TAP Vol 2 Issue 9

Cancer survivorship 2, 4, 20, 21

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Taxane-related neuropathy 3

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VOLUME 2, ISSUE 9

FDA Update 13, 14, 28

JUNE 15, 2011 ASCOPost.com

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

2011 ASCO Annual Meeting

3-Year Screening Interval Safe for Women with HPV-negative and Normal Pap Tests, Data Show

The FDA– Pharmaceutical Industry Complex

By Alice Goodman

A

large, “real-world” Screening for Cervical Cancer study has validated current recommendations ■■ First large-scale, real-world study validates ACOG, ACS, and ASCCP guidelines. from the American Con■■ Testing HPV-negative implied lower risk of cervical cancer than having a gress of Obstetricians and normal Pap test.

Gynecologists (ACOG), American Cancer Soci■■ 3-year screening interval is safe for women over age 30 with negative HPV and normal Pap test. ety (ACS), and American Society for Colposcopy ■■ Pap testing remains useful, especially in women who are HPV-positive. and Cervical Pathology (ASCCP) endorsing a Large-scale Study 3-year cervical cancer screening interval for wom“This first large-scale study of concurrent HPV en over age 30 with a negative human papillomavirus and Pap testing for cervical cancer in routine clinical (HPV) test and a normal Pap test. Furthermore, testing practice in the United States found that women who HPV-negative resulted in a very low risk of cancer that tested HPV-negative had an extremely low risk of cerwas not appreciably reduced by also having a normal vical cancer. This finding demonstrates that a 3-year Pap test. However, Pap testing remained important for screening interval is safe,” said Hormuzd Katki, PhD, HPV-positive women, because an lead investigator, Division of Cancer Epidemiology abnormal Pap test helped identify and Genetics at NCI. even more women who developed Although the Pap test is an effective screening cancer or precancer. The study was method for cervical cancer, 11,000 new cases develop highlighted at a pre–Annual MeetSEE PAGE 41 continued on page 6 ing ASCO press briefing.

Survivorship

Experts Seek to Explain the Survival Gap in Adolescents and Young Adults with Cancer Despite improvements in cancer care, survival rates in patients aged 15 to 39 have stagnated.

By Jo Cavallo

W

hile overall cancer survival rates continue to rise—there are nearly 12 million cancer survivors today, according to the latest figures from NCI— most of that improvement is among pediatric and older adult patients. For adolescent and young adult patients with cancer, defined by the NCI as those in the 15- to 39-year-old age range, survival rates have remained stagnant since 1975.

And in certain cancer types, survival rates in this population have actually decreased, Brandon Hayes-Lattin, MD making cancer the number

one disease-related cause of death in this age group.

“Survival is worse for young adults with acute lymphoblastic leukemia (ALL) than it is for children with ALL. Similarly, in breast cancer, survival rates are worse for women under 40 than for older women,” said Brandon Hayes-Lattin, MD, Medical Director, Adolescent and Young Adult Oncology Program, Knight Cancer Institute of Oregon Health & Science University, Portland, and Senior Medical Advisor to the Lance Armstrong Foundation.

By Emil J. Freireich, MD, DSc (Hon)

O

n January 17, 1961, President Dwight D. Eisenhower, in his farewell address to the nation, coined the term “the military-industrial complex.” His purpose was to warn of the inefficiencies that could result from such a relationship, which would imperil the strength of our military and the safety of our nation. In an analogous fashion, today we have an “FDA–pharmaceutical industry complex.” This relationship imperils the effectiveness of our outstanding academic medical community and their partners in the pharmaceutical industry, hindering the development of innovative and highly effective treatments for the major diseases that threaten the health of our nation. continued on page 38

Dr. Freireich is Ruth Harriet Ainsworth Chair, Distinguished Teaching Professor, and Director, Special Medical Education Programs and Adult Leukemia Research Program, The University of Texas MD Anderson Cancer Center, Houston.

The views expressed herein are those of the author and not necessarily those of The ASCO Post.

MORE IN THIS ISSUE Oncology Meetings Coverage 2011 ASCO Annual Meeting ��� 3, 6, 8, 27 American College of Obstetricians and Gynecologists 59th Annual Clinical Meeting ���������������������������������������� 8 American Society of Breast Surgeons 12th Annual Meeting ���������������������� 15, 18 Breast Cancer Prevention Research ���������� 11 Direct from ASCO ��������������������������������������� 19 Hormone Replacement and Ovarian Cancer ��������������������������������������������40 Letters to the Editor �������������������������������������42

Underlying Biology Although the exact reasons why young adult survivors don’t fare as well as other cancer survivors are continued on page 32

A Harborside Press® Publication

The ASCO Post | JUNE 15, 2011

PAGE 2

Perspective

Planning Survivorship Programs: An International Endeavor

By Mary S. McCabe, RN, MA

Editorial Board

David Khayat, MD Pitie-Salpetriere Hospital Paris, France Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Variety of Care Models

Mary S. McCabe, RN, MA Memorial Sloan-Kettering Cancer Center

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami Harold J. Burstein, MD Dana-Farber Cancer Institute Robert W. Carlson, MD Stanford University Medical Center Barrie R. Cassileth, PhD Memorial Sloan-Kettering Cancer Center Jay S. Cooper, MD Maimonides Medical Center John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

T

he March 11th report by the U.S. Centers for Disease Control and Prevention highlighted once again the growing number of cancer survivors—now approximately 12 million. This good news serves as a reminder to the oncology community of the need for formal care for this increasingly large group of individuals. How best to provide this is an international challenge, with physicians and nurses in countries such as Australia, Canada, Italy, Israel, Argentina, and the United Kingdom working together with their U.S. colleagues to share best practices so they can be instituted and evaluated in the various clinical settings where survivors are being followed.

To date, most models of care have been developed by academic medical centers, but increasingly, community practices, clinics, and hospitals are formulating plans for survivorship care. Regardless of setting and national health-care system, a number of key factors influence the type of program, including the patient population, type of services, and location of services to be provided.

These characteristics drive the clinic structure and the type of health-care provider (eg, physician or nurse) for each model.

James O. Armitage, MD Editor-in-Chief

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University 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 William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel Nagahiro Saijo, MD, PhD Kinki University School of Medicine Osaka, Japan Daniel A. Vorobiof, MD Sandton Oncology Centre Johannesburg, South Africa

Harborside Press® Publishing Staff Conor Lynch, Executive Editor Conor@harborsidepress.com

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Contributing Writers: Charlotte Bath, Barbara Boughton, Jo Cavallo, Margot J. Fromer,

In several countries, the pediatric multidisciplinary care model is being used for adult survivors. Because it is resource-intensive, it is most frequently used for the care of “complex patients” (eg, adult survivors of pediatric cancers, brain tumor survivors) requiring comprehensive care in a setting where specialists such as physi-

Mary S. McCabe, RN, MA

cians, nurses, and psychologists come together for the visit.

Another specialized approach is the disease/treatment-specific clinic model, where the focus of the care is on patients with one disease (eg, breast cancer) or patients who have received one type of treatment (eg, stem cell transplant). This model is often a good way to begin and work out problems and practice logistics, but in the long run, it may limit care to a few categories of survivors and omit the survivors with the greatest need.

A clinic that is also frequently used as a starting point for survivorship programs is the consultative model, where a “one-time” visit serves as an opportunity to develop a treatment summary and care plan, and referrals are made for subspecialty care and supportive services. The advantage of this type of model is that it can serve an unrestricted survivor population, and only core services need be provided on-site. Other services, such as physical therapy, nutrition counseling, and cardiology, are provided by community/institutional groups.

This model can be used to prepare survivors who are transitioning back to their primary care providers, with a summary plan for cancer-specific follow-up. For patients continuing continued on page 24

National Cancer Survivors Day® The 24th annual National Cancer Survivors Day® was held Sunday, June 5, 2011. America’s 12 million cancer survivors joined survivors around the world in observing this special day. Communities worldwide hosted events to celebrate life and demonstrate that life after a cancer diagnosis can be meaningful and productive.

To find out more about National Cancer Survivors Day, visit www.ncsd.org.

Alice Goodman, Caroline Helwick, Ronald Piana, Matthew Stenger, Marian Wiseman

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

For more on cancer survivorship in this issue of The ASCO Post, see pages 1, 4, 20, and 21.

ASCOPost.com | JUNE 15, 2011

PAGE 3

2011 ASCO Annual Meeting Biomarkers

Genes May Predict Taxane-related Peripheral Neuropathy

By Caroline Helwick

T

he first identification of potential genetic biomarkers for taxaneinduced peripheral neuropathy was reported at the 2011 ASCO Annual Meeting by researchers from Indiana University in Indianapolis.1 The presence of two single nucleo-

tide polymorphisms (SNPs), or common genetic variations, residing in two genes—RWDD3 and TECTA— was associated with an increased risk of developing neuropathy in a cohort of patients with breast cancer enrolled in the Eastern Cooperative On-

Expert Point of View

A

s an oncologist who frequently avoids taxanes, largely due to concerns about neuropathy, Steven Vogl, MD, of the Bronx, New York, was asked to comment on the study. He observed that while the Indiana University study has no immediate applicability, it is “a good first look.”

“I typically don’t use taxanes for patients at low risk for recurrence because it’s been difficult to consistently show they add much,” he told The ASCO Post. “But if I knew my low-risk patient had little risk of developing Steven Vogl, MD neuropathy, I might be more willing to give a taxane.”

The Schneider study is “the Taxol franchise” of the emerging business of “SNP neurotoxicity searches,” Dr. Vogl quipped. A similar study recently identified SNPs associated with chemotherapy-induced neuropathy in multiple myeloma,1,2 he noted. Specifically, ATP-binding cassette gene family SNPs were linked to thalidomide (Thalomid)-induced neuropathy, whereas the SNPs involved in vincristine-induced neuropathy were in different genes.

The discrepancies point to different pathogenic mechanisms for nerve damage from the two agents, the authors suggested.

Interpreting the Data In the current study, the findings of two relevant SNPs among 1.2 million possibilities might be due to chance, or the SNPs could be artifacts (linked by heredity to the real genetic causes), according to Dr. Vogl. “But if they were the same as those found in these myeloma studies, that would be interesting,” he suggested. Ideally, the biomarkers should discriminate those who develop mild neuropathy from those who develop severe neuropathy. “While transient grade 2 neuropathy can be miserable, it’s more important to identify patients whose neuropathy does not resolve,” he noted.

A genetic risk profile would help justify the withholding of taxanes in patients at low risk for recurrence but high risk for neuropathy, and would support the decision to use a different drug or a toxicity-modifying agent or schedule in patients at risk for both recurrence and neuropathy, he said.

Financial Disclosure: Dr. Vogl reported no potential conflicts of interest.

■

References 1. Johnson DC, Corthals SL, Walter BA, et al: Genetic factors underlying the risk of thalidomide-related neuropathy in patients with multiple myeloma. J Clin Oncol 29:797-804, 2011.

2. Becker P: Genetic Predisposition for Chemotherapy-Induced Neuropathy in Multiple Myeloma. J Clin Oncol 29:783-786, 2011.

Visit The ASCO Post website at:

cology Group clinical trial E5103. Neuropathy was reported by 60% of persons with two copies of the variant allele, said Bryan P. Schneider, MD, Associate Professor of Medicine at Indiana University Melvin and Bren Simon Cancer Center, at a preconference Brian P. Schneider, MD Mark Kris, MD media briefing. type subjects (ie, no SNPs) was 27%; “If these findings can be replithis rose to 40% among persons hetcated, this may allow physicians to erozygous for the SNP and to 60% know prior to recommending therapy among those homozygous for the whether the patient is at an inordinate variant (HR = 1.5; P = 8.5 × 10-8). risk for developing taxane-induced “The study evaluated the risk with neuropathy. This may allow for better weekly paclitaxel, but we are planning counseling, use of alternative drugs or to validate these findings in a trial lookschedules, or omission of taxanes in ing at a variety of schedules of paclitaxthe appropriate setting,” Dr. Schneider el as well as docetaxel,” Dr. Schneider commented. said.

Researchers conducted a genomeMark Kris, MD, Chair of the wide association study of 2,204 patients ASCO Cancer Communications with breast cancer enrolled in E5103, Committee, commented on the value a phase III study of adjuvant chemoof moving beyond therapy with doxorubicin, cyclophosclinical factors to emphamide, and weekly paclitaxel for 12 ploy a more refined weeks, with or without bevacizumab means of predict(Avastin). More than 1.2 million SNPs ing neuropathy risk. were evaluated per subject.

SEE PAGE 41 “I am excited to see Principal Findings these data…This study represents one Interim toxicity data at a median of the first times that molecular biolof 15 months identified 613 patients ogy has melded into the area of supwith grade 2–4 neuropathy occurring portive care,” he noted.

