■■ As first-line chemotherapy for ovarian cancer, gemcitabine plus

carboplatin does not offer an advantage over the standard of care, paclitaxel plus carboplatin.

■■ Overall survival for the gemcitabine arm may have improved with

paclitaxel consolidation therapy, but the analysis was limited by a lack of randomization for consolidation and by a high rate of censored (unrecoverable) patient data.

■■ This trial cannot answer the utility of paclitaxel for consolidation therapy.

■■ This trial cannot be interpreted as showing any survival benefit.

for 12 cycles; 352 patients received consolidation therapy. Participants who did not have a complete response received crossover therapy with single-agent gemcitabine or paclitaxel.

Crossover therapy continued every 21 days for 155 patients until complete response or disease progression.

If there is no PFS advantage, it would be hard to see how there was any OS advantage. We need to be careful that no one interprets this trial as showing any survival benefit.

Protocol Changed After the study began, the investigators changed the protocol so that paclitaxel consolidation therapy after complete response was elective, rather than mandatory, Dr. Teneriello said. They also changed the primary endpoint from overall survival (OS) to PFS. Secondary objectives were OS, response rate, and adverse events.

The overall response rate after induction therapy was 67.6% in the gemcitabine arm and 71.1% in the paclitaxel arm, Dr. Teneriello reported. This difference was not statistically significant. There also was no significant difference in response between the crossover arms. In the gemcitabine arm, 165 patients discontinued the study after

induction therapy compared with 148 in the other arm, he said.

Regarding adverse events after induction therapy, rates of anemia, thrombocytopenia, and the need for platelet transfusion were higher in the gemcitabine arm, whereas neuropathy and alopecia occurred more often in the paclitaxel arm, according to Dr. Teneriello. Among patients who received consolidation therapy, he said the only difference in adverse events between regimens was a greater incidence of neuropathy in the paclitaxel arm. These results were consistent with prior clinical experience, he noted.

Table 1 shows survival results. The better OS in the paclitaxel arm was no longer statistically significant after adjustment for covariates, Dr. Teneriello commented. Gemcitabine appeared to improve OS in patients receiving paclitaxel consolidation therapy. However, he said, “the rate of censorship [of patient data] was in all cases more than 50% and diminishes the reliability.”

Dr. Buckanovich told The ASCO Post, “If there is no PFS advantage, it would be hard to see how there was any OS advantage.

We need to be careful that no one interprets this trial as showing any survival See page 42 benefit.”

■

Reference 1. Teneriello MG, Gordon AN, Lim P, et al: Phase III trial of induction gemcitabine (G) or paclitaxel (T) plus carboplatin (C) followed by elective T consolidation in advanced ovarian cancer (OC): Final safety and efficacy report.

2010 ASCO Annual Meeting. Abstract LBA5008. Presented June 6, 2010.

ASCOPost.com | AUGUST 2010

PAGE 31

FDA Update

ODAC Recommends FDA Revoke Approval of Bevacizumab in First-line Treatment of Metastatic Breast Cancer

O

n July 20, 2010, the Oncology Drug Advisory Committee (ODAC) of the FDA recommended that the agency rescind its approval of bevacizumab (Avastin) in metastatic breast cancer.

Bevacizumab received accelerated approval to treat breast cancer in 2008 following early findings from studies showing an increase in progressionfree survival. More recent data from two new trials failed to strengthen

the early findings. FDA will make its own determination about bevacizumab in advanced breast cancer, although the agency tends to follow ODAC recommendations.

Watch for comprehensive coverage of the two news trials (AVADO and RIBBON1) of bevacizumab in metastatic breast cancer and FDA’s determination in a future issue of The ASCO Post.

Bevacizumab is currently FDAapproved for use in lung, kidney, and colorectal cancers, and in recurrent glioblastoma (accelerated approval).

■

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The ASCO Post | AUGUST 2010

PAGE 32

JCO Spotlight

‘Rapid Uptake’ of Adjuvant Chemotherapy for NSCLC Has Improved Survival Clinical trial results prove relevant to community practices.

By Caroline Helwick

A

practice, and we wanted to evaluate whether the outcomes and toxicities seen in the ‘real world’ were as expected, based on the results of the trials,” principal investigator Christopher M. Booth, MD, of Queen’s University, Kingston, Ontario, told The ASCO Post.

All patients diagnosed with NSCLC in Ontario from 2001 to 2006 who underwent surgical resection (N = 6,304) were identified using the Ontario Cancer Registry, and electronic health records were linked to these cases.

Survival was compared for two cohorts: patients Christopher M. Booth, MD Frances Shepherd, MD diagnosed from 2001 to Since 2004, several clinical trials 2003 and those diagnosed from 2004 have demonstrated that adjuvant cheto 2006. Hospitalizations within 6 motherapy improves survival in patients months of surgery served as a proxy with early-stage NSCLC (see sidebar, measure of adjuvant chemotherapy– “What’s the Evidence of Survival Benrelated toxicity. efit?”). This finding led to the establishAdjuvant Chemotherapy ment of cisplatin-based chemotherapy Rapidly Adopted as the recommended strategy,2 but how The investigators found no differwell the trial data have translated into ences in demographics or in diseaseclinical practice had not been assessed. and treatment-related characteristics In the current study, Booth and colbetween the two study cohorts. They leagues evaluated the uptake of adjudid, however, find that over the study vant chemotherapy and its impact on period the proportion of surgically reoutcomes among patients with NSCLC sected patients receiving adjuvant chein Ontario, Canada. motherapy increased from 7% (192 of “This study had two major objec2,950 patients) in the first cohort to tives. We wanted to see whether the 31% (1,032 of 3,354 patients) in the pivotal randomized controlled trials second cohort (P < .001). in NSCLC actually led to changes in

What’s the Evidence of Survival Benefit?

Adjuvant chemotherapy for NSCLC appears to have been rapidly adopted after several pivotal trials established its benefit in prolonging survival:

■■ In the International Adjuvant Lung Cancer Trial, cisplatin-based adjuvant chemotherapy was associated with a 4% absolute improvement in survival at 5 years.3

■■ In the JBR.10 trial, by the National Cancer Institute of Canada Clinical

Trials Group and North American Intergroup, adjuvant vinorelbine/ cisplatin was associated with an absolute improvement in survival of 15% at 5 years.4

■■ In the Cancer and Leukemia Group B (CALGB) 9633 trial, paclitaxel/

carboplatin was associated with a 12% absolute improvement in survival at 4 years,5 but in the final analysis the difference lost statistical significance.6,7

■■ In the Adjuvant Navelbine International Trialist Association (ANITA) trial,

the absolute improvement in survival at 5 years was 9% with vinorelbine/ cisplatin.8

ASCO 2005

40 Patients Receiving Adjuvant Chemotherapy (%)

djuvant chemotherapy for non– small cell lung cancer (NSCLC) has been largely adopted in community practice, and this adoption has led to significant improvements in survival, according to a Canadian populationbased study recently reported online in the Journal of Clinical Oncology.1

35

ASCO 2006

ASCO 2004

30 25 20 ASCO 2003

15 10 5 0 2001

2002

2003

2004

2005

2006

Year of Diagnosis Fig. 1: Proportion of patients with surgically resected non–small-cell lung cancer diagnosed in Ontario (N = 6,304) from 2001 to 2006 who received adjuvant chemotherapy. Pivotal randomized controlled trials were presented at the ASCO Annual Meeting in 2003 (International Adjuvant Lung Cancer Trial), 2004 (JBR.10 and Cancer and Leukemia Group B [CALGB] trials), 2005 (Adjuvant Navelbine International Trialist Association trial), and 2006 (updated CALGB trial). Reprinted with permission from Booth et al.1 Copyright © 2010 by the American Society of Clinical Oncology. All rights reserved.

Adjuvant chemotherapy appeared to be rapidly adopted following presentation of several pivotal randomized controlled clinical trials at ASCO Annual Meetings from 2003 to 2006 (Fig. 1).

In a sample of the postadoption cohort, 82% received cisplatin-based therapy and 17% received carboplatin—“drugs for which there is the strongest clinical trial evidence,” the authors pointed out.

The proportion of patients admitted to the hospital remained stable, at approximately 36% per cohort. However, patients admitted with metastatic disease declined by 33% (P < .001) over time. These changes were accompanied by a substantial improvement in 4-year overall survival, from 52.5% in the earlier cohort to 56.1% for more recent patients (P = .001).

The rapid uptake of adjuvant chemotherapy for NSCLC was not associated with an increased rate of hospitalization but was associated with a substantial improvement in overall survival, “suggesting that the benefits seen in clinical trials are generalizable to the general population,” Dr. Booth said.

He further told The ASCO Post that while individual practice patterns may differ between Canada and the United States, “it is unlikely that the mix of patients with NSCLC and the relative benefit of adjuvant chemotherapy differs in a major way between the two

countries. Accordingly, it is reasonable to assume that the toxicity and outcome data reported in Ontario may also apply to patients treated in the United States.”

Who Gets Adjuvant Chemotherapy?

Over half the patients receiving adjuvant chemotherapy were younger than age 50, whereas only 16% were older than 70 and just 53% were older than 60. The logistic regression analysis showed that patients receiving adjuvant chemotherapy tended to be younger, had less See page 42 comorbidity, had a shorter length of surgical stay in the hospital, had more extensive surgery, and had stage II or III disease.

“We observed wide variations in utilization of ACT [adjuvant chemotherapy] across geographic regions of Ontario,” the authors wrote.

“ACT use among surgically resected patients ranged from 22% to 44% across the province,” which suggests “there may be underutilization of this therapy in the general population,” especially the elderly.

Co-investigator Frances Shepherd, MD, of Princess Margaret Hospital, Toronto, elaborated in an interview, “There will always be some patients

ASCOPost.com | AUGUST 2010

PAGE 33

JCO Spotlight

Adjuvant Chemotherapy for NSCLC ■■ Adjuvant chemotherapy has been rapidly adopted for NSCLC,

according to findings from the general population of Ontario, Canada.

■■ Use of adjuvant chemotherapy has increased from 7% of all surgical cases in 2001-2003 to 31% in 2004-2006.

■■ The survival benefit and toxicity of adjuvant chemotherapy in the general population are as expected, based on the results of the relevant clinical trials.

who are not fit enough to receive adjuvant chemotherapy, and there also will be some who refuse. We suspect that after accounting for those patients, there may still be some who are not being referred by their surgeons. We are not able to speculate as to what proportion of patients this might represent, nor what the reasons are for nonreferral.”

The investigators will be addressing the issue of age as a factor for re-

ferral and administration of adjuvant chemotherapy in a future analysis, she added. “This is very important, since lung cancer is a malignancy of the elderly, with the median age being over 70.”

■

References 1. Booth CM, Shepherd FA, Peng Y, et al: Adoption of adjuvant chemotherapy for non–small-cell lung cancer:

A population-based outcomes study. J Clin Oncol. June 21, 2010 (early release online).

2. Booth CM, Shepherd FA: Adjuvant chemotherapy for resected non-small cell lung cancer. J Thorac Oncol 1:180187, 2006.

3. Arriagada R, Bergman B, Dunant A, et al: Cisplatin-based adjuvant chemotherapy in patients with completely resected non-small-cell lung cancer. N Engl J Med 350:351-360, 2004.

4. Winton T, Livingston R, Johnson D, et al: Vinorelbine plus cisplatin vs. observation in resected non-small-cell lung cancer. N Engl J Med 352:2589-2597, 2005.

5. Strauss GM, Herdon MA, Maddaus DM, et al: Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in stage IB non-small cell lung cancer: Report of CALGB protocol 9633 (abstract

7019). J Clin Oncol 22(14S):621s, 2004.

6. Strauss GM, Herdon JE, Maddaus MA, et al: Adjuvant chemotherapy in stage IB non-small cell lung cancer: Update of CALGB protocol 9633 (abstract 7007). J Clin Oncol 24(18S):365s, 2006.

7. Strauss GM, Herndon JE 2nd, Maddaus MA, et al: Adjuvant paclitaxel plus carboplatin compared with observation in stage IB non-small-cell lung cancer: CALGB 9633 with the Cancer and Leukemia Group B, Radiation Therapy Oncology Group, and North Central Cancer Treatment Group Study Groups. J Clin Oncol 26:5043-5051, 2008.

8. Douillard JY, Rossel R, De Lena M, et al: Adjuvant vinorelbine plus cisplatin versus observation in patients with completely resected stage IB-IIIA non-smallcell lung cancer (Adjuvant Navelbine International Trialist Association [ANITA]): A randomised controlled trial.

Lancet Oncol 7:719-727, 2006.

JCO News

ASCO Guideline Update Recommends Aromatase Inhibitors Alone or Sequenced with Tamoxifen as Adjuvant Therapy for Postmenopausal Women with Hormone Receptor–positive Breast Cancer

T

he American Society of Clinical Oncology (ASCO) recently issued a guideline update on the use of adjuvant hormone therapy for women with hormone receptor-positive breast cancer. The Update Committee, convened by ASCO, reviewed evidence compiled through a systematic review of the medical research literature to develop the recommendations. The guideline was published online in the Journal of Clinical Oncology.1 The guideline reviews recent research on both aromatase inhibitors (AIs) and tamoxifen, recommending that all postmenopausal women with hormone receptor-positive breast cancer use an AI either alone or before or after tamoxifen to reduce the risk of recurrence. Women may also use AIs for extended periods, after 5 years of tamoxifen ther-

apy, to lower their recurrence risk.

The Committee made several new recommendations, updating the previous guideline from 2004, including: ■■ Most postmenopausal women should consider taking an AI either as the initial adjuvant therapy or after 2 to 3 years of tamoxifen.

Women can take up to 5 years of an AI therapy. AI therapy can also begin after 5 years of tamoxifen therapy. In that setting, a woman could receive up to 10 years of hormone treatment to reduce the risk of recurrence.

■■ Tamoxifen should be given to all preand perimenopausal women; AIs are only effective in postmenopausal women. The guideline recommends that women who are pre- or perimenopausal at the time of diagnosis be treated with 5 years of tamoxifen.

■■ The Committee found no clinically important differences in effectiveness among the three commercially available AIs (anastrozole [Arimidex], letrozole [Femara], and exemestane [Aromasin]). This is the first update where data are available for each in all three clinical settings (primary, sequential, or extended adjuvant).

■■ The guideline also includes a review characterizing side-effect profiles of tamoxifen and AIs, compiled from the 12 trials considered. While the two drug classes work differently, overall, most women have relatively mild side effects on either drug.

When compared with tamoxifen, aromatase inhibitors may reduce the chance of blood clots and uterine cancer and may increase the risk of osteoporosis and fractures.

■

Reference 1. Burstein HJ, Prestrud AA, Seidenfeld J, et al: American Society of Clinical Oncology Clinical Practice Guideline: Update on Adjuvant Endocrine Therapy for Women With Hormone Receptor– Positive Breast Cancer. J Clin Oncol (early release online). July 12, 2010.

The clinical practice guideline and other clinical tools and resources are available at www.asco.org/ guidelines/endocrinebreast or via the 2D barcode shown below.

See page 42 for more information about using 2D barcodes

Don’t miss “In the Literature” See pages 36-37 in this issue of The ASCO Post for more news from the peer-reviewed literature, including Journal of Clinical Oncology, Journal of Oncology Practice, and The New England Journal of Medicine.

The ASCO Post | AUGUST 2010

PAGE 34

QOPI

First U.S. Practices to Receive National Certification for Delivering High-quality Cancer Care to Patients

A

SCO and its affiliate, the Quality Oncology Practice Initiative (QOPI®) Certification Program, have recognized the first oncology practices to obtain the new QOPI certification.

The QOPI certification program recognizes oncology practices that meet or exceed QOPI standards for more than 24 selected rigorous, evidence- or expert consensus opinion–based mea-

sures for cancer care, and additionally, show evidence of meeting 17 specific chemotherapy safety standards.

“Having a national certification program that acknowledges the high-

Informed patients make better decisions. The practice resources that are available on Cancer.Net enable patients to gather information and form appropriate questions, which lead to the right care decisions.

Larry Norton, MD Memorial Sloan-Kettering Cancer Center

Visit Cancer.Net for the most trusted cancer information from the world’s leading oncologists.

• • • • • • •

120+ cancer types Find an Oncologist database Medical illustrations Clinical trials information Managing side effects Coping and survivorship resources Information in Spanish

www.cancer.net

est standards of cancer care delivery is a major milestone for health care in America,” said Douglas W. Blayney, ASCO Past President.

Diverse Cross Section The first practices to obtain the QOPI certification represent a diverse cross section of cancer care in America. They include: ■ Adele R. Decof Comprehensive Cancer Ctr, Providence, RI ■ Blue Ridge Cancer Care, Roanoke, VA ■ Cancer Ctr at Presbyterian, Albuquerque, NM ■ Carolyn B. Hendricks, MD, PA, Bethesda, MD ■ Coastal Cancer Ctr, Myrtle Beach, SC ■ Commonwealth Hematology Oncology, Quincy, MA ■ Crystal Run Healthcare, LLP, Middletown, NY ■ Fox Valley Hematology & Oncology, SC, Appleton, WI ■ Gundersen Lutheran Ctr for Cancer and Blood Disorders, LaCrosse, WI ■ Hematology Oncology Associates of Brooklyn, NY ■ Louisiana Oncology Assoc, Lafayette, LA ■ Lynchburg Hematology Oncology, Lynchburg, VA ■ Maine General Medical Center Harold Alfond Ctr for Cancer Care, Augusta, ME ■ Mass General/North Shore Cancer Center, Danvers, MA ■ Medical Oncology and Hematology Associates, Des Moines, IA ■ Medical Oncology Associates of Augusta, PC, Augusta, GA ■ Mountain States Tumor Inst, Boise, ID ■ Northern Michigan Hematology/ Oncology, Petoskey, MI ■ Oncology Hematology Associates, Weinberg Cancer Inst, Baltimore, MD ■ Space Coast Medical Associates, LLP, Titusville, FL ■ Sparrow Regional Cancer Ctr, Sparrow Medical Oncology, Lansing, MI ■ The Center for Cancer and Blood Disorders, Fort Worth, TX ■ The Chao Family Comprehensive Cancer Ctr (Division of Hematology/ Oncology), Orange, CA ■ The Jones Clinic, Germantown, TN ■ The West Clinic, Memphis, TN ■ Vita Medical Associates, Bethlehem, PA ■ West Michigan Cancer Ctr, Kalamazoo, MI For more information about QOPI, visit http://qopi.asco.org/.

■

ASCOPost.com | AUGUST 2010

PAGE 35

In the News Melanoma

Impressive Survival Benefit with Ipilimumab Spurs Interest in Compassionate Use Protocol for Patients with Advanced Melanoma

By Charlotte Bath In the News focuses on recent reports in the mainstream press 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.

T

he phones are ringing off the hook with calls from patients and referring physicians,” said Steven O’Day, MD, Chief of Research and Director of the Melanoma Center at The Angeles Clinic and Research Institute in Los Angeles, and one of the lead investigators of a study showing improved survival among patients with advanced melanoma who received ipilimumab.

The presentation of the study results at the Plenary Session of the 2010 ASCO

Annual Meeting1 garnered coverage by major media outlets, including The Washington Post, The New York Times, and the PBS NewsHour, and generated great interest among patients with advanced melanoma and their physicians.

“Patients heard that this is the first drug to improve survival in melanoma, so they want to know whether they can be considered for the compassionate use protocol that we have open at our center,” Dr. O’Day said. “Referring doctors have heard the same thing, and they are trying to refer their metastatic melanoma patients to one of the centers that are doing compassionate care.” A total of 56 centers in the United States are participating in the Compassionate Use Trial for Unresectable Melanoma with Ipilimumab.