Financial Disclosure: Dr. Schneider at any time point during or after treatreported that he is on the advisory board for ment. Significant clinical predictors of Genentech. Dr. Kris reported no potential neuropathy included increasing age (P conflicts of interest. = .0004) and African-American race Reference (P = 2.3 × 10-11). In addition, six SNPs 1. Schneider BP, Li L, Miller K et al: with minor allele frequency (MAF) > Genetic associations with taxane-induced 5% were associated with neuropathy. neuropathy by genome wide association The strongest association was study (GWAS) in E5103. J Clin Oncol found for an SNP in RWDD3. The 29(15 suppl):Abstract 1000, 2011. incidence among homozygous wild-

■

Predicting Taxane-induced Neuropathy ■■ SNPs in two genes (RWDD3 and TECTA) were associated with increased risk for paclitaxel-induced neuropathy.

■■ 60% risk of neuropathy in patients homozygous for SNP RWDD3.

ASCOPost.com

The ASCO Post | JUNE 15, 2011

PAGE 4

Expert’s Corner Survivorship

A Conversation with Patricia A. Ganz, MD

The importance of instituting survivorship care plans for all patients with cancer

By Jo Cavallo

Patricia A. Ganz, MD

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esearching the effects of cancer on patients’ quality of life and championing the development and implementation of survivorship care plans have been at the forefront of the 20-year-long career of Patricia A. Ganz, MD, Director of the Division of Prevention and Control Research at UCLA’s Jonsson Comprehensive Cancer Center and Director of the UCLA-LIVESTRONG Survivorship Center of Excellence.

Six years ago, Dr. Ganz was on the Institute of Medicine (IOM) committee that prepared the report, From Cancer Patient to Cancer Survivor: Lost in Transition, which recommends providing survivors with a comprehensive care summary and follow-up plan to monitor cancer recurrences and spot late effects of treatment.

Although the IOM report was published in 2006, a recent survey conducted by the Oncology Nursing Society found that only about 25% of the nurses surveyed had a formal survivorship program in place at their institutions—the result, said the respondents, reflected lack of

time and sufficient funding.

But the urgency of having a system in place that tracks ongoing medical and psychosocial problems that arise as a result of a cancer diagnosis is growing, given the rising number of cancer survivors—according to the NCI, there are nearly 12 million cancer survivors in the United States—and a looming shortage of oncologists to care for them long term.

These factors, combined with the decentralization of cancer care over the past 2 decades from cancer centers to community hospitals and private practices where patients may see multiple specialists, are making the need to universally adopt survivorship care plans imperative.

largely devolved from the cancer centers and hospitals into community-based settings. Today, 80% of patients are being treated in the community by medical oncologists in three-person (or larger) practices. In those offices, there may be an initial consult record that shows the stage of a patient’s disease and the therapy planned, but there’s no summary that details how many cycles of treatment the patient received or what the toxicities were. When patients received chemotherapy as hospital inpatients, there was a hospital discharge summary, and you could figure out what went on with that patient. But since most cancer care is now ambulatory and patients are

Institutionalizing survivorship care plans in community practices was going to be very challenging because community physicians did not have the time and money to implement these procedures.

The ASCO Post talked with Dr. Ganz about how survivorship care plans can be implemented to improve the coordination and quality of care after cancer treatment ends.

Standardizing Survivorship Support Why is it taking so long for survivorship care plans to become a standard part of cancer care?

About 20 years ago, oncology care

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seeing not just their medical oncologist, but a radiation therapist and a surgeon as well (sometimes in separate locations), there’s no one record that details their care.

When the IOM report was finished, I took its message to various organizations, and I thought, “This is a piece of cake. You finish treating a patient with chemotherapy, you know what stage disease the patient had, you know what drugs you administered, you know

what the toxicity was, so just record it.

Write a summary note, and tell the patient what to do going forward.”

But there wasn’t a groundswell of enthusiasm for this practice in the medical oncology community because it was not considered to be part of standard care. Unlike surgeons, who were required to dictate an operative note for hospital accreditation and billing purposes, no equivalent procedure was in place for medical oncology. I soon realized that institutionalizing survivorship care plans in community practices was going to be very challenging because community physicians did not have the time and money to implement these procedures. ASCO also worked with electronic health record vendors to incorporate a survivorship care plan template in their software programs, but they’re still not doing very much with it.

If the comprehensive cancer centers and other major medical centers where cancer is being treated can institutionalize a survivorship care plan and make it an expectation of care, then as these physicians move into the communities to practice there will be a demand for it there. It may take 10 or 15 years for these things to change unless there are reimbursement or policy changes sooner.

Costs and Components Is it expensive to implement survivorship care plans? What elements should every plan include?

It doesn’t cost a lot of time and effort to implement these plans if one thinks continued on page 25

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PAGE 6

2011 ASCO Annual Meeting HPV and Pap Screening

Study Specifics

continued from page 1

The NCI-initiated study was done in collaboration with Kaiser Permanente Northern California to test the safety of the current ACOG, ACS, and ASCCP guidelines in a real-world patient population. The study included 331,818 women age 30 and older enrolled in the Kaiser Permanente Northern California’s co-testing program between 2003 and 2005. The women were followed through 2009.

Testing HPV-negative implied lower risk of cervical cancer than having a normal Pap test. The 5-year risk of cancer for women who were HPV-negative and had a normal Pap test was only 3.2 per 100,000 women per year. Looking at each test separately, a negative HPV test was associated with a 5-year risk of 3.8 cervical cancers per 100,000 women per year; a normal Pap test was associated with a 5-year risk of 7.5 cervical cancers per 100,000 women per year.

The HPV test identified more women at high risk of cancer or precancer than the Pap test. Women who were HPV-positive had a 7.6% 5-year risk of cervical cancer or precancer, whereas women with an abnormal Pap test had only a 4.7% 5-year risk of cervical cancer or precancer. In contrast, women testing HPV-negative had a 0.2% 5-year risk of cervical cancer or precancer, while women with a normal Pap test had a 0.4% 5-year risk of cervical cancer. “These findings demonstrate the superior ability of HPV testing to separate women into groups

annually in the United States, and cervical cancer accounts for 4,000 deaths each year. HPV causes almost every cervical cancer, but there is typically a 20-year interval between infection with HPV and the development of cervical cancer. Based on several clinical trials and research cohorts showing that HPV testing could further reduce cancer rates when done in concert with the Pap test, guidelines from ACOG, ACS, and ASCCP incorporated concurrent HPV testing with Pap testing at each clinical visit for women over age 30 (ie, co-testing). Guidelines currently recommend a 3-year interval for women who are HPVnegative and have a normal Pap smear.

Hormuzd Katki, PhD

Despite the existence of these guidelines, co-testing has not been widely adopted by physicians and by women, who may fear that extending the screening interval beyond 1 year is not safe, Dr. Katki explained. “The last piece of evidence required is to show that the 3-year screening interval is safe in routine clinical practice,” he noted.

Expert Point of View

“T

his is a wonderful population-based study… that makes us comfortable with the current recommendations. The issue of how frequently one or the other test should be used is an evolving area,” said George W. Sledge, Jr, MD. Dr. Sledge is ASCO Immediate Past President.

Dr. Sledge pointed out that this study mirrors a trend in oncology—that is, going from cytopathology to molecular techniques. “This trend will become increasingly important,” he commented. Dr. Sledge is Ballve-Lantero Professor of Oncology and Professor of Pathology and Laboratory Medicine at the Indiana University School of Medicine.

George W. Sledge, Jr, MD

■

Financial Disclosure: Dr. Sledge reported no potential conflicts of interest.

at high and low risk of cancer and precancer,” Dr. Katki stated.

Pap Testing Remains Useful However, Dr. Katki emphasized that the Pap test remained useful for HPV-positive women. “For HPV-positive women, a positive Pap test identified an additional 6 in 100 women at risk for cervical cancer or precancer over 5 years,” he noted. “For HPV-positive women, abnormal Pap tests help identify immediate disease, whereas a normal Pap test signifies that cancer, if it occurs, is more likely to develop in the future.”

Based on their findings, the authors suggest that a screening program with a single HPV test could be used first, and if negative, no additional testing would be needed for at least 3 years;

the Pap test would be reserved only for women who were HPV-positive. “This program could retain nearly all the safety of co-testing, but in our population, would have reduced the number of Pap tests by 95%. Still, we need to test this hypothesis in practice,” Dr. Katki stated. He pointed out that if the HPV test is positive, the same sample could be used for the Pap test, avoiding a second visit for the Pap test.

■

Financial Disclosure: Dr. Katki reported no potential conflicts of interest.

Reference 1. Katki HA, Kinney WK, Fetterman B, et al: Cervical cancer risk for 330,000 women undergoing concurrent HPV testing and cervical cytology in routine clinical practice. J Clin Oncol 29(15 suppl):Abstract 1508, 2011.

Novel Drugs

Cabozantinib Broadly Active in Multiple Tumor Types

By Caroline Helwick

C

abozantinib (XL184), an oral inhibitor of MET kinase and the vascular endothelial growth factor receptor (VEGFR2), produced high rates of disease control in several solid tumor types and controlled bone metastases in many patients, according to a phase II study presented at the 2011 ASCO Annual Meeting.1 “Antitumor activity was seen in 12 of 13 tumor types studied to date, and impressive bone scan improvement was observed in prostate cancer,” said Michael S. Gordon, MD, of Pinnacle Oncology Hematology in Scottsdale, Arizona, at a preconSEE PAGE 41 ference press brief-

ing. “The implications of these results are very exciting. It is unusual to find a targeted therapy, absent of a specific molecular mutation in tumors, that works in bony disease and has this degree of activity.”

MET signaling, which is blocked by cabozantinib, is integral to the process of tumor cell invasion and metastasis in soft tissue and bone.

Discontinuation Design The study was a randomized discontinuation open-label trial that included 398 patients with advanced, progressive solid tumors, either with (39%) or without (61%) bone metastases. Patients were treated for 12 weeks with oral cabozantinib and then

Cabozantinib in Solid Tumors ■■ Novel MET/VEGFR2 inhibitor produced high disease control rates in multiple solid tumor types.

■■ Disease control rate was 76% in hepatocellular carcinoma and 71% in prostate cancer.

■■ Bone metastases were improved in 86% of patients with prostate cancer.

assessed for tumor shrinkage.

While the overall major objective response rate was 9%, the disease control rate (partial response or stable disease) was high, Dr. Gordon reported.

“Some tumor shrinkage with cabozantinib was observed in the majority of patients,” he said. Disease control rates

were highest in hepatocellular carcinoma (76%), prostate cancer (71%), ovarian cancer (58%), melanoma (45%), breast cancer (45%), and non– small cell lung cancer (40%).

Under the study’s discontinuation design, subjects with partial responscontinued on page 8

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE T HE 5 - Y E AR S UR V IVAL R ATE I S 17 % F O R PATIENTS W ITH M E TAS TATIC S OF T TIS S UE SA RC OMA , YE T S I G N I F ICANT THER APEUTIC A D VAN CE MENTS AR E LAG GING. 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.

Merck Oncology

Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1003549-0001

The ASCO Post | JUNE 15, 2011

PAGE 8

2011 ASCO Annual Meeting Novel Drugs

Cabozantinib in Multiple Tumor Types continued from page 6

es stayed on the drug while those with stable disease were randomly assigned to cabozantinib or placebo.

Patients with progressive disease were removed from the trial. This design allows for prompt evaluation of the disease-stabilizing activity of cabozantinib, compared with the traditional model of randomizing all patients to

the experimental arm or placebo, he explained.

Robust Effect on Metastatic Bone Lesions Effects on metastatic bone lesions were observed in five tumor types— prostate cancer, breast cancer, melanoma, renal cell cancer, and thyroid cancer. In patients with prostate cancer, complete or partial responses based on bone scans were seen in 86% of pa-

Expert Point of View

M

ark G. Kris, MD, Chair of the ASCO Cancer Communications Committee, commented at the press briefing that the study represents “an example of the evolution of targeted cancer therapies in that we are seeing early signs of benefit by going after multiple targets in the cancer cell. We saw important tumor shrinkage that translated into stronger bones and less pain from bony metastases,” he said.

■

Financial Disclosure: Dr. Kris reported no potential conflicts of interest.

tients. This was often accompanied by pain relief, Dr. Gordon reported.

“The effect on bone metastases led to pain relief in many patients, and to a reduction in biomarkers of bone resorption, as well as a reduction in biomarkers of bone formation,” he added.

Over half the patients had declines of at least 50% in plasma C-telopeptide.