If Not This Trial, Maybe Another Eligibility criteria include histologically confirmed stage III (unresectable)

Expect Questions

W

ith treatment options for advanced melanoma so limited and the results of the ipilimumab studies so promising, patients may be asking how they can participate in the Compassionate Use Trial for Unresectable Melanoma with Ipilimumab.

What is the primary objective of the study?

The primary objective of the study is to provide treatment with ipilimumab to subjects who have serious or immediately life-threatening unresectable stage III or stage IV melanoma; who have no alternative treatment options; and whose physicians believe, based upon available data on benefit and risk, that it is appropriate to administer ipilimumab for eligible subjects, including those previously enrolled in ipilimumab studies MDX010-16 or MDX010-20.

Where are the trial sites located?

■■ There are 56 trial sites in 27 different states. The sites are listed on the NCI website.

What are the eligibility criteria?

Eligibility criteria include: ■■ Histologically confirmed stage III (unresectable) or stage IV melanoma ■■ Must have failed at least one systemic therapy for malignant melanoma or be intolerant to at least one prior systemic treatment.

■■ Must be at least 28 days since treatment with chemotherapy, biochemotherapy, or immunotherapy, and recovered from any clinically significant toxicity experienced during treatment. Must have recovered from prior surgery or radiation. Systemic corticosteroids should be eliminated or weaned to the minimum dose before starting ipilimumab treatment.

■■ Life expectancy must be ≥ 16 weeks ■■ Must be at least 16 years old Where can patients and physicians get additional information about the study?

Additional information, including a listing of trial sites by state and a complete list of eligibility and exclusion criteria, is available via the 2D barcode at right and at www. cancer.gov/search/viewclinicaltrials.aspx?cdrid=559274.

See page 42

Clear Step Forward for Immunology in Cancer The results from trials using ipilimumab for advanced melanoma represent “a clear step forward for immunology in cancer,” Steven O’Day, MD, believes. Some people had doubted whether it would be possible to treat people with advanced cancers because of major immunosuppression. “So it is very reassuring and exciting,” Dr. O’Day said, “to show that even in the worst situations where tumor has spread all over the body and the Steven O'Day, MD immune system is in shreds, this drug may be able to resurrect and empower the immune system to eradicate or control cancer for years on end.”

■

or stage IV melanoma and the failure of (or patient intolerance to) at least one prior systemic treatment for malignant melanoma. “We try to screen for those two qualities,” Dr. O’Day said about those who call The Angeles Clinic and Research Institute and express interest in the ipilimumab compassionate trial.

“Then we have them come and see us for a full consultation, because they may not be eligible for this study, but we have a number of other clinical trials in melanoma that they may be eligible for,” he explained. “The only way we can continue to make progress in advanced melanoma is for patients to get on clinical trials.”

Dr. O’Day reported that calls were also pouring into other centers, including those of other investigators and coauthors of the study, which was published online in The New England Journal of Medicine2 to coincide with the ASCO presentation. “Their centers are also getting many calls, and they are working to get patients in and on the trial if they can. Clearly the melanoma centers across the country are feeling the stress of patients wanting access to a very exciting drug,” he said. “Melanoma impacts younger people in the prime of their lives, and without any other good treatment options, it makes total sense that they would quickly try to get to centers where they could get access to potentially lifesaving drugs.”

Significant Survival Differences The study’s reported survival differences with ipilimumab were significant.

Patients who received ipilimumab, either with or without an experimental melanoma peptide vaccine, had “nearly doubled 1-year and 2-year survival rates” compared to patients receiving the vaccine alone, Dr. O’Day said. Median overall survival was 6.4 months among patients receiving the vaccine alone and 10.1 among patients receiving ipilimumab alone. (For a detailed report on the study, see the July issue of The ASCO Post, page 1.)

“What’s really important” about the survival curves, Dr. O’Day pointed out, is that they show that ipilimumab “is not only improving average survival in a disease that has never been shown to have improved survival at all, but the tail of the curve appears to plateau after about 2 years. In the study that was presented, survival was up to 4½ years, but we have other trials that are now 7 and 8 years out.

With ipilimumab in metastatic melanoma, we now have patients who are longterm survivors, meaning beyond 5 years.”

The phase III study results are consistent with the results from earlier phase II studies with ipilimumab suggesting long-term survival effects.

“This drug was tested extensively in phase II trials, and the median and long-term survival findings in this recent study were nearly identical to results in more than 1,400 patients who were part of the phase II trials,” Dr. O’Day said. “The median survival from those phase II studies was anywhere from 10 months to 15 months and the survival rates were approximately 50% at 1 year and 25% at 2 years. It is continued on page 36

The ASCO Post | AUGUST 2010

PAGE 36

In the News

Advanced Melanoma continued from page 35

reassuring that it’s not just one study, but multiple studies are showing these very impressive survival results.”

May Not Be Optimal Dose “I think what is really fascinating,” he added, “is that most of the phase II data from the 1,400 patients was with a higher dose of the drug: 10 mg as opposed to 3 mg. We did a study of three different dose levels—0.3 vs 3 vs 10 mg—and the

10-mg dose looks a little bit better than 3 mg. So we may be below the optimal dose. We may not even be using the most effective dose of this drug yet. That makes it even more impressive.”

A study comparing ipilimumab at 10 mg and dacarbazine (DTIC-Dome) chemotherapy vs dacarbazine and placebo as first-line treatment for metastatic stage IV melanoma “has been completed, and hopefully we should get results within the next 12 months,” Dr. O’Day said.

An ongoing study is testing ipilimumab

in patients with stage III resected disease.

“These patients are at high risk for metastases,” Dr. O’Day said, and “are being randomized to 10 mg of ipilimumab vs placebo. The European Organisation for Research and Treatment of Cancer (EORTC) is conducting the study internationally, but many U.S. sites are participating, including The Angeles Clinic and Research Institute.

Patients continue to be recruited for study, which Dr. O’Day said had an accrual goal of 950 patients.

■

In the Literature

References 1. O’Day S, Hodi FS, McDermott DF, et al: A phase III, randomized, double-blind, multicenter study comparing monotherapy with ipilimumab or gp100 peptide vaccine and the combination in patients with previously treated, unresectable stage III or IV melanoma. 2010 ASCO Annual Meeting. Abstract 4. Presented June 6, 2010.

2. Hodi FS, O’Day SJ, McDermott DF, et al: Improved survival with ipilimumab in patients with metastatic melanoma. N Engl J Med. June 5, 2010 (epub ahead of print).

Emerging Clinical Data on Cancer Diagnosis and Management LUNG CANCER First-line Gefitinib Improves Progression-free Survival in Patients with Mutated EGFR and Advanced NSCLC First-line treatment with the tyrosine kinase inhibitor (TKI) gefitinib (Iressa) improved progression-free survival (PFS) in patients with advanced non–small cell lung cancer (NSCLC) who were selected on the basis of sensitive epidermal growth factor receptor (EGFR) mutations, according to results of a phase III prospective, randomized study. The study demonstrated that “the use of gefitinib results in progressionfree survival that is twice as long as that obtained with the use of carboplatin– paclitaxel” in patients with mutatedEGFR NSCLC, the authors reported.

Moreover, gefitinib was associated with a “tolerable toxicity profile, including less hematologic toxicity and neurotoxicity than is seen with chemotherapy.”

Previous studies had suggested that EGFR TKIs are effective against mutated-EGFR NSCLC and that subgroups of patients with NSCLC with sensitivity to gefitinib had a high incidence of EGFR mutations. The authors therefore “hypothesized that selecting patients on the basis of EGFR mutations rather than clinical factors would result in a population with a greater sensitivity to gefitinib.” The investigators developed a rapid and sensitive method to detect sensitive EFGR mutations.

Study patients had advanced NSCLC and were younger than 75 years old. Half of the 230 patients, enrolled from 43 institutions in Japan, were randomly assigned to receive gefitinib at 250 mg/d orally and the other half were given standard chemotherapy with paclitaxel and carboplatin.

Two Analyses The preplanned interim analysis found a significant difference in PFS between the two treatment groups, resulting in early termination of the study.

The final analysis also showed a significant difference in PFS: 10.8 months in the gefitinib group vs 5.4 months for in the standard chemotherapy group (P < .001). The 1-year PFS rates were 42.1% in the gefitinib group vs 3.2% in the chemotherapy group and the 2-year rates were 8.4% in the gefitinib group vs 0% in the chemotherapy group. The objective response rate was significantly higher in the gefitinib group (73.7% vs 30.7% in the chemotherapy group).

Overall survival did not differ significantly, with a median survival time and 2-year survival rate of 30.5 months and 61.4% in the gefitinib group and 23.6 months and 46.7% in the chemotherapy group.

“Selection of patients on the basis of EGFR-mutation status is strongly recommended,” the authors concluded. They noted, however, that the best timing for treatment remains undetermined, and that the efficacy of first-line vs later use of gefitinib “needs to be tested in studies with large samples or in a meta-analysis.”

Maemondo M, et al: N Engl J Med 362:2380-2388, 2010.

HEAD AND NECK CANCER Positive HPV Status Is Strong Prognostic Factor for Survival in Patients with Oropharyngeal Cancer Patients with oropharyngeal tumors with a positive human papillomavirus (HPV) status had better 3-year rates of overall survival and a reduced risk of death compared to those with HPV-

negative tumors followed in a retrospective analysis of patients with stage III or IV oropharyngeal squamous cell carcinoma. The study authors concluded that “tumor HPV status is a strong and independent prognostic factor for survival among patients with oropharyngeal cancer.”

The patients were enrolled in the Radiation Therapy Oncology Group (RTOG) 0129 study. The randomized trial compared accelerated-fractionation radiotherapy with standardfractionation radiotherapy—each regimen was combined with cisplatin therapy—among patients with untreated, pathologically confirmed stage III or IV squamous cell carcinoma of the oral cavity, oropharynx, hypopharynx, or larynx without distant metastases.