Effects on prostate-specific antigen, however, were minimal. “They do not mirror the benefits on bone scans that tend to appear quickly,” he said.

Patients with anemia had a mean rise of 2.3 g/dL in hemoglobin, which was sustained. Side effects were similar to those seen with other tyrosine kinase inhibitors.

Future Trials

Mark Kris, MD

Due to the encouraging results, the prostate and ovarian cancer cohorts were expanded to 150 patients.

The larger number will help inform the design of future phase III trials, he said. A clinical trial in medullary thyroid cancer is fully enrolled. A trial

Michael S. Gordon, MD

in patients with prostate cancer will begin by the end of 2011 and use a reduction in bone metastases as the primary endpoint.

■

Financial Disclosure: Dr. Gordon reported receiving research funding from Exelixis.

Reference 1. Gordon MS, Vogelzang NJ, Schoffski P, et al: Cabozantinib (XL184) has activity in both soft tissue and bone: Results of a phase II randomized discontinuation trial in patients with advanced solid tumors. J Clin Oncol 29(15 suppl):Abstract 3010, 2011.

Gynecologic Oncology

Important Briefs from the ACOG 59th Annual Clinical Meeting

By Alice Goodman

S

everal presentations at the 59th Annual Clinical Meeting of the American College of Obstetricians and Gynecologists (ACOG), held April 30–May 4 in Washington, DC, focused on cancers associated with the reproductive tract and issues important to women’s health. Four noteworthy studies presented at the meeting are summarized below.

Oncofertility Achieving or maintaining fertility in younger patients with cancer is a major challenge that has spawned a new term (ie, oncofertility) and an NIH-funded multidisciplinary organization (The Oncofertility Consortium) to provide information to patients, health professionals, educators, and researchers.

Teresa K. Woodruff, PhD, a pioneer in the field of oncofertility, reviewed current options for preserving female fertility, including cryopreservation of embryos, eggs, and ovarian tissue to be used after cancer treatment is completed. She also described a cutting edge technique aimed at producing live human offspring grown in vitro, not in vivo.

“The frozen embryo is the most mature option we have, but patients

that is achieved, the next step will be to activate the egg.

Detecting Cervical Cancer

Teresa K. Woodruff, PhD

don’t always have time to take advantage of this technology,,” Dr. Woodruff said. “For those patients, removing an ovary is an option to protect fertility.”

Dr. Woodruff and colleagues at Northwestern University, Feinberg School of Medicine, are working with a three-dimensional supportive environment for the ovarian follicle using alginate, a gelatinous material that does not interact with mammalian cells. The in vitro process has spawned live offspring from mice and produced eggs and embryos in nonhuman primates.

Using 40 secondary follicles from 19 patients with cancer, they have gotten good quality eggs and are now trying to recapitulate human folliculogenesis in vitro, which would eliminate the need for tissue transplantation. Once

An investigational scanning device detected cervical dysplasia up to 2 years earlier than traditional methods—including Pap smear, human papillomavirus test, colposcopy, and biopsy—in a longitudinal pivotal trial reported by Leo B. Twiggs, MD, University of Miami Miller School of Medicine.

The LuViva™ device relies on spectroscopic technology measuring the spectral output (changes in light relative to depth) of cervical tissue. The technique is painless and noninvasive, does not require tissue sampling or laboratory analysis, and produces results within minutes, he said. The cost of the portable device has not yet been determined.

The study enrolled 1,607 women referred for LuViva at seven clinical centers on the basis of an abnormal Pap smear or other finding that suggested endometrial dysplasia. All patients underwent LuViva scanning, as well as an additional Pap test, colposcopy, and biopsy. Each subject acted as her own control.

Among 801 women who had colposcopy within the previous 2 years, LuViva detected cervical intraepithelial neoplasia grade 2 or higher (CIN2+) in 91% of women vs 76% for standard care (all the other methods

Leo B. Twiggs, MD

mentioned above). Dr. Twiggs stated that relying on LuViva instead of standard methods would have reduced the number of false-positive tests by 39% for women with normal histology and by 30% for women with low-grade dysplasia (CIN1).

Age Bias in Ovarian Cancer Older women (over age 65) appear to be treated less aggressively than the standard of care for ovarian cancer, according to a retrospective study of continued on page 10

The case for Vectibix® Q2W dosing schedule1

– The recommended dose of Vectibix® is 6 mg/kg every 14 days

60-minute infusion1

– Vectibix® is given by intravenous infusion over 60 minutes - Doses greater than 1000 mg should be administered over 90 minutes

Premedication not standardized1

– The use of premedication was not standardized in the clinical trials – The utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown

No loading dose1

– No loading dose is required

1% severe infusion reactions reported1

– Across several clinical trials of Vectibix® monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3-4) – Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion – Immediately and permanently discontinue Vectibix® infusion in patients experiencing severe (grade 3 or 4) infusion reactions – Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix® infusions

INDICATION: Vectibix® is indicated as a single agent for the treatment of occurred in 1 patient. In a single-arm study of 24 patients receiving Vectibix® plus

epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%. (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical irinotecan-containing chemotherapy regimens. studies of Vectibix®. Of the 2 cases, 1 involved a patient with underlying idiopathic The effectiveness of Vectibix® as a single agent for the treatment of EGFR-expressing pulmonary fibrosis and resulted in death. The second patient had symptoms of mCRC is based on progression-free survival. Currently, no data demonstrate an pulmonary fibrosis, which was confirmed by CT. Additionally, a third patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia. Permanently improvement in disease-related symptoms or increased survival with Vectibix®. discontinue Vectibix® therapy in patients developing interstitial lung disease, Retrospective subset analyses of metastatic colorectal cancer trials have not shown pneumonitis, or lung infiltrates. a treatment benefit for Vectibix® in patients whose tumors had KRAS mutations in In a randomized, controlled clinical trial, median magnesium levels decreased by codon 12 or 13. Use of Vectibix® is not recommended for the treatment of colorectal 0.1 mmol/L in the Vectibix® arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring cancer with these mutations. oral or IV electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred Important Safety Information, including Boxed WARNINGS: 6 weeks or longer after the initiation of Vectibix®. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS during and for 8 weeks after the completion of Vectibix® therapy. Institute appropriate Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and treatment (eg, oral or intravenous electrolyte repletion) as needed. were severe (NCI-CTC grade 3 or higher) in 12% of patients receiving Vectibix® Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear monotherapy. [See Dosage and Administration (2.1), Warnings and Precautions sunscreen and hats, and limit sun exposure while receiving Vectibix® and for 2 months (5.1), and Adverse Reactions (6.1)]. after the last dose.

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have patients. Fatal infusion reactions occurred in postmarketing experience. [See been reported with Vectibix®. Monitor for evidence of keratitis or ulcerative keratitis.

Dosage and Administration (2.1), Warnings and Precautions (5.2), and Adverse Interrupt or discontinue Vectibix® for acute or worsening keratitis.

Reactions (6.1, 6.3)].

Adequate contraception in both males and females must be used while receiving In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC Vectibix® and for 6 months after the last dose of Vectibix® therapy. Vectibix® may be grade 3 and higher) in 16% of patients with mCRC receiving Vectibix®. Subsequent to transmitted from the mother to the developing fetus and has the potential to cause the development of severe dermatologic toxicities, infectious complications, including fetal harm when administered to pregnant women. sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and Discontinue nursing or discontinue drug, taking into account the importance of the drainage were reported. Withhold or discontinue Vectibix® for severe or life-threatening drug to the mother. If nursing is interrupted, it should not be resumed earlier than dermatologic toxicity and monitor for inflammatory or infectious sequelae.

2 months following the last dose of Vectibix®.

Terminate the infusion for severe infusion reactions.

The most common adverse events of Vectibix® are skin rash with variable presentations, Vectibix® is not indicated for use in combination with chemotherapy. In an interim hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including analysis of a randomized clinical trial, the addition of Vectibix® to the combination of diarrhea resulting in dehydration. ® bevacizumab and chemotherapy resulted in decreased overall survival and increased The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, incidence of NCI-CTC grade 3-5 (87% vs 72%) adverse reactions. NCI-CTC grade 3-4 severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion adverse reactions occurring at a higher rate in patients treated with Vectibix® included reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. rash/dermatitis/acneiform (26% vs 1%); diarrhea (23% vs 12%); dehydration Please see brief summary of Prescribing Information on next page.

(16% vs 5%), primarily occurring in patients with diarrhea; hypokalemia (10% vs 4%); Reference: 1. Vectibix® (panitumumab) stomatitis/mucositis (4% vs < 1%); and hypomagnesemia (4% vs 0%). NCI-CTC grade prescribing information, Amgen.

3-5 pulmonary embolism occurred at a higher rate in patients treated with Vectibix® (7% vs 4%) and included fatal events in 3 (< 1%) patients treated with Vectibix®.

In a single-arm study of 19 patients receiving Vectibix® in combination with IFL, the incidence of NCI-CTC grade 3-4 diarrhea was 58%; in addition, grade 5 diarrhea

©2011 Amgen Inc. All rights reserved. 04-11 MC48257-B

The ASCO Post | JUNE 15, 2011

PAGE 10

News

ACOG Briefs continued from page 8

women in the state of New Hampshire.

The study included 281 women identified in the state’s tumor registry who were age 65 to 99 years (mean age, 77 years). Aggressiveness of care was de-

termined using an Aggressiveness Index based on the current standard of care (1 = least aggressive, 5 = most aggressive).

Slightly less than two-thirds of patients (63.4%) had surgery, and 148 had chemotherapy (52.8%). Of Trim: 7.875” Live: 7”

Vectibix® (panitumumab) Injection for intravenous Infusion Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

WARNING: DERMATOLOGIC TOXICITY and INFUSION REACTIONS Dermatologic Toxicity: Dermatologic toxicities occurred in 89% of patients and were severe (NCI-CTC grade 3 and higher) in 12% of patients receiving Vectibix monotherapy. [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Infusion Reactions: Severe infusion reactions occurred in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience [see Dosage and Administration, Warnings and Precautions, and Adverse Reactions].

Table 1. Per-Patient Incidence of Adverse Reactions Occurring in ≥ 5% of Patients With a Between-Group Difference of ≥ 5% (Study 1) Patients Treated With Vectibix Plus BSC (n = 229) Best Supportive Care (BSC) Alone (n = 234) Grade* All Grades (%) Grade 3–4 (%) All Grades (%) Grade 3–4 (%) Fatigue 26 4 15 3 General Deterioration 11 8 4 3 Digestive Abdominal Pain 25 7 17 5 Nausea 23 1 16 <1 Diarrhea 21 2 11 0 Constipation 21 3 9 1 Vomiting 19 2 12 1 Stomatitis 7 0 1 0 Mucosal Inflammation 6 <1 1 0 Metabolic/Nutritional Hypomagnesemia (Lab) 38 4 2 0 Peripheral Edema 12 1 6 <1 Respiratory Cough 14 <1 7 0 Skin/Appendages All Skin/Integument Toxicity 90 16 9 0 Skin 90 14 6 0 Erythema 65 5 1 0 Dermatitis Acneiform 57 7 1 0 Pruritus 57 2 2 0 Nail 29 2 0 0 Paronychia 25 2 0 0 Skin Exfoliation 25 2 0 0 Rash 22 1 1 0 Skin Fissures 20 1 <1 0 Eye 15 <1 2 0 Acne 13 1 0 0 Dry Skin 10 0 0 0 Other Nail Disorder 9 0 0 0 Hair 9 0 1 0 Growth of Eyelashes 6 0 0 0 *Version 2.0 of the NCI-CTC was used for grading toxicities. Skin toxicity was coded based on a modification of the NCI-CTCAE, version 3.0.

Body System Body as a Whole

Dermatologic, Mucosal, and Ocular Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients receiving Vectibix. Skin toxicity was severe (NCI-CTC grade 3 and higher) in 16% of patients. Ocular toxicities occurred in 15% of patients and included, but were not limited to, conjunctivitis (4%), ocular hyperemia (3%), increased lacrimation (2%), and eye/eyelid irritation (1%). Stomatitis (7%) and oral mucositis (6%) were reported. One patient experienced an NCI-CTC grade 3 event of mucosal inflammation. The incidence of paronychia was 25% and was severe in 2% of patients. Nail disorders occurred in 9% of patients [see Warnings and Precautions]. Median time to the development of dermatologic, nail, or ocular toxicity was 14 days after the first dose of Vectibix; the median time to most severe skin/ocular toxicity was 15 days after the first dose of Vectibix; and the median time to resolution after the last dose of Vectibix was 84 days. Severe toxicity necessitated dose interruption in 11% of Vectibixtreated patients [see Dosage and Administration]. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, and abscesses requiring incisions and drainage, were reported.

Infusion Reactions: Infusional toxicity was defined as any event within 24 hours of an infusion during the clinical study described as allergic reaction or anaphylactoid reaction, or any event occurring on the first day of dosing described as allergic reaction, anaphylactoid reaction, fever, chills, or dyspnea. Vital signs and temperature were measured within 30 minutes prior to initiation and upon completion of the Vectibix infusion. The use of premedication was not standardized in the clinical trials. Thus, the utility of premedication in preventing the first or subsequent episodes of infusional toxicity is unknown. Across several clinical trials of Vectibix monotherapy, 3% (43/1336) experienced infusion reactions of which approximately 1% (6/1336) were severe (NCI-CTC grade 3–4). In one patient, Vectibix was permanently discontinued for a serious infusion reaction [see Dosage and Administration].

Immunogenicity: As with all therapeutic proteins, there is potential for immunogenicity. The immunogenicity of Vectibix has been evaluated using two different screening immunoassays for the detection of anti-panitumumab antibodies: an acid dissociation bridging enzyme-linked immunosorbent assay (ELISA) (detecting high-affinity antibodies) and a Biacore® biosensor immunoassay (detecting both high- and low-affinity antibodies). The incidence of binding antibodies to panitumumab (excluding predose and transient positive patients), as detected by the acid dissociation ELISA, was 3/613 (< 1%) and as detected by the Biacore® assay was 28/613 (4.6%). For patients whose sera tested positive in screening immunoassays, an in vitro biological assay was performed to detect neutralizing antibodies. Excluding predose and transient positive patients, 10/613 patients (1.6%) with postdose samples and 3/356 (0.8%) of the patients with follow-up samples tested positive for neutralizing antibodies. No evidence of altered pharmacokinetic profile or toxicity profile was found between patients who developed antibodies to panitumumab as detected by screening immunoassays and those who did not. The incidence of antibody formation is highly dependent on the sensitivity and specificity of the assay.

Additionally, the observed incidence of antibody (including neutralizing antibody) positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to panitumumab with the incidence of antibodies to other products may be misleading.

Postmarketing Experience: The following adverse reactions has been identified during post-approval. Because these reactions are reported in a population of uncertain size, it is not always possible to reliably estimate their frequency or established a causal relationship to drug exposure: • Skin and subcutaneous tissue disorders: Angioedema [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Skin and subcutaneous tissue disorders: Skin necrosis • Immune system disorders: Anaphylactoid reaction [see Boxed Warning, Dosage and Administration (2.1), and Warnings and Precautions (5.2)] • Eye disorders: Keratitis/ulcerative keratitis [see Warnings and Precautions (5.7)] DRUG INTERACTIONS: No formal drug-drug interaction studies have been conducted with Vectibix.

USE IN SPECIFIC POPULATIONS Pregnancy – Category C: There are no studies of Vectibix in pregnant women. Reproduction studies in cynomolgus monkeys treated with 1.25 to 5 times the recommended human dose of panitumumab resulted in significant embryolethality and abortions; however, no other evidence of teratogenesis was noted in offspring. [see Reproductive and Developmental Toxicology]. Vectibix should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus.

Based on animal models, EGFR is involved in prenatal development and may be essential for normal organogenesis, proliferation, and differentiation in the developing embryo. Human IgG is known to cross the placental barrier; therefore, panitumumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Women who become pregnant during Vectibix treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-772-6436 (1-800-77-AMGEN) to enroll.

Nursing Mothers: It is not known whether panitumumab is excreted into human milk; however, human IgG is excreted into human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in nursing infants from Vectibix, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. If nursing is interrupted, based on the mean half-life of panitumumab, nursing should not be resumed earlier than 2 months following the last dose of Vectibix [see Clinical Pharmacology (12.3) in Full Prescribing Information].

Pediatric Use: The safety and effectiveness of Vectibix have not been established in pediatric patients. The pharmacokinetic profile of Vectibix has not been studied in pediatric patients.

Geriatric Use: Of 229 patients with mCRC who received Vectibix in Study 1, 96 (42%) were ≥ age 65. Although the clinical study did not include a sufficient number of geriatric patients to determine whether they respond differently from younger patients, there were no apparent differences in safety and effectiveness of Vectibix between these patients and younger patients.

OVERDOSAGE Doses up to approximately twice the recommended therapeutic dose (12 mg/kg) resulted in adverse reactions of skin toxicity, diarrhea, dehydration, and fatigue.

PATIENT COUNSELING INFORMATION Advise patients to contact a healthcare professional for any of the following: • Skin and ocular/visual changes [see Boxed Warning and Warnings and Precautions], • Signs and symptoms of infusion reactions including fever, chills, or breathing problems [see Boxed Warning, Dosage and Administration, Warnings and Precautions and Adverse Reactions], • Diarrhea and dehydration [see Warnings and Precautions], • Persistent or recurrent coughing, wheezing, dyspnea, or new onset facial swelling [see Warnings and Precautions, and Adverse Reactions], • Pregnancy or nursing [see Use in Specific Populations].

Advise patients of the need for: • Periodic monitoring of electrolytes [see Warnings and Precautions], • Limitation of sun exposure (use sunscreen, wear hats) while receiving Vectibix and for 2 months after the last dose of Vectibix therapy. [see Warnings and Precautions], • Adequate contraception in both males and females while receiving Vectibix and for 6 months after the last dose of Vectibix therapy [see Use in Specific Populations].

This brief summary is based on the Vectibix® prescribing information v11, 3/2011 Rx Only This product, its production, and/or its use may be covered by one or more US Patents, including US Patent No. 6,235,883, and 7,807,798 as well as other patents or patents pending. ©2006-2011 Amgen Inc. All rights reserved.

MC46026-E

age 4 years younger than those who were not; the average age of those receiving multiagent chemotherapy was 6 years younger than those who received single-agent chemotherapy.

A trend was observed toward less aggressive treatment in women with more medical comorbidities (assessed by the Charlson Comorbidity Index).

“Despite this being a healthy population overall, there appears to be a bias toward less aggressive care with older age,” said lead author Elizabeth Lokich, MD, DartmouthHitchcock Medical Center. She suggested that many patients included in the registry were from more rural areas and may have been treated by physicians who were “less aware of how well older patients can do with surgery and chemotherapy [than oncologists at Dartmouth].”

She and her coauthors plan to conduct another study to examine the factors that underlie suboptimal treatment of ovarian cancer in older patients.

Markers for Lymph Node Metastases A retrospective study of 343 women who had undergone total abdominal hysterectomy, bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymph node dissection for endometrioid adenocarcinoma of the endometrium suggests that tumors that stain estrogen receptor (ER)-positive, progesterone receptor (PR)-positive, and p53-negative are not likely to be associated with lymph node metastases. None of the 108 patients with grade 1 tumors that stained ER-positive, PR-positive, and p53-negative had positive lymph nodes; among 143 patients with grade 2 disease and 70 with grade 3 disease, positive nodes were detected in only 6 (4.4%) patients with ERpositive, PR-positive, p53-negative tumors.

The study was reported at a poster session by lead author Karina Zapiecki, MD, Division of Gynecologic Oncology, University of Toledo College of Medicine, Ohio. Future studies will look at the correlation between staining in diagnostic biopsy specimens and nodal status.

Trim: 10.75” Live: 10”

INDICATIONS AND USAGE Vectibix is indicated as a single agent for the treatment of epidermal growth factor receptor (EGFR)-expressing, metastatic colorectal carcinoma (mCRC) with disease progression on or following fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy regimens [see Clinical Studies (14) in Full Prescribing Information].

The effectiveness of Vectibix as a single agent for the treatment of EGFR-expressing, metastatic colorectal carcinoma is based on progressionfree survival [see Clinical Studies (14) in Full Prescribing Information]. Currently, no data demonstrate an improvement in disease-related symptoms or increased survival with Vectibix. Retrospective subset analyses of metastatic colorectal cancer trials have not shown a treatment benefit for Vectibix in patients whose tumors had KRAS mutations in codon 12 or 13. Use of Vectibix is not recommended for the treatment of colorectal cancer with these mutations. [see Clinical Studies (14) in Full Prescribing Information].

DOSAGE AND ADMINISTRATION Recommended Dose and Dose Modifications: The recommended dose of Vectibix is 6 mg/kg, administered as an intravenous infusion over 60 minutes, every 14 days. Doses higher than 1000 mg should be administered over 90 minutes [see Dosage and Administration].

Appropriate medical resources for the treatment of severe infusion reactions should be available during Vectibix infusions.

Dose Modifications for Infusion Reactions [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Reduce infusion rate by 50% in patients experiencing a mild or moderate (grade 1 or 2) infusion reaction for the duration of that infusion.

Terminate the infusion in patients experiencing severe infusion reactions. Depending on the severity and/or persistence of the reaction, permanently discontinue Vectibix.

Dose Modifications for Dermatologic Toxicity [see Boxed Warning, Warnings and Precautions, and Adverse Reactions] • Withhold Vectibix for dermatologic toxicities that are grade 3 or higher or are considered intolerable. If toxicity does not improve to ≤ grade 2 within 1 month, permanently discontinue Vectibix.

• If dermatologic toxicity improves to ≤ grade 2, and the patient is symptomatically improved after withholding no more than two doses of Vectibix, treatment may be resumed at 50% of the original dose.

– If toxicities recur, permanently discontinue Vectibix.

– If toxicities do not recur, subsequent doses of Vectibix may be increased by increments of 25% of the original dose until the recommended dose of 6 mg/kg is reached.

Do not administer Vectibix as an intravenous push or bolus.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS Dermatologic Toxicity: In Study 1, dermatologic toxicities occurred in 90% of patients and were severe (NCI-CTC grade 3 and higher) in 16% of patients with mCRC receiving Vectibix. The clinical manifestations included, but were not limited to, dermatitis acneiform, pruritus, erythema, rash, skin exfoliation, paronychia, dry skin, and skin fissures. Subsequent to the development of severe dermatologic toxicities, infectious complications, including sepsis, septic death, necrotizing fasciitis and abscesses requiring incisions and drainage were reported.

Withhold Vectibix for severe or life-threatening dermatologic toxicity. [see Boxed Warning, Adverse Reactions, and Dosage and Administration].

Infusion Reactions: In Study 1, 4% of patients experienced infusion reactions and in 1% of patients, these reactions were graded as severe (NCICTC grade 3–4).

Infusion reactions, manifesting as anaphylactoid reactions, bronchospasm, and hypotension, can occur following Vectibix administration [see Boxed Warning, and Adverse Reactions]. In clinical studies, severe infusion reactions occurred with the administration of Vectibix in approximately 1% of patients. Fatal infusion reactions occurred in postmarketing experience. Terminate the infusion for severe infusion reactions. [see Dosage and Administration].

Increased Toxicity With Combination Chemotherapy: Vectibix is not indicated for use in combination with chemotherapy. In an interim analysis of Study 2, the addition of Vectibix to the combination of bevacizumab and chemotherapy resulted in decreased overall survival and increased incidence of NCI-CTC grade 3–5 (87% vs 72%) adverse reactions [see Clinical Studies (14) in Full Prescribing Information]. NCICTC grade 3–4 adverse drug reactions occurring at a higher rate in Vectibix-treated patients included rash/dermatitis acneiform (26% vs 1%), diarrhea (23% vs 12%), dehydration (16% vs 5%), primarily occurring in patients with diarrhea, hypokalemia (10% vs 4%), stomatitis/mucositis (4% vs < 1%), and hypomagnesemia (4% vs 0). NCI-CTC grade 3–5 pulmonary embolism occurred at a higher rate in Vectibix-treated patients (7% vs 4%) and included fatal events in three (< 1%) Vectibix-treated patients. As a result of the toxicities experienced, patients randomized to Vectibix, bevacizumab, and chemotherapy received a lower mean relative dose intensity of each chemotherapeutic agent (oxaliplatin, irinotecan, bolus 5-FU, and/or infusional 5-FU) over the first 24 weeks on study, compared with those randomized to bevacizumab and chemotherapy. In a single-arm study of 19 patients receiving Vectibix in combination with IFL, the incidence of NCI-CTC grade 3–4 diarrhea was 58%; in addition, grade 5 diarrhea occurred in one patient. In a single-arm study of 24 patients receiving Vectibix plus FOLFIRI, the incidence of NCI-CTC grade 3 diarrhea was 25%.

Severe diarrhea and dehydration which may lead to acute renal failure and other complications have been observed in patients treated with Vectibix in combination with chemotherapy.