HPV tumor status was analyzed only for patients with oropharyngeal squamous cell carcinoma because of the low prevalence of HPV among the other tumor types. The majority of patients (433 of 721, or 60.1%) did have oropharyngeal squamous cell carcinoma, and HPV status was determined for 323 (74.6%) of those patients. The post hoc analysis was not part of the RTOG 0129 protocol.

Four Predictive Factors At a median follow-up of 4.8 years, the 3-year rate of overall survival was similar in the groups receiving accelerated-fractionation or standard-fractionation radiotherapy (70.3% vs 64.3%; P = .18). Proportional-hazards models were used to compare the risk of death according to HPV status. Patients with HPV-positive tumors (206, or 63.8%) had better 3-year rates of overall survival (82.4% vs 57.1%) than those with HPV-negative tumors (P < .001, by log-rank test). The 3-year rates of progression-free survival were 73.7% for

patients with HPV-positive tumors and 43.4% for those with HPV-negative tumors. After adjustment for age, race, tumor and nodal stage, tobacco exposure, and treatment assignment, patients with HPV-positive tumors had a 58% reduction in the risk of death (HR = 0.42; 95% CI = 0.27–0.66).

Using recursive-partitioning analysis, the authors classified patients as having a low, intermediate, or high risk of death on the basis of four factors: HPV status, pack-years of tobacco smoking, tumor stage, and nodal stage.

“Though no direct evidence from formal clinical trials exists to guide treatment decisions for the individual patient on the basis of tumor HPV status, this study provides a direction for future clinical research,” the authors noted. “Should our risk model be validated in other cohorts, it will be important to incorporate tumor HPV status and tobacco exposure as nonantatomical determinants of risk classification and therapy selection for patients with oropharyngeal squamous cell carcinoma,” they concluded.

Ang KK, et al: N Engl J Med 363:24-35, 2010.

BREAST CANCER Bevacizumab plus Docetaxel Improves PFS in Women with HER2-negative Breast Cancer The addition of bevacizumab (Avastin), 15 mg/kg every 3 weeks, to docetaxel significantly improved progression-free survival (PFS) in women with HER2-negative, locally recurrent or metastatic breast cancer, according to an updated analysis of the Avastin and Docetaxel (AVADO) study. The randomized, double-blind phase III study randomly assigned 736

ASCOPost.com | AUGUST 2010

PAGE 37

In the Literature

patients who had not received chemotherapy for metastatic disease to receive docetaxel at 100 mg/m2 and either placebo or bevacizumab at 7.5 or 15 mg/kg every 3 weeks.

The combination including bevacizumab at the 15 mg/kg dose showed superior median PFS, the primary endpoint of the study. In the updated, stratified analysis, median PFS times were 8.1 months with placebo, 9 months with the 7.5 mg/kg bevacizumab dose (HR = 0.80; P = .045), and 10 months for the 15 mg/kg bevacizumab dose (HR = 0.67; P < .001).

Clinical Benefit Confirmed Response rates in patients with measurable disease at baseline were best with bevacizumab at 15 mg/kg (64%), compared with 55% for bevacizumab at 7.5 mg/kg and 46% for placebo. Overall survival was similar in all three treatment arms, with medians of 31 months, although the trial was not powered or designed to detect a survival difference.

“One-year survival was numerically higher in both bevacizumab arms than in the placebo arms,” the authors reported, and this increase reached statistical significance for bevacizumab at 15 mg/kg arm (P = 0.2). The combination with bevacizumab had limited impact on the known toxicity profile of docetaxel.

“This randomized, double-blind study confirmed the clinical benefit of combining bevacizumab with a taxane, as previously reported in trial E2100,” the authors stated. E2100 used a combination of bevacizumab and weekly paclitaxel. “Comparison of median PFS in these two trials appears to favor the combination with paclitaxel,” they added. “Taken together with the results of the E2100 study, these data suggest

that the combination of bevacizumab with taxane chemotherapy should be considered as an option for the firstline treatment of HER2-negative [metastatic breast cancer].”

Miles DW, et al: J Clin Oncol 28:32393247, 2010.

CERVICAL CANCER Pazopanib Demonstrates Benefit in Patients With Advanced Cervical Cancer Pazopanib (Votrient) improved progression-free survival (PFS) and overall survival (OS) among women with advanced and recurrent cervical cancer enrolled in a phase II, openlabel study comparing pazopanib or lapatinib (Tykerb) monotherapy to combined therapy with the two agents.

Pazopanib is an oral multitargeted antivascular agent and lapatinib is an oral dual anti–epidermal growth factor receptor (EGFR) and anti-HER2/neu tyrosine kinase inhibitor.

“Cervical cancer is heavily dependent on angiogenesis, perhaps even more so than most solid tumors,” the authors pointed out. “Most studies,” they added, conclude that the overexpression of EGFR and HER2/neu in cervical tumors is associated with poor outcomes.”

‘Futility Boundary’ Crossed In the current study, 230 patients with measurable stage IVB persistent/ recurrent cervical carcinoma not amenable to curative therapy and who had received at least one previous chemotherapy regimen for metastatic disease were randomly assigned to pazopanib at 800 mg once daily, lapatinib at 1,500 mg once daily, or lapatinib plus pazopanib combination therapy. The com-

©Charles Barsotti/The New Yorker Collection/www.cartoonbank.com

bined therapy was discontinued at the planned interim analysis because “the futility boundary was crossed” for combination therapy vs lapatinib monotherapy, and the combination led to serious adverse effects.

Pazopanib improved both PFS (the primary endpoint of the study) and OS. Median PFS was 17.1 weeks for patients receiving lapatinib vs 18.1 weeks for patients receiving pazopanib (P < .013) Median OS was 39.1 weeks for patients receiving lapatinib vs 50.7 weeks for patients receiving pazopanib (P = .045). Most adverse effects were grade 1 or 2.

“This study confirms the activity of antiangiogenesis agents in advanced and recurrent cervical cancer and demonstrates the benefit of pazopanib based on the prolonged PFS and favorable toxicity profile,” the authors concluded.

Monk BJ, et al: J Clin Oncol July 6, 2010 (early release online).

DRUG SAFETY Safety Project Seeks to Ensure Safe Prescribing of Oral Chemotherapy The increasing use of oral chemotherapy agents, coupled with a narrow, dose-dependent safety margin of agents such as capecitabine (Xeloda) and temozolomide, prompted the launching of a safety project at the Mayo Clinic in Rochester, Minnesota, “to ensure that each prescription for capecitabine and temozolomide receives an independent double check.”

As formulated by a multidisciplinary task force, the “double check required that an oncology pharmacist review an electronic version of the patient’s prescription; make sure that the prescription given to the patient included the correctly calculated, clinically appropriate dose, which was in alignment with the previously published, internally approved chemotherapy regimens described earlier; and discuss and resolve dose discrepancies directly with the prescribing healthcare provider in a timely manner.” A discrepancy of 10% or greater between prescribed and intended dose would prompt a telephone call and electronic message to the prescribing health-care provider. “In turn, the pharmacist was to provide medical record documentation that a double check had occurred with a description of outcome,” the task force decided.

The task force worked with technology staff to receive a download from the outpatient electronic prescribing system by 6 AM the following day of all patients who had received a capecitabine or temozolomide prescription. This download enabled oncology pharmacy staff to double check dosing as a highpriority, daily task. Electronic ordering systems also enabled health-care providers to offer clinical justification for dose modifications, making it easier for pharmacy staff to understand their rationale. The early detection and rapid correction of any dose discrepancy was considered a “near miss.”

Capecitabine Dose Discrepancies Over 4 months, these new safety mechanisms detected 12 prescriptions with a 10% or greater discrepancy from the intended dose, yielding monthly near-miss rates of 3.7%, 4%, 1.7%, and 0.8%. “Although more temozolomide than capecitabine prescriptions were issued, the problematic drug in all but one of these situations was capecitabine,” according to the project’s preliminary outcomes report.

“Capecitabine dose discrepancies involved treatment duration, frequency of dosing, and incorrect data for the calculation, such as the wrong height and/or weight. None of these discrepancies represented a nonsensical, extremely high dose, and most appeared to trend toward underdosing. A review of the medical records of patients with a 10% or greater dose discrepancy did not provide evidence of compromised clinical outcomes attributable to the near miss,” the report’s authors noted.

The study found that a safety double check can be accomplished and that “more importantly, a safety double check is, in fact, valuable,” the authors concluded. “After 1 month, our nearmiss rate was 3.7%, but it improved, perhaps because health-care providers learned of their shortcomings and subsequently strove to improve their prescribing practices. This high rate raises the question of what might have happened had we not implemented safety mechanisms.” The safety double check is now “an inherent part of the Mayo Clinic infrastructure within the Division of Medical Oncology, and it serves to ensure the safe and accurate prescribing of these drugs,” the authors reported. “Over time, we anticipate the potential expansion of this double check to include other oral agents.”

Jatoi A, et al: J Oncol Pract 6:210-212, 2010.

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ASCOPost.com | AUGUST 2010

PAGE 39

News Renal Cell Cancer

Challenges Remain for Use of Targeted Therapies in Renal Cell Cancer

By Barbara Boughton

N

ovel targeted therapies have extended survival for patients with renal cell cancer, and provide the practicing oncologist with a new array of treatment options. Although clinical data about the effectiveness of targeted therapies for both treatment-naive and metastatic renal cell cancer patients is increasingly robust, questions remain about how to choose among them, according to sev-

Elisabeth I. Heath, MD

eral speakers at an educational session of the 2010 Genitourinary (GU) Cancers Symposium.1 The toxicities associated with targeted therapies are generally manageable, but the use of these agents requires proactive monitoring, researchers at the symposium commented. The 2010 Genitourinary Cancers Symposium was cosponsored by ASCO, the American Society for Therapeutic Radiology and Oncology, and the Society of Urologic Oncology.