Pulmonary Fibrosis: Pulmonary fibrosis occurred in less than 1% (2/1467) of patients enrolled in clinical studies of Vectibix. Following the initial fatality described below, patients with a history of interstitial pneumonitis, pulmonary fibrosis, evidence of interstitial pneumonitis, or pulmonary fibrosis were excluded from clinical studies. Therefore, the estimated risk in a general population that may include such patients is uncertain. One case occurred in a patient with underlying idiopathic pulmonary fibrosis who received Vectibix in combination with chemotherapy and resulted in death from worsening pulmonary fibrosis after four doses of Vectibix. The second case was characterized by cough and wheezing 8 days following the initial dose, exertional dyspnea on the day of the seventh dose, and persistent symptoms and CT evidence of pulmonary fibrosis following the 11th dose of Vectibix as monotherapy. An additional patient died with bilateral pulmonary infiltrates of uncertain etiology with hypoxia after 23 doses of Vectibix in combination with chemotherapy. Permanently discontinue Vectibix therapy in patients developing interstitial lung disease, pneumonitis, or lung infiltrates.

Electrolyte Depletion/Monitoring: In Study 1, median magnesium levels decreased by 0.1 mmol/L in the Vectibix arm; hypomagnesemia (NCI-CTC grade 3 or 4) requiring oral or intravenous electrolyte repletion occurred in 2% of patients. Hypomagnesemia occurred 6 weeks or longer after the initiation of Vectibix. In some patients, both hypomagnesemia and hypocalcemia occurred. Patients’ electrolytes should be periodically monitored during and for 8 weeks after the completion of Vectibix therapy. Institute appropriate treatment, eg, oral or intravenous electrolyte repletion, as needed.

Photosensitivity: Exposure to sunlight can exacerbate dermatologic toxicity. Advise patients to wear sunscreen and hats and limit sun exposure while receiving Vectibix.

Ocular Toxicities: Keratitis and ulcerative keratitis, known risk factors for corneal perforation, have been reported with Vectibix use. Monitor for evidence of keratitis or ulcerative keratitis. Interrupt or discontinue Vectibix therapy for acute or worsening keratitis.

EGF Receptor Testing: Detection of EGFR protein expression is necessary for selection of patients appropriate for Vectibix therapy because these are the only patients studied and for whom benefit has been shown [see Indications and Usage and Clinical Studies (14) in Full Prescribing Information]. Patients with colorectal cancer enrolled in Study 1 were required to have immunohistochemical evidence of EGFR expression using the Dako EGFR pharmDx® test kit. Assessment for EGFR expression should be performed by laboratories with demonstrated proficiency in the specific technology being utilized. Improper assay performance, including use of suboptimally fixed tissue, failure to utilize specific reagents, deviation from specific assay instructions, and failure to include appropriate controls for assay validation, can lead to unreliable results. Refer to the package insert for the Dako EGFR pharmDx® test kit, or other test kits approved by FDA, for identification of patients eligible for treatment with Vectibix and for full instructions on assay performance.

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the label: • Dermatologic Toxicity [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Infusion Reactions [see Boxed Warning, Dosage and Administration, and Warnings and Precautions] • Increased Toxicity With Combination Chemotherapy [see Warnings and Precautions] • Pulmonary Fibrosis [see Warnings and Precautions] • Electrolyte Depletion/Monitoring [see Warnings and Precautions] • Photosensitivity [see Warnings and Precautions] The most common adverse events of Vectibix are skin rash with variable presentations, hypomagnesemia, paronychia, fatigue, abdominal pain, nausea, and diarrhea, including diarrhea resulting in dehydration.

The most serious adverse events of Vectibix are pulmonary fibrosis, pulmonary embolism, severe dermatologic toxicity complicated by infectious sequelae and septic death, infusion reactions, abdominal pain, hypomagnesemia, nausea, vomiting, and constipation. Adverse reactions requiring discontinuation of Vectibix were infusion reactions, severe skin toxicity, paronychia, and pulmonary fibrosis.

Clinical Trials Experience: Because clinical trials are conducted under widely varying conditions, adverse reaction rates in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. The adverse reaction information from clinical studies does, however, provide a basis for identifying the adverse events that appear to be related to drug use and for approximating rates.

Safety data are available from 15 clinical trials in which 1467 patients received Vectibix; of these, 1293 received Vectibix monotherapy and 174 received Vectibix in combination with chemotherapy [see Warnings and Precautions].

The data described in Table 1 and in other sections below, except where noted, reflect exposure to Vectibix administered as a single agent at the recommended dose and schedule (6 mg/kg every 2 weeks) in 229 patients with mCRC enrolled in Study 1, a randomized, controlled trial.

The median number of doses was five (range: one to 26 doses), and 71% of patients received eight or fewer doses. The population had a median age of 62 years (range: 27 to 82 years), 63% were male, and 99% were white with < 1% black, < 1% Hispanic, and 0% other.

those treated with chemotherapy, 71.2% had adjuvant chemotherapy, 10.3% had adjuvant and neoadjuvant therapy, 90.4% had multiagent chemotherapy, and 9.6% had singleagent chemotherapy. Those treated with chemotherapy were on aver-

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Financial Disclosure: Dr. Lokich reported no potential conflicts of interest. Dr. Woodruff reported no potential conflicts of interest. Dr. Twiggs reported that he is on the speakers bureau for Merck and was previously on the speakers bureau for GlaxoSmithKline.

ASCOPost.com | JUNE 15, 2011

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News Translational Research

‘Paradoxical’ Result Tying Estrogen to Reduced Risk of Breast Cancer Is Consistent with Laboratory Data

By Charlotte Bath

R

esults from the Women’s Health Initiative1 showing a decreased incidence of breast cancer among postmenopausal hysterectomized women who took estrogen replacement therapy (ERT) may seem paradoxical, but “comply exactly” with laboratory research, according to V. Craig Jordan, OBE, PhD, DSc, Scientific Director and Vice Chairman of Oncology at the Lombardi Comprehensive Cancer Center, Georgetown University.

trogen receptor modulators (SERMs) such as tamoxifen and raloxifene (for which he received the American Cancer Society Award for Chemoprevention at the 2006 ASCO Annual Meeting), it may even seem paradoxical that Dr. Jordan is the author of the paper linking estrogen to decreased incidence of breast cancer. Dr. Jordan acknowledged the irony, noting that he now introduces himself by saying, “It’s not that I’m antiestrogen.

I’m proestrogen under the right circumstances.” (In fact, his Karnofsky Lecture at the 2008 Annual Meeting was titled “The Paradoxical Actions of Estrogen in Breast Cancer—Survival or Death?”2)

‘Fuel for the Fire’ Leslie G. Ford, MD

“Though paradoxical because estrogen is recognized to stimulate breast cancer growth, laboratory data support a mechanism of estrogen-induced apoptosis under the correct environmental circumstances. Long-term antiestrogen treatment or estrogen deprivation causes the eventual development and evolution of antihormone resistance,” wrote Dr. Jordan and coauthor Leslie G. Ford, MD, of the NCI’s Division of Cancer Prevention, in an article recently published online in Cancer Prevention Research.1 To those familiar with Dr. Jordan’s work over the years with selective es-

“It is widely held that estrogen can be carcinogenic in breast tissue and is the ‘fuel for the fire’ to stimulate the growth of estrogen receptor (ER)-positive breast cancer cells.

This knowledge, supported by an enormous body of laboratory data, provides the conceptual basis for the successful development of antihormonal strategies to treat breast cancer,” the research paper noted. The Women’s Health Initiative’s observed decrease in invasive cancer, which was sustained for 5 years after ERT was stopped, “seems to run counter to the perceived wisdom of the role of estrogen in breast carcinogenesis,” the authors wrote. The reduction in breast cancer seen in the Women’s Health Initiative study, however, “is

‘It’s Darwinian’

D

epriving breast cancer cells of estrogen, whether by oophorectomy or treatment with tamoxifen or aromatase inhibitors, will induce “a crisis point, and about 80% of the cells will die off,” V. Craig Jordan, OBE, PhD, DSc, reported. After a while, “by chance, some of the cells that have the right configuration of molecular biology and biochemistry will learn to grow towards the little signal” that the small amount of remaining estrogen provides.

“Cancer cells are very clever,” he said. “All of these cells can die out, but the ones that grow towards the food are the survivors. It’s Darwinian. It’s survival of the fittest, and the one that can survive on the little bit of estrogen is the one that starts to grow. So it grows up and it has the fidelity to keep reproducing the ones that survive. Now you’ve got cells that have a completely different survival mechanism to grow, an absolutely different set of pathways. They reconfigure themselves by an outgrowth of the cells that can survive with virtually no estrogen. Then the estrogen comes back and, in effect, says, ‘You’ve got the wrong pathways. You’re out of here.’”

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Essence of Translational Research

I

V. Craig Jordan, OBE, PhD, DSc

like to do research where there is a clear implication for human beings. In the clinical research I have been doing year after year, we have discovered things about human beings that can now be understood in the context of laboratory research that is being done. That’s the essence of translational research. It is a conversation between the laboratory and the clinic. It’s nature communicating with us. If we ask a question of nature, nature doesn’t lie. It just tells you what the answer is.

—V. Craig Jordan, OBE, PhD, DSc

consistent nevertheless with parallel laboratory studies completed over the last 20 years,” they noted. An article in the Journal of the American Medical Association on the Women’s Health Initiative study reported a statistically significant lower cumulative breast cancer incidence of 0.27% in women taking conjugated equine estrogens, compared with 0.35% in the placebo group.3 “The key to all of this is that the clones of breast cancer cells that grow out in the laboratory or in a premenopausal woman’s body are feeding on all of this fuel—the estrogen—and keep replicating,” Dr. Jordan explained in an interview with The ASCO Post.

With menopause or use of an antihormone therapy, the cells that can only grow with the fuel of estrogen start to die out. “The cells that survive the transition have a nimbleness in their capacity to adapt to a low-estrogen environment. These cells start to reproduce preferentially, and over a period of time, they are growing on a minute signal of estrogen that would be available in a postmenopausal woman, or in a woman taking an aromatase inhibitor or tamoxifen,” he said.

“With a postmenopausal woman, what you basically have is estrogen withdrawal with a little bit of estrogen around,” he continued. “What you see with ERT in the Women’s Health Initiative is a profound effect of the estrogen that is available to what are probably nascent cells.” If a woman takes estrogen replacement therapy, these cells are suddenly swamped by the incoming estrogen; they are overwhelmed, go through apoptosis, and die.

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Interpreting the Findings “The result from the Women’s Health Initiative Trial of ERT in hysterectomized women, which showed a sustained reduction in the incidence of breast cancer, provides additional evidence that the strategy to decipher the mechanism of physiologic estrogen to induce apoptosis has significance for both treatment and prevention,” Drs. Jordan and Ford wrote.

Dr. Jordan stressed that the findings from Women’s Health Initiative apply only to postmenopausal women who have had hysterectomies. These women could take estrogen without fear that it might cause breast SEE PAGE 41 cancer, and such an approach might even decrease the risk, but recommending estrogen to reduce breast cancer risk “would be premature,” Dr. Jordan said. “What we have to do now is take on board this very important clinical result [from the Women’s Health Initiative trial] and study the mechanism in detail. It may be that if hysterectomized women take estrogen replacement therapy, they at least have no increase in breast cancer,” he suggested.

“Absolutely no one should be saying that estrogen replacement therapy is a potential chemopreventive for breast cancer in women,” Dr. Ford said.

The Women’s Health Initiative trial result “is a piece of information that tells us about the safety of estrogen replacement therapy. So women can have the benefits of estrogen replacement therapy with regard to their bones and their well-being, and in reducing the continued on page 12

The ASCO Post | JUNE 15, 2011

PAGE 12

News

Estrogen Replacement Therapy continued from page 11

frequency and severity of hot flashes,” Dr. Ford said. “But they still need mammograms.”

Dr. Jordan pointed out that estradiol “is available for physicians to use for the treatment of metastatic breast cancer.” Physicians can use it “as a discretionary measure. If their patients have had multiple endocrine therapies, they should be able to consider that as an option that may provide some months of relief for their patients instead of going on to chemotherapy,” he said.

“Nobody should be rushing off to the doctor saying, ‘I want to prevent breast cancer. Forget raloxifene. Give me some estrogen,’” Dr. Jordan continued. He also stressed that for women who are currently taking antihormone therapy to prevent metastatic breast disease, “You don’t stop the treatment plan.”

Ongoing Research Finding out more about how estrogen functions in cells that have been deprived of estrogen for years will provide additional tools for developing therapeutic paradigms, Dr. Jordan said. He cited the Study of Letrozole Extension (SOLE) trial, which is comparing breast cancer recurrence rates among women who have completed 4 to 6 years of adjuvant endocrine therapy with a SERM and/or aromatase inhibitor and were then randomly assigned to letrozole

Coming in the July 1 and July 15 issues of

The ASCO Post Comprehensive coverage of the 2011 ASCO Annual Meeting

visit ASCOPost.com

either continuously or intermittently with 3-month drug holidays every year for 5 years. “Let’s see if the woman’s own estrogen, like little pulses every 3 months, can improve recurrence rates in the intermittent-letrozole arm compared with the continuous-letrozole arm. That may just drive antihormone therapy more,” Dr. Jordan said.

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Financial Disclosure: Dr. Jordan and Dr. Ford reported no potential conflicts of interest.

References 1. Jordan VC, Ford LG: Paradoxical clinical effect of estrogen on breast cancer risk: A “new” biology of estrogen-induced apoptosis. Cancer Prevention Research.

April 10, 2011 (early release online).

2. Jordan VC: The 38th David A. Karnofsky Lecture: The paradoxical actions of estrogen in breast cancer—survival or death? J Clin Oncol 26(18S):3073-3082, 2008.

3. LaCroix AZ, Chlebowski RT, Manson JE, et al: Health outcomes after stopping conjugated equine estrogens among postmenopausal women with prior hysterectomy. JAMA 305:1305-1314, 2011.

TREANDA® is his chemo.

This is his therapy.

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PAGE 13

FDA Update

New Drug Application Submitted for Vemurafenib in Melanoma

D

aiichi Sankyo announced that applications have been submitted for market approval for vemurafenib (PLX4032/RG7204) for the treatment of metastatic melanoma to the FDA and the European Medi-

cines Agency (EMA). Additionally, a premarketing application for approval for a companion diagnostic test has been submitted in the United States.

Vemurafenib is an oral, novel drug that targets the oncogenic BRAF mu-

tation present in about half of melanoma cancers and about 8% of all solid tumors.

In April 2011, Daiichi Sankyo, Co, Ltd, acquired Plexxikon, which discovered and is co-developing vemu-

rafenib with Roche. Daiichi Sankyo, Inc, will copromote vemurafenib in the United States with Genentech under Plexxikon’s copromotion agreement with Genentech, a member of the Roche Group.

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Single-agent TREANDA tripled median PFS in patients with CLL* PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

Survival distribution function

.25”

5.5”

ASCOPost.com | JUNE 15, 2011

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

P<.0001 HR†=0.27 (95% CI‡: 0.17, 0.43)

0

5

10

15

20

25

30

35

40

45

Months *TREANDA (95% CI: 11.7, 23.5) vs chlorambucil (95% CI: 5.6, 8.6). † HR=hazard ratio. ‡ CI=confidence interval.

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatmentnaïve patients with Binet stage B or C (Rai stages I-IV) CLL who required treatment (N=301). Patients were scheduled to receive either TREANDA 100 mg/m2 intravenously on Days 1 and 2 (n=153) or chlorambucil 0.8 mg/kg orally on Days 1 and 15 (n=148) of a 28-day treatment cycle, up to 6 cycles • TREANDA was generally well tolerated in the pivotal phase 3 trial

Discover the elements of efficacy and safety LEARN MORE AT TREANDA.COM Please see accompanying brief summary of full Prescribing Information.

Built for Action™ ©2011 Cephalon, Inc. All rights reserved. TRE-2215 January 2011 Printed in USA.

T:10.5”

Selected Safety Information • Serious adverse reactions, including myelosuppression, infections, infusion reactions and anaphylaxis, tumor lysis syndrome, skin reactions including SJS/TEN, other malignancies, and extravasation, have been associated with TREANDA. Some reactions, such as myelosuppression, infections, and SJS/TEN (when TREANDA was administered concomitantly with allopurinol and other medications known to cause SJS/TEN), have been fatal. Patients should be monitored closely for these reactions and treated promptly if any occur • Adverse reactions may require interventions such as decreasing the dose of TREANDA, or withholding or delaying treatment. Myelosuppression is frequently severe and should be expected when treating patients with TREANDA • TREANDA is contraindicated in patients with a known hypersensitivity to bendamustine or mannitol.

Women should be advised to avoid becoming pregnant while using TREANDA

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TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL).

Efficacy relative to first-line therapies other than chlorambucil has not been established.

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• The most common non-hematologic adverse reactions (frequency ≥15%) were pyrexia (24%), nausea (20%), and vomiting (16%) (n=153). The most common hematologic abnormalities (frequency ≥15%) were anemia (89%), thrombocytopenia (77%), neutropenia (75%), lymphopenia (68%), and leukopenia (61%) (n=150)

The ASCO Post | JUNE 15, 2011

PAGE 14

FDA Update

FDA Approves Sunitinib for Pancreatic Neuroendocrine Tumors

T

he FDA approved sunitinib (Sutent) to treat patients with progressive neuroendocrine cancerous tumors located in the pancreas that cannot be removed by surgery or that have metastasized.

This is the second new approval by

the FDA to treat patients with this disease. On May 5, the agency approved everolimus (Afinitor) for this indication.

The safety and effectiveness of sunitinib was established in a single study of 171 patients with metastatic or loT:7.75” S:7”

The Grade 3 and 4 hematology laboratory test values by treatment group in the randomized CLL clinical study are described in Table 2. These findings confirm the myelosuppressive effects seen in patients treated with TREANDA. Red blood cell transfusions were administered to 20% of patients receiving TREANDA compared with 6% of patients receiving chlorambucil.

Table 2: Incidence of Hematology Laboratory Abnormalities in Patients Who Received TREANDA or Chlorambucil in the Randomized CLL Clinical Study TREANDA Chlorambucil (N=150) (N=141) All Grades Grade 3/4 All Grades Grade 3/4 Laboratory Abnormality n (%) n (%) n (%) n (%) Hemoglobin Decreased 134 (89) 20 (13) 115 (82) 12 (9) Platelets Decreased 116 (77) 16 (11) 110 (78) 14 (10) Leukocytes Decreased 92 (61) 42 (28) 26 (18) 4 (3) Lymphocytes Decreased 102 (68) 70 (47) 27 (19) 6 (4) Neutrophils Decreased 113 (75) 65 (43) 86 (61) 30 (21) In the randomized CLL clinical study, 34% of patients had bilirubin elevations, some without associated significant elevations in AST and ALT. Grade 3 or 4 increased bilirubin occurred in 3% of patients.

Increases in AST and ALT of Grade 3 or 4 were limited to 1% and 3% of patients, respectively. Patients treated with TREANDA may also have changes in their creatinine levels. If abnormalities are detected, monitoring of these parameters should be continued to ensure that significant deterioration does not occur. Post-Marketing Experience. The following adverse reactions have been identified during postapproval use of TREANDA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure: anaphylaxis; and injection or infusion site reactions including pruritus, irritation, pain, and swelling. Skin reactions including SJS and TEN have occurred when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. [See Warnings and Precautions] OVERDOSAGE: The intravenous LD of bendamustine HCl is 240 mg/m2 in the mouse and rat. Toxicities included sedation, tremor, ataxia, convulsions and respiratory distress. Across all clinical experience, the reported maximum single dose received was 280 mg/m2. Three of four patients treated at this dose showed ECG changes considered dose-limiting at 7 and 21 days post-dosing. These changes included QT prolongation (one patient), sinus tachycardia (one patient), ST and T wave deviations (two patients), and left anterior fascicular block (one patient). Cardiac enzymes and ejection fractions remained normal in all patients. No specific antidote for TREANDA overdose is known. Management of overdosage should include general supportive measures, including monitoring of hematologic parameters and ECGs. DOSAGE AND ADMINISTRATION: Dosing Instructions for CLL. Recommended Dosage: The recommended dose is 100 mg/m2 administered intravenously over 30 minutes on Days 1 and 2 of a 28-day cycle, up to 6 cycles. Dose Delays, Dose Modifications and Reinitiation of Therapy for CLL: TREANDA administration should be delayed in the event of Grade 4 hematologic toxicity or clinically significant ≥ Grade 2 nonhematologic toxicity. Once non-hematologic toxicity has recovered to ≤ Grade 1 and/or the blood counts have improved [Absolute Neutrophil Count (ANC) ≥ 1 x 109/L, platelets ≥ 75 x 109/L], TREANDA can be reinitiated at the discretion of the treating physician. In addition, dose reduction may be warranted. [See Warnings and Precautions] Dose modifications for hematologic toxicity: for Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle; if Grade 3 or greater toxicity recurs, reduce the dose to 25 mg/m2 on Days 1 and 2 of each cycle. Dose modifications for non-hematologic toxicity: for clinically significant Grade 3 or greater toxicity, reduce the dose to 50 mg/m2 on Days 1 and 2 of each cycle.

Dose re-escalation in subsequent cycles may be considered at the discretion of the treating physician.

Reconstitution/Preparation for Intravenous Administration. • Aseptically reconstitute each TREANDA vial as follows: • 25 mg TREANDA vial: Add 5 mL of only Sterile Water for Injection, USP. • 100 mg TREANDA vial: Add 20 mL of only Sterile Water for Injection, USP. Shake well to yield a clear, colorless to a pale yellow solution with a bendamustine HCl concentration of 5 mg/mL. The lyophilized powder should completely dissolve in 5 minutes. If particulate matter is observed, the reconstituted product should not be used. • Aseptically withdraw the volume needed for the required dose (based on 5 mg/mL concentration) and immediately transfer to a 500 mL infusion bag of 0.9% Sodium Chloride Injection, USP (normal saline). As an alternative to 0.9% Sodium Chloride Injection, USP (normal saline), a 500 mL infusion bag of 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, may be considered. The resulting final concentration of bendamustine HCl in the infusion bag should be within 0.2–0.6 mg/mL. The reconstituted solution must be transferred to the infusion bag within 30 minutes of reconstitution. After transferring, thoroughly mix the contents of the infusion bag. The admixture should be a clear and colorless to slightly yellow solution. • Use Sterile Water for Injection, USP, for reconstitution and then either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, for dilution, as outlined above. No other diluents have been shown to be compatible. • Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Any unused solution should be discarded according to institutional procedures for antineoplastics. Admixture Stability. TREANDA contains no antimicrobial preservative. The admixture should be prepared as close as possible to the time of patient administration. Once diluted with either 0.9% Sodium Chloride Injection, USP, or 2.5% Dextrose/0.45% Sodium Chloride Injection, USP, the final admixture is stable for 24 hours when stored refrigerated (2-8°C or 36-47°F) or for 3 hours when stored at room temperature (15-30°C or 59-86°F) and room light. Administration of TREANDA must be completed within this period.

DOSAGE FORMS AND STRENGTHS: TREANDA for Injection single-use vial containing either 25 mg or 100 mg of bendamustine HCl as white to off-white lyophilized powder.

HOW SUPPLIED/STORAGE AND HANDLING: Safe Handling and Disposal. As with other potentially toxic anticancer agents, care should be exercised in the handling and preparation of solutions prepared from TREANDA. The use of gloves and safety glasses is recommended to avoid exposure in case of breakage of the vial or other accidental spillage. If a solution of TREANDA contacts the skin, wash the skin immediately and thoroughly with soap and water. If TREANDA contacts the mucous membranes, flush thoroughly with water. Procedures for the proper handling and disposal of anticancer drugs should be considered. Several guidelines on the subject have been published. There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. How Supplied. TREANDA (bendamustine hydrochloride) for Injection is supplied in individual cartons as follows: NDC 63459-390-08 TREANDA (bendamustine hydrochloride) for Injection, 25 mg in 8 mL amber single-use vial and NDC 63459-391-20 TREANDA (bendamustine hydrochloride) for Injection, 100 mg in 20 mL amber single-use vial. Storage. TREANDA may be stored up to 25°C (77°F) with excursions permitted up to 30°C (86°F) (see USP Controlled Room Temperature). Retain in original package until time of use to protect from light.

50

Manufactured by: Manufactured for: Pharmachemie B.V. Cephalon, Inc. The Netherlands Frazer, PA 19355 TREANDA is a trademark of Cephalon, Inc., or its affiliates. ©2008-2010 Cephalon, Inc., or its affiliates.

TRE-2074 (Label Code: 00016287.03) This brief summary is based on TREANDA full Prescribing Information.

March 2010 All rights reserved.

months compared to 5.4 months for patients who received placebo.

In patients treated with sunitinib for neuroendocrine pancreatic tumors, the most commonly reported side effects included diarrhea, nausea, vomiting, fatigue, anorexia, hypertension, asthenia, abdominal pain, changes in hair color, stomatitis, and neutropenia.

Sunitinib is also FDA-approved to treat patients with metastatic renal cell carcinoma and those with gastrointestinal stromal tumor. The drug is marketed by Pfizer.