Research Limitations Targeted therapies, including vascular endothelial growth factor (VEGF) inhibitors like sorafenib (Nexavar) and mammalian target of rapamycin (mTOR) inhibitors such as temsirolimus (Torisel), have improved survival rates among metastatic renal cell cancer patients—extending average lifespan to 2 years, according to Gary R. Hudes, MD, of the Fox Chase Cancer Center. But questions about how to compare these targeted agents and how to use them in practice have still not been entirely resolved, he noted. Very few clinical trials have compared targeted therapies head-tohead, although a number of comparative phase III trials—as well as those that are studying targeted therapies in combination—are ongoing, Dr. Hudes said. He also noted that a study published in the Journal of Clinical Oncology in 2009 found that choice of initial therapy did not impact overall survival in renal cell cancer patients.2 “We have an increasing number of options especially for favorable- and intermediate-risk patients, but optimal therapy is not yet well defined,” Dr. Hudes said.

“We need comparative efficacy and tolerability trials, as well as those that study these agents in combination and in the adjuvant setting,” he said.

Choosing Targeted Agents for Renal Cell Cancer ■■ New targeted therapies have expanded the effective treatment options for treatment-naive and metastatic renal cell cancer patients. However, questions remain about how to choose among targeted therapies, and how they might best be used in combination.

■■ Clinical evidence on targeted therapies for metastatic renal cell cancer varies from robust to limited, but patient convenience and insurance issues are also important when choosing therapies.

■■ Proactive monitoring and early management of treatment-related side

effects such as hypertension, skin changes, and metabolic toxicities are necessary for patients to get the full benefit of targeted therapies.

Treatment of refractory or resistant metastatic renal cell cancer, however, continues to be challenging for clinicians, according to Elisabeth I. Heath, MD, of the Karmanos Cancer Institute at Wayne State University in Detroit.

A growing number of FDA-approved targeted therapies are available in the metastatic setting, and it can be difficult to judge which to use for patients who have failed previous therapies.

VEGF inhibitors for metastatic renal cell cancer include sorafenib, sunitinib (Sutent), bevacizumab (Avastin), and pazopanib (Votrient).

Of these agents, sorafenib has the most robust clinical data supporting its use in metastatic renal cell carcinoma after failed cytokine therapy, Dr. Heath

said. In the phase III TARGET investigation (Treatment Approaches in Renal Cancer Global Evaluation Trial), sorafenib therapy resulted in a significantly improved progression-free survival, and in an expanded access study of patients with advanced renal cell cancer, sorafenib resulted in prolonged stable disease, Dr. Heath said.3 Among the mTOR inhibitors, minimal evidence supports the use of temsirolimus for metastatic renal cell cancer, but significant data also exist regarding the use of everolimus (Afinitor) in post–targeted therapy failure as well as post–cytokine therapy failure, according to Dr. Heath. One phase III trial of everolimus compared with continued on page 40

Related Abstracts from the 2010 ASCO Annual Meeting

U

se your smartphone to view selected renal cell cancer abstracts via the See page 42 2D barcode. For more information about the 2D barcode, see page 42.

Sorafenib Trials 4589: Updated results of an Italian study comparing sorafenib (Nexavar) plus interleukin (IL)-2 vs sorafenib alone in first-line treatment for metastatic renal cell carcinoma demonstrated that the combination was feasible, producing a 1-year progression-free survival (PFS) rate of 31.6 %, vs 28.9 % for sorafenib monotherapy. Subgroup analysis suggested that good-prognosis patients benefit more from the addition of IL-2 (PFS = 47.4% vs 32.1%).

4628: As previously reported from the phase II RAPSODY trial, patients with metastatic renal cell carcinoma achieved a significantly improved median PFS when treated with sorafenib plus interferon alfa-2a (Roferon A).

In this follow-up analysis of predictive factors, the researchers found that baseline vascular endothelial growth factor receptor (VEGFR)-2 level (median overall value = 8.108 pg/mL) predicted for an improved median PFS (P = .013).

Temsirolimus/Bevacizumab Trial 4516: In the French TORAVA phase II trial, evaluating the combination of temsirolimus (Torisel) plus bevacizumab (Avastin) in patients with metastatic renal cell carcinoma, the toxicity profile of the combination proved higher than expected, leading

to a high dropout rate. Moreover, the investigators reported, the study results do not suggest evidence of any additive efficacy for the two drugs.

Everolimus Trials 4608: The international RECORD-1 study demonstrated significant efficacy for everolimus (Afinitor) in elderly patients with metastatic renal cell carcinoma after treatment with VEGFR tyrosine kinase inhibitors (TKIs) failed. The drug decreased risk of disease progression by 67% compared with placebo (P < .001)—similar to results seen in the general patient population.

4611: Based on an indirect comparison of everolimus and sorafenib in patients with sunitinib-refractory metastatic renal cell carcinoma (from the RECORD-1 trial and a phase II Italian study), investigators reported the esti-

mated incremental life-years gained for patients treated with everolimus vs sorafenib was 1.135 years. They concluded that a survival benefit might exist with the use of everolimus compared to sorafenib in this population.

4690: Given the crossover design of RECORD-1, investigators believed the treatment effect of everolimus might have been underestimated. Using a rank-preserving structural failure time (RPSFT) model—whereby each day spent on everolimus is assumed to prolong survival time compared to a day spent on placebo, by a multiplicative factor—these authors confirmed the survival benefit for patients with VEGFR-TKI–refractory metastatic renal cell carcinoma treated with the drug.

■

The ASCO Post | AUGUST 2010

PAGE 40

News

Targeted Therapies in RCC continued from page 39

placebo found few objective responses but a significant improvement in progression-free survival.4 Ongoing trials are also testing the effectiveness of combination therapies, and research has led to new agents that target novel pathways involved in renal

cell cancer. “The list of emerging targets is tremendous, and not all are related to mTOR or VEGF,” Dr. Heath said. When deciding upon treatment choices for patients with metastatic disease, clinical data should be considered important— but so should the mechanisms of biologic resistance, patient convenience, and insurance questions, she added.

Monitoring and Managing Toxicities Although targeted therapies offer the promise of improved efficacy for renal cell cancer patients, they come with mild to moderate toxicities, according to Thomas E. Hutson, DO, PharmD, of the Baylor Sammons Cancer Center and Texas Oncology

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If you completed your final subspecialty training between 2001 and 2006 and are interested in becoming a future leader in ASCO, our Leadership Development Program is for you.

Participants in this yearlong program will learn valuable leadership skills and gain exposure to the roles and mission of ASCO and the Society’s powerful place in developing the future of cancer care.

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*Application Criteria: Applicants must be active members of ASCO, have completed their final subspecialty training between 2001 and 2006, and be a physician (MD, DO or international equivalent with explanation) who is licensed and resides in North America. Each applicant must demonstrate service or leadership involvement in outside activities beyond clinical and/or academic experience.

The application process requires a letter of support from a supervisor or senior member from your institution, and a brief essay explaining your desire to be part of the program. If your letter of support is not from a current ASCO member, you must submit a secondary letter of support from a member of ASCO. Leadership Development Program participants will be reimbursed for most travel and housing costs incurred through the program.

in Dallas. Because these agents are not curative and must be administered chronically, management of toxicities is an important issue. Some of the toxicities associated with targeted agents include cardiovascular disorders such as hypertension, skin conditions, and changes in glucose and cholesterol metabolism, Dr. Hutson said. Cardiovascular toxicity appears to be linked to VEGF inhibition, and the development and severity of hypertension is thought to reflect the extent of target inhibition, Dr. Hutson said. As many as 50% of patients on VEGF and mTOR inhibitors also experience skin changes such as hand-foot syndrome, skin rashes, and mucositis/functional stomatitis, he added. Alterations in glucose and cholesterol metabolism are unique and expected toxicities of the mTOR inhibitors.

Management of toxicities requires regular monitoring and early intervention, Dr. Hutson said. Antihypertensive therapy and, in severe cases, temporary suspension of therapy may be required to control hypertension.

Skin toxicities can be managed with supportive and palliative interventions, as well as education of the patient and caregiver regarding early and prompt recognition of skin changes.

Oncologists should also monitor patients carefully for metabolic toxicities, and these side effects may require diet modification, initiation of insulin, oral agents for glycemic control, or lipidlowering agents. “Optimal treatment with targeted agents requires proactive intervention and management of side effects to avoid dose reductions or interruptions, and to make sure that patients get the full benefit of these therapies,” Dr. Hutson said.

■

References 1. Genitourinary Cancers Symposium.

General Session VIII: Renal Cancer— Metastatic Renal Cell Carcinoma. Presented March 7, 2010.

2. Heng DY, Xie W, Regan MM, et al: Prognostic factors for overall survival in patients with metastatic renal cell carcinoma treated with vascular endothelial growth factor-targeted agents: Results from a large, multicenter study. J Clin Oncol 27:5794-5799, 2009.

3. Escudier B, Eisen T, Stadler WM, et al: Sorafenib in advanced clear-cell renal-cell carcionoma. N Engl J Med 356:125-134, 2007.

4. Motzer RJ, Escudier B, Oudard S, et al: Efficacy of everolimus in advanced renal cell carcinoma: A double-blind randomized placebo-controlled phase III trial. Lancet 372:449-456, 2008.

ASCOPost.com | AUGUST 2010

PAGE 41

News Survivorship

For Childhood Cancer Survivors, Anthracycline-related Cardiac Toxicity Modulated by CBR Genotypes

By Caroline Helwick

S

urvivors of childhood cancer who were treated with anthracyclines are likely to develop cardiomyopathy years later, the Children’s Oncology Group reported at the 2010 ASCO Annual Meeting. The risk is increased among those who received low doses of anthracyclines, if they carry particular variants of the carbonyl reductase genes (CBR1 and CBR2), said senior author Smita Bhatia, MD, MPH, Professor and Chair of the Department of Population Sciences at the City of Hope National Medical Center, Duarte, California.

“Although we depend heavily on anthracyclines for treating children with cancer, we are fully aware of their toxic effects to the heart. We also know that some patients, despite exposure to higher doses, don’t develop heart problems while others with little exposure have considerable cardiac damage,” she said at an ASCO press briefing.