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Trabectedin New Drug Application Withdrawn

C

entocor Ortho Biotech Products, LP, announced that it has voluntarily withdrawn the New Drug Application (NDA) for trabectedin (Yondelis) for the treatment of women with recurrent ovarian cancer. The withdrawal is based on the FDA’s recommendation that an additional phase III study be conducted to obtain approval.

The NDA was submitted to the FDA in November 2008. The FDA issued a Complete Response letter in September 2009 and requested additional information, including overall survival data from the pivotal OVA301 trial and additional clinical pharmacology studies. The OVA-301 overall survival data were the subject of a poster presentation on June 5 at the ASCO Annual Meeting.

Trabectedin is a novel cytotoxic antitumor agent that was originally derived from the marine tunicate, Ecteinascidia turbinata. The compound is now produced synthetically. Trabectedin binds to the minor groove of DNA and bends it toward the major groove, causing DNA adducts that interfere with cell division and genetic transcription processes and DNA repair machinery.

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Brief Summary of Prescribing Information for Chronic Lymphocytic Leukemia INDICATIONS AND USAGE: TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Efficacy relative to first line therapies other than chlorambucil has not been established.

CONTRAINDICATIONS: TREANDA is contraindicated in patients with a known hypersensitivity (eg, anaphylactic and anaphylactoid reactions) to bendamustine or mannitol. [See Warnings and Precautions] WARNINGS AND PRECAUTIONS: Myelosuppression. Patients treated with TREANDA are likely to experience myelosuppression. In the two NHL studies, 98% of patients had Grade 3-4 myelosuppression.

Three patients (2%) died from myelosuppression-related adverse reactions; one each from neutropenic sepsis, diffuse alveolar hemorrhage with Grade 3 thrombocytopenia, and pneumonia from an opportunistic infection (CMV). In the event of treatment-related myelosuppression, monitor leukocytes, platelets, hemoglobin (Hgb), and neutrophils closely. In the clinical trials, blood counts were monitored every week initially. Hematologic nadirs were observed predominantly in the third week of therapy. Hematologic nadirs may require dose delays if recovery to the recommended values have not occurred by the first day of the next scheduled cycle. Prior to the initiation of the next cycle of therapy, the ANC should be ≥ 1 x 109/L and the platelet count should be ≥ 75 x 109/L. [See Dosage and Administration]. Infections. Infection, including pneumonia and sepsis, has been reported in patients in clinical trials and in post-marketing reports.

Infection has been associated with hospitalization, septic shock and death. Patients with myelosuppression following treatment with TREANDA are more susceptible to infections. Patients with myelosuppression following TREANDA treatment should be advised to contact a physician if they have symptoms or signs of infection. Infusion Reactions and Anaphylaxis. Infusion reactions to TREANDA have occurred commonly in clinical trials. Symptoms include fever, chills, pruritus and rash. In rare instances severe anaphylactic and anaphylactoid reactions have occurred, particularly in the second and subsequent cycles of therapy.

Monitor clinically and discontinue drug for severe reactions. Patients should be asked about symptoms suggestive of infusion reactions after their first cycle of therapy. Patients who experienced Grade 3 or worse allergic-type reactions were not typically rechallenged. Measures to prevent severe reactions, including antihistamines, antipyretics and corticosteroids should be considered in subsequent cycles in patients who have previously experienced Grade 1 or 2 infusion reactions. Discontinuation should be considered in patients with Grade 3 or 4 infusion reactions. Tumor Lysis Syndrome. Tumor lysis syndrome associated with TREANDA treatment has been reported in patients in clinical trials and in postmarketing reports. The onset tends to be within the first treatment cycle of TREANDA and, without intervention, may lead to acute renal failure and death. Preventive measures include maintaining adequate volume status, and close monitoring of blood chemistry, particularly potassium and uric acid levels.

Allopurinol has also been used during the beginning of TREANDA therapy. However, there may be an increased risk of severe skin toxicity when TREANDA and allopurinol are administered concomitantly. Skin Reactions. A number of skin reactions have been reported in clinical trials and post-marketing safety reports. These events have included rash, toxic skin reactions and bullous exanthema. Some events occurred when TREANDA was given in combination with other anticancer agents, so the precise relationship to TREANDA is uncertain. In a study of TREANDA (90 mg/m2) in combination with rituximab, one case of toxic epidermal necrolysis (TEN) occurred. TEN has been reported for rituximab (see rituximab package insert). Cases of Stevens-Johnson syndrome (SJS) and TEN, some fatal, have been reported when TREANDA was administered concomitantly with allopurinol and other medications known to cause these syndromes. The relationship to TREANDA cannot be determined. Where skin reactions occur, they may be progressive and increase in severity with further treatment. Therefore, patients with skin reactions should be monitored closely. If skin reactions are severe or progressive, TREANDA should be withheld or discontinued. Other Malignancies. There are reports of pre-malignant and malignant diseases that have developed in patients who have been treated with TREANDA, including myelodysplastic syndrome, myeloproliferative disorders, acute myeloid leukemia and bronchial carcinoma. The association with TREANDA therapy has not been determined. Extravasation. There are postmarketing reports of bendamustine extravasations resulting in hospitalizations from erythema, marked swelling, and pain.

Precautions should be taken to avoid extravasations, including monitoring of the intravenous infusion site for redness, swelling, pain, infection, and necrosis during and after administration of TREANDA. Use in Pregnancy. TREANDA can cause fetal harm when administered to a pregnant woman. Single intraperitoneal doses of bendamustine in mice and rats administered during organogenesis caused an increase in resorptions, skeletal and visceral malformations, and decreased fetal body weights.

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. 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 following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

Table 1: Non-Hematologic Adverse Reactions Occurring in Randomized CLL Clinical Study in at Least 5% of Patients Number (%) of patients TREANDA Chlorambucil (N=153) (N=143) System organ class Preferred term All Grades Grade 3/4 All Grades Grade 3/4 Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17) Gastrointestinal disorders Nausea 31 (20) 1 (<1) 21 (15) 1 (<1) Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0 General disorders and administration site conditions Pyrexia 36 (24) 6 (4) 8 (6) 2 (1) Fatigue 14 (9) 2 (1) 8 (6) 0 Asthenia 13 (8) 0 6 (4) 0 Chills 9 (6) 0 1 (<1) 0 Immune system disorders Hypersensitivity 7 (5) 2 (1) 3 (2) 0 Infections and infestations Nasopharyngitis 10 (7) 0 12 (8) 0 Infection 9 (6) 3 (2) 1 (<1) 1 (<1) Herpes simplex 5 (3) 0 7 (5) 0 Investigations Weight decreased 11 (7) 0 5 (3) 0 Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0 Respiratory, thoracic and mediastinal disorders Cough 6 (4) 1 (<1) 7 (5) 1 (<1) Skin and subcutaneous tissue disorders Rash 12 (8) 4 (3) 7 (5) 3 (2) Pruritus 8 (5) 0 2 (1) 0

cally advanced disease who received the drug or a placebo. The study was designed to measure progressionfree survival. Results from the study demonstrate that sunitinib improved progression-free survival to 10.2

■

More FDA Updates on page 28

ASCOPost.com | JUNE 15, 2011

PAGE 15

American Society of Breast Surgeons 12th Annual Meeting Multidisciplinary Care

Radiotherapy in DCIS: Recurrence Patterns Are Different

By Caroline Helwick

F

or women with ductal carcinoma in situ (DCIS), radiation therapy after excision is not a slam-dunk in terms of benefits, according to a study presented at the American Society of Breast Surgeons 12th Annual Meeting.1 In a study that focused on the pattern of breast cancer recurrence in women with DCIS, many but not all women benefited from radiotherapy, reported investigators from Hoag Memorial Hospital Presbyterian in New-

port Beach, California, and the University of Southern California (USC), Los Angeles. While women treated with radiation after breast-conserving surgery had a significantly lower recurrence rate, they also experienced more invasive recurrences and had cancers that recurred much later after initial diagnosis, said Janie Weng Grumley, MD, lead investigator and a fellow in breast oncology at the USC Keck School of Medicine. The study affirmed the need

■■ For DCIS, excision plus radiotherapy led to significantly fewer

recurrences, more invasive recurrences, more recurrences after 10 years, and lower survival rates than excision alone in a retrospective analysis from USC.

■■ Other recent analyses have produced results that contradict the USC findings.

for long-term follow-up of patients with DCIS, she said.

Survival Rates Favored Excision Alone

Nonrandomized Analysis Viewed with Skepticism

By Lori J. Pierce, MD University of Michigan, Ann Arbor

T

he findings from Grumley et al contradict the results from randomized trials of lumpectomy vs lumpectomy and radiotherapy for ductal carcinoma in situ (DCIS) and highlight the potential pitfalls of retrospective analyses. The metaanalysis of the DCIS trials revealed a significant 54% reduction in ipsilateral breast events with the addition of radiotherapy,1 and unlike the Grumley USC analysis, an equal proportion of these ipsilateral events were invasive in both the radiotherapy Lori J. Pierce, MD and nonradiotherapy arms. As a result, breast cancer–specific and overall survivals were identical with or without radiotherapy.

Furthermore, in a recent analysis by the National Surgical Adjuvant Breast and Bowel Project (NSABP), which considered the long-term outcomes of women enrolled in the B‑17 and B-24 trials who specifically experienced an invasive ipsilateral recurrence, again no significant differences were observed in breast cancer mortality and overall mortality with or without radiotherapy.2 Clearly, the NSABP investigators found no deleterious effect of radiotherapy, as suggested in the USC analysis.

Differences in nonrandomized comparisons for factors such as tumor size, nuclear grade, margin width, patient age, and year of treatment clearly affect reported outcomes. Moreover, treatment algorithms such as (modifications of) the Van Nuys Prognostic Index, by design, select patients with higher tumor burden to receive radiotherapy. So it is not surprising that the results from the nonrandomized analysis from USC differ from those reported in the randomized trials. It is only through studies that are without selection bias that the long-term benefits of radiotherapy can be fully appreciated.

Financial Disclosure: Dr. Pierce reported no potential conflicts of interest.

Radiotherapy in DCIS

■

References 1. Early Breast Cancer Trialists’ Collaborative Group: Overview of the randomized trials of radiotherapy in ductal carcinoma in situ of the breast. J Natl Cancer Inst Monogr 41:162-177, 2010.

2. Wapnir IL, Dignam JJ, Fisher B, et al: Long-term outcomes of invasive ipsilateral breast tumor recurrences after lumpectomay in NSABP B-17 and B-24 randomized clinical trials for DCIS. J Natl Cancer Inst 103:478-488, 2011.

“This is the first study to focus on the pattern of recurrence in patients with DCIS treated with lumpectomy,” Dr. Grumley noted. “Radiation therapy accompanying lumpectomy of DCIS is known to reduce local cancer recurrence by 50%, but when the cancer does come back, perhaps surprisingly, we found major differences in the recurrence pattern between patients who did and did not receive radiation. As more patients opt for breast-conserving therapy without radiation, a clear understanding of the differences in the pattern of recurrence will be important.”

The study was a prospective but not randomized 10-year trial that followed 1,014 DCIS patients following breast-conserving surgery with (n = 353) or without radiation (n = 651).

The study found the 10-year probability of recurrence to be 30% after excision alone and 18% after excision plus radiotherapy (P = .01). The breast cancer–specific survival rates were 99.7% and 98.3%, which, though seemingly similar, significantly favored excision alone (P = .01), Dr. Grumley reported.

Among women whose disease recurred, local recurrences were documented in 95% of the excision-only group and 88% of the radiotherapy group (P = .08), while distant recurrences were observed in 3% and 10%, respectively, which were not significantly different (P = .08). But with excision alone, invasive recurrences were less likely (38% vs 54%; P = .0459), as were recurrences after

10 years (9% vs 33%, respectively; P < .001).

“Patients who are radiated have fewer recurrences; however, when they did recur, they were more likely to be invasive, in a different quadrant, and took longer from time of initial diagnosis to recurrence,” she noted. “And radiated patients had a slightly but significantly lower probability of survival.”

Other Recurrence Data The average time to recurrence overall for patients not receiving radiation was approximately 4 years, compared to almost 8 years for those receiving radiation.

DCIS lesions recurring in the same area SEE PAGE 41 of the breast were observed at a mean time of 4 years for patients not treated with radiation, but at 6 years for radiated patients.

“Overall, far fewer patients receiving radiation for DCIS have cancer recurrences. However, given current protocols for treatment and follow-up, a small subgroup of radiated DCIS patients may not be deriving maximum benefit from radiation therapy or not benefiting from it at all,” Dr. Grumley commented. “It also demonstrates that for a statistically significant number of these women, a 5-year cancerfree status is not a landmark.”

■

Financial Disclosure: Dr. Grumley reported no potential conflicts of interest.