The findings may guide a more personalized approach to preventing cardiac toxicity associated with anthracyclines.

CBRs are enzymes that help metabolize anthracyclines into substances that can damage the heart. Variants in the CBR1 and CBR3 genes are known

to affect the enzyme’s activity. Dr. Bhatia and colleagues examined the potential effects of the CBR1 and CBR3 variants on cardiomyopathy risk.

Their investigation was a case-control study of 165 childhood cancer survivors who developed cardiomyopathy and 323 cancer survivor controls with no heart disease, constituting the largest case series of documented cardiomyopathy. Participants were diagnosed with cancer between 1966 and 2008, and approximately 80% were treated after 1981. Mean time from the primary diagnosis was 7 years.

Low Doses Associated with High Risk for Certain Genotypes “There was a clear dose-response relationship when the anthracycline dose was treated as a discrete variable,” noted Javier G. Blanco, PhD, who presented the data at the 2010 ASCO Annual Meeting.1 Dr. Blanco is Associate Professor of Pharmaceutical Sciences, State University of New York at Buffalo.

After adjustment for age at diagnosis, gender, radiation to the heart, race, ethnicity and other factors, the investigators calculated the odds of devel-

Expert Point of View

M

elissa M. Hudson, MD, of the Division of Cancer Survivorship at St. Jude Children’s Research Hospital in Memphis, Tennessee, commented on this “relatively rare but potentially life-threatening outcome of childhood cancer survivors,” noting that the findings were “very exciting” in that they may allow for personalization of treatment.

The unique observation of a clear associaMelissa M. Hudson, MD tion between anthracycline-related cardiac toxicity and genotype, she said, helps to explain the rather baffling observation of heart disease on the heels of low drug exposure. Knowing that certain patients may be genetically predisposed should foster interventional approaches to prevent this.

■

Genotype and Anthracycline Cardiotoxicity ■■ Cumulative anthracycline exposure in the treatment of childhood can-

cers raises the risk of cardiomyopathy, in a dose-dependent fashion, by as much as 22-fold, a large matched control study found.

■■ Specific CBR1 and CBR3 genotypes render patients more susceptible to cardiac damage at low exposures.

■■ The findings raise interest in personalizing the use of anthracyclines in

the treatment of childhood cancers, instituting preventive measures for persons deemed at highest risk.

oping cardiomyopathy, based on total cumulative anthracycline exposure compared to no exposure and found odds ratios of: ■■ 2.02 for 1 to 100 mg/m2 ■■ 3.56 for 101 to 200 mg/m2 ■■ 11.43 for 201 to 300 mg/m2 ■■ 22.32 for 301 mg/m2 and higher More interesting was the effect of CBR genotype on risk. Among children with cardiomyopathy who received anthracyclines in high doses (> 250 mg/m2), the CBR genes had little effect on cardiomyopathy risk since the risk was already high due to the cumulative exposure. But among those who developed cardiomyopathy after receiving low doses (< 250 mg/ m2), both CBR1 and CBR3 variants increased the risk for cardiac damage, Dr. Blanco reported at the pediatric oncology session.

When 250 mg/m2 was used as the cut-off for high vs low exposure, subjects carrying two copies of the CBR1 and CBR3 variant (GG genotype) had a 6.48-fold increased risk compared to just 1.75 for those with one or no copies (GA or AA genotype). However, at doses higher than 250 mg/m2, the high-risk variant carried an odds ratio of 16.76, which was lower than the odds ratio of 22.33 for those without the variant. The trend is consistent across all dose groups.

By variant in an adjusted analysis, the odds ratios were 5.3 for CBR1, 3.1

for CBR3, and 4.8 for CBR1/3 combined, at doses up to 250 mg/m2.

“We identified the impact of CBR1 and CBR3 genotype status on anthracycline-related cardiomyopathy, and it occurs only among those exposed to lower cumulative doses,” he concluded.

Dr. Blanco said the findings have meaning in terms of possible interventions. “Among patients who need exposures lower than 250 mg/m2, such as those treated for acute lymphoblastic leukemia or Hodgkin lymphoma, primary prevention is important, and we See page 42 could individualize therapy, perhaps using genotyping and noncardiotoxic alternatives.

For children requiring higher doses, such as for acute myeloid leukemia or sarcoma, the emphasis would be on secondary prevention, perhaps with cardioprotectants, risk-based surveillance, and pharmacologic interventions to ameliorate the development of cardiotoxicity.”

■

Reference 1. Blanco JG, Sun C, Landier W, et al: Anthracycline-related cardiomyopathy in childhood cancer survivors and association with polymorphisms in the carbonyl reductase genes: A Children’s Oncology Group study. 2010 ASCO Annual Meeting. Abstract 9512. Presented June 7, 2010.

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The ASCO Post | AUGUST 2010

PAGE 42

Appointments

Recess Appointment of Donald Berwick, MD, MPP, to Lead CMS Announced In a recess appointment, President Barack Obama recently named Dr. Donald Berwick Chief of the Center for Medicare and Medicaid Services (CMS). Dr. Berwick is President and Chief Executive Officer of the Institute for Healthcare Improvement, Clinical Professor of Pediatrics and Health Care Policy at the Harvard Medical School, and Professor of Health Policy and Management at the Harvard School of Public Health. He is also a pediatrician, adjunct staff in the Department of Medicine at Boston’s Children’s Hospital and a consultant in pediatrics at Massachusetts General Hospital. Dr. Berwick has served as Chair of the National Advisory Council of the Agency

for Healthcare Research and Quality, and as an elected member of the Institute of Medicine.

Barbara McAneny, MD, Newly Elected to the AMA Board of Trustees Dr. Barbara L. McAneny was recently elected as the newest member of the Board of Trustees of the American Medical Association (AMA). Dr. McAneny’s experience includes serving as President of the New Mexico Medical Society and the New Mexico Chapter of the American College of Physicians. She previously served on the ASCO Board of Directors and the Practicing Physicians’ Advisory Council, a congressionally designated physician committee that advises Health and Human Services on Medicare. Currently,

she acts as Chair of the AMA Council on Medical Service, serves on the Specialty and Service Society Governing Council and is the delegate for ASCO. Dr. McAneny is cofounder of her multidisciplinary oncology practice and manages the New Mexico Cancer Center. Dr. McAneny’s term on the Board will last 4 years.

Harold E. Varmus, MD, Sworn in as NCI’s 14th Director Dr. Harold E. Varmus recently took the oath of office to become NCI’s 14th Director. Dr. Varmus was director of NIH from 1993 until the end of 1999. During his tenure at NIH, Varmus helped to initiate a 5-year doubling of the NIH budget. More recently, President Barack Obama appointed him cochair of the President’s Council of

Advisors on Science and Technology.

Dr. Varmus spent 23 years as a faculty member at the University of California, San Francisco, Medical School, where he worked on the replication cycles of retroviruses and hepatitis B viruses, the functions of genes implicated in cancer, and the development of mouse models of human cancer. Dr. Varmus was corecipient of the Nobel Prize in Physiology or Medicine in 1989 for studies of the genetic basis of cancer. He most recently served as President of Memorial Sloan-Kettering Cancer Center in New York City.

Watch for additional coverage of these important appointments in future issues of The ASCO Post.

What Are Two-Dimensional Barcodes? two-dimensional (2D) barcode, also known as a matrix code, is a graphic image that contains information stored both horizontally (like the one-dimensional UPC used in supermarkets) and vertically. The added dimension in a 2D barcode enables the image to represent thousands of characters—essentially a portable database—compared with only 10 to 20 characters stored in the conventional unidimensional barcode. Given that added capacity, 2D barcodes are increasingly being used for fast data access in a variety of settings, and in documents from drivers’ licenses to tax returns.

Perhaps not surprisingly, the real boom in 2D barcode use has been in mobile marketing. Companies have developed technology that enables camera phones to scan matrix codes from a website, print publication, or poster. The consumer can then access content embedded in the code or be redirected to targeted content via the phone’s Web browser.

The 2D barcodes used in this issue of The ASCO Post will connect readers to further information about the articles they are reading. For instance, a report from the ASCO Annual Meeting may include a barcode that will connect readers online to the original abstract of the study discussed. In this way, the editors of The ASCO Post hope to provide readers with further resources and validated information about the news in these pages.

Find examples of 2D barcodes on the pages of this issue.

Using the ScanLife application (see right), scan these codes with your camera phone, and see where they bring you.

Watch for more barcodes in future issues of The ASCO Post.

Important: Getting the application There are 3 ways to download the ScanLife application.

1. Simply text the word “scan” to 43588.

Or 2. 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”.

Or 3. Visit the application store for your smartphone (such as the iTunes Store or the Android Market).

The application is free, though standard data rates for your phone do apply.

Scanning 2D codes When you see a code that 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 of 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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AVASTINÂŽ (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).]

Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis.

[See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTINÂŽ (bevacizumab) Suspend Avastin administration for â&#x2030;Ľ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in SpeciďŹ c Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).]

5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients.

Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy.

[See Dosage and Administration (2.4).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: t Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] t 4VSHFSZ BOE 8PVOE )FBMJOH $PNQMJDBUJPOT [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] t )FNPSSIBHF [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] t /PO (BTUSPJOUFTUJOBM 'JTUVMB 'PSNBUJPO [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] t "SUFSJBM 5ISPNCPFNCPMJD &WFOUT [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] t )ZQFSUFOTJWF $SJTJT [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] t 3FWFSTJCMF 1PTUFSJPS -FVLPFODFQIBMPQBUIZ 4ZOESPNF [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] t 1SPUFJOVSJB [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

The most common adverse reactions observed in Avastin patients at a rate > 10% and at least twice the control arm rate, are epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain and exfoliative dermatitis.

Across all studies, Avastin was discontinued in 8.4 to 21% of patients because of adverse reactions.

6.1 Clinical Trial 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 Avastin in 2661 patients with mCRC, non-squamous NSCLC, MBC, glioblastoma, or mRCC in controlled (Studies 1, 2, 4, 5, 6 and 9) or uncontrolled, single arm (Study 7) trials treated at the recommended dose and schedule for a median of 8 to 16 doses of Avastin. [See Clinical Studies (14).] The population was aged 21-88 years (median 59), 46.0% male and 84.1% white. The population included 1089 first- and second-line mCRC patients who received a median of 11 doses of Avastin, 480 first-line metastatic NSCLC patients who received a median of 8 doses of Avastin, 592 MBC patients who had not received chemotherapy for metastatic disease received a median of 8 doses of Avastin, 163 glioblastoma patients who received a median of 9 doses of Avastin, and 337 mRCC patients who received a median of 16 doses of Avastin.

Surgery and Wound Healing Complications The incidence of post-operative wound healing and/or bleeding complications was increased in patients with mCRC receiving Avastin as compared to patients receiving only chemotherapy.

Among patients requiring surgery on or within 60 days of receiving study treatment, wound IFBMJOH BOE PS CMFFEJOH DPNQMJDBUJPOT PDDVSSFE JO PG QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP PG QBUJFOUT XIP SFDFJWFE CPMVT *'- BMPOF In Study 7, events of post-operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage 5IF JODJEFODF PG FQJTUBYJT XBT IJHIFS WT JO QBUJFOUT XJUI N$3$ SFDFJWJOH CPMVT *'- QMVT "WBTUJO DPNQBSFE XJUI QBUJFOUT SFDFJWJOH CPMVT *'- QMVT QMBDFCP "MM CVU POF PG UIFTF FWFOUT were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic FWFOUT XFSF NPSF GSFRVFOU JO QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO XIFO DPNQBSFE UP UIPTF SFDFJWJOH CPMVT *'- QMVT QMBDFCP BOE JODMVEFE HBTUSPJOUFTUJOBM IFNPSSIBHF WT NJOPS gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving DIFNPUIFSBQZ BMPOF *O 4UVEZ QBUJFOUT PO UIF CPMVT *'- QMVT "WBTUJO BSN BOE QBUJFOUT PO UIF CPMVT *'- QMVT QMBDFCP BSN SFDFJWFE GVMM EPTF XBSGBSJO GPMMPXJOH B venous thromboembolic event. Among these patients, an additional thromboembolic event PDDVSSFE JO PG QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BOE PG QBUJFOUT SFDFJWJOH CPMVT *'- BMPOF The overall incidence of Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events in Study 1 was 15.1% in patients SFDFJWJOH CPMVT *'- QMVT "WBTUJO BOE JO QBUJFOUT SFDFJWJOH CPMVT *'- QMVT QMBDFCP *O Study 1, the incidence of the following Grade 3â&#x20AC;&#x201C;4 venous thromboembolic events was higher in QBUJFOUT SFDFJWJOH CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP QBUJFOUT SFDFJWJOH CPMVT *'- QMVT placebo: deep venous thrombosis (34 vs. 19 patients) and intra-abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of (SBEF PS OFVUSPQFOJB XBT JODSFBTFE JO N$3$ QBUJFOUT SFDFJWJOH *'- QMVT "WBTUJO

DPNQBSFE UP QBUJFOUT SFDFJWJOH *'- BMPOF *O 4UVEZ UIF JODJEFODF PG (SBEF neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus "WBTUJO DPNQBSFE XJUI QBUJFOUT SFDFJWJOH 1$ BMPOF 'FCSJMF OFVUSPQFOJB XBT also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

In Study 7, one fatal event of neutropenic infection occurred in a patient with previously treated glioblastoma receiving Avastin alone. The incidence of any grade of infection in patients receiving Avastin alone was 55% and the incidence of Grade 3-5 infection was 10%.

Proteinuria Grade 3-4 proteinuria ranged from 0.7 to 7.4% in Studies 1, 2, 4 and 9. The overall incidence of proteinuria (all grades) was only adequately assessed in Study 9, in which the incidence was 20%. Median onset of proteinuria was 5.6 months (range 15 days to 37 months) after initiation of Avastin. Median time to resolution was 6.1 months (95% CI 2.8 months, 11.3 months). Proteinuria did not resolve in 40% of patients after median follow up of 11.2 months and required permanent discontinuation of Avastin in 30% of the patients who developed proteinuria (Study 9). [See Warnings and Precautions (5.8).]

Congestive Heart Failure The incidence of Grade â&#x2030;Ľ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence PG (SBEF DPOHFTUJWF IFBSU GBJMVSF $)' XBT JODSFBTFE JO QBUJFOUT JO UIF "WBTUJO QMVT paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior BOUISBDZDMJOFT GPS .#$ UIF SBUF PG $)' XBT GPS QBUJFOUT SFDFJWJOH "WBTUJO BT DPNQBSFE to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

Metastatic Colorectal Cancer (mCRC) The data in Table 1 and Table 2 were obtained in Study 1, a randomized, double-blind, controlled trial comparing chemotherapy plus Avastin with chemotherapy plus placebo.

Avastin was administered at 5 mg/kg every 2 weeks.

All Grade 3â&#x20AC;&#x201C;4 adverse events and selected Grade 1â&#x20AC;&#x201C;2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life-threatening (Grade 3â&#x20AC;&#x201C;4) adverse events, which occurred at a higher incidence (â&#x2030;Ľ 2%) in patients receiving CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP CPMVT *'- QMVT QMBDFCP BSF QSFTFOUFE JO 5BCMF

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracilâ&#x20AC;&#x201C;based chemotherapy.

1.2 Non-Squamous Nonâ&#x20AC;&#x201C;Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic nonâ&#x20AC;&#x201C;squamous nonâ&#x20AC;&#x201C;small cell lung cancer in combination with carboplatin and paclitaxel.

1.3 Metastatic Breast Cancer (MBC) Avastin is indicated for the treatment of patients who have not received chemotherapy for metastatic HER2-negative breast cancer in combination with paclitaxel.

The effectiveness of Avastin in MBC is based on an improvement in progression free survival.

There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.3).]

Avastin is not indicated for patients with breast cancer that has progressed following anthracycline and taxane chemotherapy administered for metastatic disease.

1.4 Glioblastoma Avastin is indicated for the treatment of glioblastoma with progressive disease following prior therapy as a single agent.

The effectiveness of Avastin in glioblastoma is based on an improvement in objective response rate. There are no data demonstrating an improvement in disease-related symptoms or increased survival with Avastin. [See Clinical Studies (14.4).]

1.5 Metastatic Renal Cell Carcinoma (mRCC) Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa.

4 CONTRAINDICATIONS None.

5 WARNINGS AND PRECAUTIONS 5.1 Gastrointestinal Perforations Serious and sometimes fatal gastrointestinal perforation occurs at a higher incidence in Avastin treated patients compared to controls. The incidence of gastrointestinal perforation ranged from 0.3 to 2.4% across clinical studies. [See Adverse Reactions (6.1).]

The typical presentation may include abdominal pain, nausea, emesis, constipation, and fever.

Perforation can be complicated by intra-abdominal abscess and fistula formation. The majority of cases occurred within the first 50 days of initiation of Avastin.

Discontinue Avastin in patients with gastrointestinal perforation. [See Boxed Warning, Dosage and Administration (2.4).]

5.2 Surgery and Wound Healing Complications Avastin impairs wound healing in animal models. [See Nonclinical Toxicology (13.2).] In clinical trials, administration of Avastin was not allowed until at least 28 days after surgery.

In a controlled clinical trial, the incidence of wound healing complications, including serious and fatal complications, in patients with mCRC who underwent surgery during the course of Avastin treatment was 15% and in patients who did not receive Avastin, was 4%. [See Adverse Reactions (6.1).]

Avastin should not be initiated for at least 28 days following surgery and until the surgical wound is fully healed. Discontinue Avastin in patients with wound healing complications requiring medical intervention.

The appropriate interval between the last dose of Avastin and elective surgery is unknown; however, the half-life of Avastin is estimated to be 20 days. Suspend Avastin for at least 28 days prior to elective surgery. Do not administer Avastin until the wound is fully healed. [See Boxed Warning, Dosage and Administration (2.4).]

5.3 Hemorrhage Avastin can result in two distinct patterns of bleeding: minor hemorrhage, most commonly Grade 1 epistaxis; and serious, and in some cases fatal, hemorrhagic events. Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, hematemesis, CNS hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin compared to patients receiving only chemotherapy. Across indications, the incidence of Grade â&#x2030;Ľ 3 hemorrhagic events among patients receiving Avastin ranged from 1.2 to 4.6%.

[See Adverse Reactions (6.1).]

Serious or fatal pulmonary hemorrhage occurred in four of 13 (31%) patients with squamous cell histology and two of 53 (4%) patients with non-squamous non-small cell lung cancer receiving Avastin and chemotherapy compared to none of the 32 (0%) patients receiving chemotherapy alone.

In clinical studies in nonâ&#x20AC;&#x201C;small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin-treated patients (rate 1.2%, 95% CI 0.06%â&#x20AC;&#x201C;5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3â&#x20AC;&#x201C;4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of â&#x2030;Ľ1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non-Gastrointestinal Fistula Formation Serious and sometimes fatal non-gastrointestinal fistula formation involving tracheo-esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin-treated patients compared to controls. The incidence of non-gastrointestinal perforation was â&#x2030;¤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm.

Across indications, the incidence of Grade â&#x2030;Ľ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in SpeciďŹ c Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.

Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5-18%.

Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI-CTC Grade 3â&#x2C6;&#x2019;4 Adverse Events in Study 1 appropriate anti-hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [â&#x2030;Ľ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin-induced or -exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin. *'- 1MBDFCP *'- "WBTUJO Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).]

NCI-CTC Grade 3-4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms #PEZ BT B 8IPMF Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra-Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).]

Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy.

14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick aCentral laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. reading should undergo further assessment with a 24-hour urine collection.

AVASTINÂŽ (bevacizumab) AVASTINÂŽ (bevacizumab) Grade 1â&#x20AC;&#x201C;4 adverse events which occurred at a higher incidence (â&#x2030;Ľ 5%) in patients receiving Table 4 CPMVT *'- QMVT "WBTUJO BT DPNQBSFE UP UIF CPMVT *'- QMVT QMBDFCP BSN BSF QSFTFOUFE JO 5BCMF NCI-CTC Grades 1â&#x2C6;&#x2019;5 Adverse Events in Study 9 Grade 1â&#x20AC;&#x201C;4 adverse events were collected for the first approximately 100 patients in each of 0DDVSJOH BU )JHIFS *ODJEFODF <Ăś > JO *'/ Îą "WBTUJO WT *'/ Îą + Placebo) UIF UISFF USFBUNFOU BSNT XIP XFSF FOSPMMFE VOUJM FOSPMMNFOU JO "SN '6 -7 "WBTUJO

was discontinued.

4ZTUFN 0SHBO $MBTT *'/ Îą 1MBDFCP *'/ Îą + Avastin Preferred term* (n = 304) (n = 337) Table 2 Gastrointestinal disorders NCI-CTC Grade 1-4 Adverse Events in Study 1 Diarrhea 16% 21% 0DDVSSJOH BU )JHIFS *ODJEFODF <Ăś > JO *'- "WBTUJO WT *'-

General disorders and administration Arm 1 Arm 2 Arm 3 site conditions

*'- 1MBDFCP *'- "WBTUJO '6 -7 "WBTUJO 'BUJHVF

(n = 98) (n = 102) (n = 109) Investigations 8FJHIU EFDSFBTFE

#PEZ BT B 8IPMF Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders 8FJHIU -PTT

Hypertension 9% 28% Dry Mouth 2% 7% 4% *Adverse events were encoded using MedDRA, Version 10.1.

Colitis 1% 6% 1% Hemic/Lymphatic 5IF GPMMPXJOH BEWFSTF FWFOUT XFSF SFQPSUFE BU B GPME HSFBUFS JODJEFODF JO UIF *'/ Îą plus Thrombocytopenia 0% 5% 5% "WBTUJO BSN DPNQBSFE UP *'/ Îą alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1).

Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme-linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti-Avastin antibodies were not detected.

Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital BOE VOEFSMZJOH EJTFBTF 'PS UIFTF SFBTPOT DPNQBSJTPO PG UIF JODJEFODF PG BOUJCPEJFT UP "WBTUJO Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second-line mCRC The following adverse reactions have been identified during post-approval use of Avastin.

Only Grade 3-5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3â&#x20AC;&#x201C;5 always possible to reliably estimate their frequency or establish a causal relationship to non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events) occurring at a higher incidence drug exposure. Ăś JO QBUJFOUT SFDFJWJOH '0-'09 QMVT "WBTUJO DPNQBSFE UP QBUJFOUT SFDFJWJOH Body as a Whole: Polyserositis '0-'09 BMPOF XFSF GBUJHVF WT EJBSSIFB WT TFOTPSZ OFVSPQBUIZ Cardiovascular: Pulmonary hypertension, RPLS (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Digestive: Intestinal necrosis, mesenteric venous occlusion, anastomotic ulceration hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Hemic and lymphatic: Pancytopenia neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under-estimate the true adverse event rates due to the reporting mechanisms used Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) Respiratory: Nasal septum perforation, dysphonia in Study 2.

7 DRUG INTERACTIONS Unresectable Non-Squamous Non-Small Cell Lung Cancer (NSCLC) Only Grade 3-5 non-hematologic and Grade 4-5 hematologic adverse events were collected A drug interaction study was performed in which irinotecan was administered as part of the in Study 4. Grade 3â&#x20AC;&#x201C;5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events (occurring '0-'*3* SFHJNFO XJUI PS XJUIPVU "WBTUJO 5IF SFTVMUT EFNPOTUSBUFE OP TJHOJĂĽDBOU FGGFDU PG at a higher incidence (â&#x2030;Ľ2%) in 427 patients receiving PC plus Avastin compared with 441 patients bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38. receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), be a difference in the mean exposure of either carboplatin or paclitaxel when each was febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 administered alone or in combination with Avastin. However, 3 of the 8 patients receiving or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin (3% vs. 0%). without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.

Metastatic Breast Cancer (MBC) In Study 9, there was no difference in the mean exposure of interferon alfa administered in Only Grade 3â&#x20AC;&#x201C;5 non-hematologic and Grade 4â&#x20AC;&#x201C;5 hematologic adverse events were collected in combination with Avastin when compared to interferon alfa alone.

Study 5. Grade 3â&#x20AC;&#x201C;4 adverse events occurring at a higher incidence (â&#x2030;Ľ2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory 8 USE IN SPECIFIC POPULATIONS neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without 8.1 Pregnancy neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), Pregnancy Category C bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, (3% vs. 0.3%) and proteinuria (3% vs. 0%). including an increased incidence of speciďŹ c gross and skeletal fetal alterations. Adverse fetal outcomes Sensory neuropathy, hypertension, and fatigue were reported at a â&#x2030;Ľ 5% higher absolute incidence in were observed at all doses tested. Other observed effects included decreases in maternal and fetal the paclitaxel plus Avastin arm compared with the paclitaxel alone arm. body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]

'BUBM BEWFSTF SFBDUJPOT PDDVSSFE JO PG QBUJFOUT XIP SFDFJWFE QBDMJUBYFM QMVT "WBTUJO Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ from the mother to the developing fetus, and has the potential to cause fetal harm when abdominal, and pain/weakness/hypotension (2). administered to pregnant women. Because of the observed teratogenic effects of known inhibitors Avastin is not approved for use in combination with capecitabine or for use in second or third of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential line treatment of MBC. The data below are presented to provide information on the overall benefit to the pregnant woman justifies the potential risk to the fetus. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, 8.3 Nursing Mothers controlled study in which all adverse events were collected for all patients. All patients in It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk.

Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in metastatic disease. Grade 1â&#x20AC;&#x201C; 4 events which occurred at a higher incidence (â&#x2030;Ľ5%) in patients substantial amounts. Because many drugs are secreted in human milk and because of the potential for receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to in Table 3. discontinue nursing or discontinue drug, taking into account the half-life of the bevacizumab (approximately 20 days [range 11â&#x20AC;&#x201C;50 days]) and the importance of the drug to the mother. [See Clinical Table 3 Pharmacology (12.3).]

NCI-CTC Grade 1â&#x2C6;&#x2019;4 Adverse Events in Study 6 (Occurring at Higher 8.4 Pediatric Use Incidence [â&#x2030;Ľ5%] in Capecitabine + Avastin vs. Capecitabine Alone) The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Capecitabine been established.

Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Capecitabine + Avastin to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and (n = 215) (n = 229) exposure). The incidence and severity of physeal dysplasia were dose-related and were partially #PEZ BT B 8IPMF reversible upon cessation of treatment.

Asthenia 47% 57% 8.5 Geriatric Use Headache 13% 33% In Study 1, severe adverse events that occurred at a higher incidence (â&#x2030;Ľ 2%) in patients aged â&#x2030;Ľ65 Pain 25% 31% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Cardiovascular hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Hypertension 2% 24% survival was similar in elderly patients as compared to younger patients.

Digestive *O 4UVEZ QBUJFOUT BHFE Ăś ZFBST SFDFJWJOH "WBTUJO QMVT '0-'09 IBE B HSFBUFS SFMBUJWF SJTL Stomatitis 19% 25% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

Metabolic/Nutrition In Study 4, patients aged â&#x2030;Ľ 65 years receiving carboplatin, paclitaxel, and Avastin had a 8FJHIU MPTT

greater relative risk for proteinuria as compared to younger patients. [See Warnings and Musculoskeletal Precautions (5.8).]

Myalgia 8% 14% In Study 5, there were insufficient numbers of patients â&#x2030;Ľ 65 years old to determine whether Respiratory the overall adverse events profile was different in the elderly as compared with younger patients.

Dyspnea 18% 27% Of the 742 patients enrolled in Genentech-sponsored clinical studies in which all adverse events were Epistaxis 1% 16% captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any Skin/Appendages severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition Exfoliative dermatitis 75% 84% to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased Urogenital cough, and voice alteration.

Albuminuria 7% 22% In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged â&#x2030;Ľ65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with Glioblastoma as compared to those receiving chemotherapy alone, regardless of age. However, All adverse events were collected in 163 patients enrolled in Study 7 who either received chemotherapy the increase in arterial thromboembolic events incidence was greater in patients aged â&#x2030;Ľ 65 years Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination (5.5).] with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated 10 OVERDOSAGE with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), 16 patients and with severe headache in three of 16 patients. epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade â&#x2030;Ľ3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin-related adverse events (Grade 1â&#x20AC;&#x201C; 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound-healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3â&#x20AC;&#x201C;5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound-healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3â&#x20AC;&#x201C;5 adverse events occurring at a IJHIFS JODJEFODF Ăś JO QBUJFOUT SFDFJWJOH JOUFSGFSPO BMGB *'/ Îą) plus Avastin DPNQBSFE UP QBUJFOUT SFDFJWJOH *'/ Îą plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, 7453214 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Manufactured by: haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract Genentech, Inc. 4835706 hemorrhage, and traumatic hematoma). %/" 8BZ *OJUJBM 6 4 "QQSPWBM 'FCSVBSZ $PEF 3FWJTJPO %BUF +VMZ (SBEF o BEWFSTF FWFOUT PDDVSSJOH BU B IJHIFS JODJEFODF Ăś JO QBUJFOUT SFDFJWJOH *'/ Îą plus 4PVUI 4BO 'SBODJTDP $" 94080-4990 Š 2009 Genentech, Inc "WBTUJO DPNQBSFE UP UIF *'/ Îą plus placebo arm are presented in Table 4.

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

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