Reference 1. Grumley JW, Lagios MD, Rayhanabad J, et al: Difference in recurrence patterns by treatment in patients with DCIS. American Society of Breast Surgeons 12th Annual Meeting. Abstract 1642. Presented April 29, 2011.

THE FIGHT IS CHANGING. It’s more personal than ever. Now, genetic biomarker tests may help deliver the right cancer treatment to the right patient.

Bio-specific medicine is changing the way we treat cancer. In many instances, doctors can now test a tumor’s distinct profile with the goal of providing more targeted, more effective treatments with fewer side effects.

The battle is being redefined. And it starts by testing. See how at www.canceritspersonal.com

CRI00102/280033-01 ©2011 Pfizer Inc. All rights reserved.

The ASCO Post | JUNE 15, 2011

PAGE 18

American Society of Breast Surgeons 12th Annual Meeting Risk Factors

More Evidence Links Vitamin D Deficiency to Breast Cancer

By Caroline Helwick

P

atients with breast cancer and deficient levels of 25-hydroxyvitamin D are more likely to have aggressive tumor profiles and unfavorable prognostic markers than women with optimal levels of vitamin D, according to research presented at the 12th Annual MeetSEE PAGE 41 ing of the American Society of Breast Surgeons, held in Washington, DC.1 “This is one of only a few studies to examine the role of vitamin D in breast cancer progression, rather than in cancer development. The magnitude of the findings was quite surprising,” said Luke J. Peppone, PhD, Research Assistant Professor of Radiation Oncology at the Uni-

versity of Rochester Medical Center, Rochester, New York, a study investigator.

Mounting data point to a role for vitamin D deficiency in the development of breast cancer. The current study linked vitamin D deficiency with prognostic factors and outcomes.

“Vitamin D deficiency is common among patients with breast cancer. The vitamin D receptor modulates cellcycle proliferation, induction of differentiation, and activation of apoptosis,” co-investigator Kristin Skinner, MD, also of the University of Rochester, explained in a press briefing.

The study examined the association between vitamin D levels around the time of diagnosis with demographic, pathologic, and genetic characteristics of breast cancer in 194 pa-

Expert Point of View

■■ Patients with breast cancer had significantly lower mean vitamin D levels than age-matched controls without cancer.

■■ Vitamin D deficiency more than doubled the risk for breast cancer.

■■ Patients with breast cancer and suboptimal levels of vitamin D were

significantly more likely to have tumors with aggressive profiles and worse prognostic markers.

tients at the University of Rochester Medical Center. Noncancer controls were selected from among the 37,337 women who underwent vitamin D testing at the University during the same time period.

Vitamin D levels were classified as optimal (≥ 32 ng/mL), suboptimal (< 32 ng/mL), insufficient (20– 31 ng/mL), or deficient (< 20 ng/mL).

Notable Associations

J

ulie R. Gralow, MD, Professor of Oncology at the University of Washington, Seattle, said the data reported by Rickles et al at the American Society of Breast Surgeons Annual Meeting support the Goodwin study presented at the 2008 ASCO Annual Meeeting.1 In that earlier Canadian cohort of 512 women, subjects with vitamin D deficiency had a 94% increased risk for distant recurrence and a 73% risk for death. The prognostic significance of vitamin D levels was independent of patient age or Julie R. Gralow, MD weight, tumor stage, or tumor grade.

“The additional Oncotype information on these patients is new and important,” she noted.

“What will really be critical is to show that changing the vitamin D level through supplementation and monitoring blood levels can impact either the development of breast cancer (or at least aggressive breast cancer), or the outcome of the cancer with aggressive features at diagnosis,” Dr. Gralow said.

The Southwest Oncology Group is initiating a 1-year pilot study of vitamin D repletion/supplementation in premenopausal women at risk for developing breast cancer. The endpoints will be changes in mammographic density and proliferation markers (Ki‑67) in biopsies of breast epithelium, she said.

Financial Disclosure: Dr. Gralow reported no potential conflicts of interest.

Vitamin D and Breast Cancer

■

Reference 1. Goodwin PJ, Ennis M, Pritchard KI, et al: Frequency of vitamin D (Vit D) deficiency at breast cancer (BC) diagnosis and association with risk of distant recurrence and death in a prospective cohort study of T1-3, NO-1, MO BC (abstract 511). J Clin Oncol 26(15S):9s, 2008.

(vs ≤ 18): 3.2 ■■ triple-negative breast cancer: 3.1 ■■ ER-negative status: 2.6

Luke J. Peppone, PhD

“Our patients with breast cancer had significantly lower mean vitamin D levels than age-matched noncancer controls,” Dr. Skinner announced. “If you were deficient, the odds ratio for developing breast cancer was 2.4, compared to a woman with optimal levels.”

A woman with breast cancer was 1.76 times more likely to be deficient in vitamin D, vs controls, she added.

Mean 25-hydroxy-vitamin D level was 37.4 ng/mL in controls, compared with 32.7 ng/mL in patients with breast cancer (P = .002).

Patients with breast cancer and suboptimal levels of vitamin D were also more likely to have tumors with more aggressive profiles and worse prognostic markers, such as estrogen receptor (ER)-negative status, triple-negative tumors, basal-like molecular phenotype, and Oncotype DX high-risk tumors, the study found.

The odds ratios for some of the most notable associations were: ■■ non-Caucasian race: 3.6 ■■ basal-like gene profile (vs luminal A/B): 3.4 ■■ Oncotype recurrence score > 18

Kristin Skinner, MD

■■ premenopausal status: 2.3 ■■ invasive breast tumors: 2.2 Older women had significantly higher mean vitamin D levels than younger women, she added.

“These results may help to explain the observed decreased survival rate among vitamin D–deficient patients with breast cancer and the poorer prognosis seen in young, premenopausal, and non-Caucasian patients,” Dr. Skinner suggested.

Dr. Skinner routinely measures vitamin D in her patients and prescribes replacement treatment (1,000–2,000 IU/d) if they are low. “We get them above 32 ng/mL, then we titrate replacement to reach 50 ng/mL,” she told The ASCO Post.

■

Financial Disclosure: Dr. Peppone and Dr. Skinner reported no potential conflicts of interest.

Reference 1. Rickles A, Peppone L, Huston A et al: Serum 25-hydroxyvitamin D and prognostic tumor characteristics in breast cancer patients. American Society of Breast Surgeons 12th Annual Meeting. Abstract 1701. Presented April 29, 2011.

ASCOPost.com | JUNE 15, 2011

PAGE 19

Direct from ASCO

ASCO Launches Initiative to Showcase Progress Against Cancer

T

o demonstrate the value of the U.S. clinical cancer research system and the urgent need to strengthen and support clinical trials, a new ASCO website highlights the great progress made in clinical cancer research since the signing of the National Cancer Act in 1971.

Over the past 40 years, major milestones have been reached in every area of cancer care: prevention, screening, chemotherapy, surgery, radiation, and—increasingly—molecularly targeted treatments. At the same time, better ways of managing nausea, pain, and other side effects are enabling patients to live better, more fulfilling lives.

ASCO members have been pioneers in developing new drugs, surgical advances, radiation therapy, imaging, and supportive care that have led to longer and better lives for patients with cancer. Recognizing these important achievements will help ASCO build upon the success of the past and point the

Volume 7, Issue 3

May 2011

Journal of oncology Practice The Authoritative Resource for Oncology Practices

Report on the ASCO 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, MD, et al Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, MD, et al Current Hepatitis B Screening Practices and Clinical Experience of Reactivation in Patients Undergoing Chemotherapy for Solid Tumors: A Nationwide Survey of Medical Oncologists

By Fiona L. Day, FRACP, et al Barriers to Recruitment of Rural Patients in Cancer Clinical Trials

By Shamsuddin Virani, MB, BS, et al Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, MHSA

www.jop.ascopubs.org

way to the future.

The new website, CancerProgress.Net, includes a multimedia timeline of the important progress in cancer treatment over the past 4 decades. CancerProgress.

Net is the first data-rich, interactive resource of its type, providing a visual history of advances in cancer treatment and prevention.

As a result of the U.S. investment in clinical cancer research, more people are surviving cancer than ever before: ■■ Two out of three people live at least 5 years after a cancer diagnosis, up from one out of two in the 1970s.

■■ The U.S. cancer death rate has dropped 16% since the early 1990s.

■■ Five-year survival rates for breast cancer, testicular cancer, and childhood leukemia are now over 90%.

For the nearly 12 million cancer survivors across the United States,

What’s Hot in

JOP jop.ascopubs.org

1.

Report on the ASCO October 2010 Provider-Payer Initiative Meeting

By Michael N. Neuss, et al 7(3): 136

2.

Subspecialization in Community Oncology: Option or Necessity?

By Dean H. Gesme, et al 7(3): 199

3.

Current Hepatitis B screening practices and clinical experience of reactivation in patients undergoing chemotherapy for solid tumors: A nationwide survey of medical oncologists

By Fiona L. Day, et al 7(3): 141

4.

Partners and Partnerships: Trends in Private Oncology Practice

By Thomas A. Paivanas, et al 7(3): 195

5.

A Screening Tool to Enhance Clinical Trial Participation at a Community Center, involved in a Radiation Oncology “Disparities” Program

By Julian Proctor, et al 7(3): 161

this investment has been a foundation of hope, promise, and progress in the fight to decrease the burden of cancer. In spite of the progress, much more work needs to be done.

More than 1.5 million Americans are expected to be diagnosed with cancer this year. Continuing to invest in a strong clinical trials system

will lead to even greater progress in the future.

Explore ASCO’s CancerProgress.

Net, an interactive new site showcasing advances in all aspects of care for patients with cancer.

■

© 2011. American Society of Clinical Oncology. All Rights Reserved.

Breast Cancer Symposium to Offer Uniquely Interdisciplinary Approach for Attendees All aspects of the field represented in research presentations and interactive education sessions

M

any breast cancer–focused meetings and conferences are held each year, but the Breast Cancer Symposium, which takes place this year in San Francisco, September 8–11, is one of the few that takes an interdisciplinary approach to delivering practical, howto clinical information for attend-

ees from all disciplines involved in researching, diagnosing, and treating breast cancer.

“Instead of involving one or two modalities that are part of the diagnosis and treatment of breast cancer, we try to involve them all—from imaging to pathology to surgery to radiation oncology to medical oncology to geneticists: the entire gamut of people who are involved with patients,” commented radiation oncologist Robert R. Kuske, MD, one of the founders of Phoenix-based Arizona Breast Cancer Specialists. A pioneer of breast brachytherapy, Dr. Kuske is the symposium’s Program Committee continued on page 20

The ASCO Post | JUNE 15, 2011

PAGE 20

Direct from ASCO

Breast Cancer Symposium continued from page 19

Interdisciplinary Sponsorship, Too

Cochair. “To be a true breast specialist and to bring a well-rounded approach to patients, you need to know the other specialties and what they bring to bear.”

The truly interdisciplinary approach of the symposium is reflected in its varied array of sponsors.

Along with ASCO, they are the American Society of Breast Dis-

ease, American Society of Breast Surgeons, American Society for Radiation Oncology, National Consortium of Breast Centers, and Society of Surgical Oncology.

“Each society has its own meeting, but to have this multi-

disciplinary convergence in one meeting, with each of these organizations working together to create an educational program that speaks to each of those disciplines, is unique,” said Shawna C. Willey, MD, FACS, Associate Professor of Surgery and Director of the Betty Lou Ourisman Breast Health Center, which is part of the Lombardi Comprehensive Cancer Center at Georgetown University Hospital in Washington, DC. Dr. Willey is the symposium’s Steering Committee Chair.

Important Networking In addition to the multidisciplinary sessions, there will be ample opportunity to connect with colleagues, which can be just as valuable.

“I personally have benefitted from ties that I have made at this meeting and the crossfertilization of ideas there,” Dr. Kuske said. Offering a specific example, he said that speaking continued on page 21

Equip Your Patients for Cancer Survivorship

T

o help patients navigate the road ahead after active treatment has finished, Cancer.Net— ASCO’s patient information website—offers a variety of resources on survivorship (www.cancer.net/ survivors). Your patients will find cancer treatment summary forms to help them keep track of the cancer treatment they received and work with you to develop a survivorship care plan. Other topics of interest include late effects, childhood cancer survivorship, rehabilitation, advocacy, and survivors’ personal stories. This information is also available in Spanish (www.cancer. net/espanol).

■

© 2011. American Society of Clinical Oncology. All Rights Reserved.

ASCOPost.com | JUNE 15, 2011

PAGE 21

Direct from ASCO

Breast Cancer Symposium continued from page 20

with colleagues at last year’s symposium led him to look closely at estrogen receptor (ER)-negative patients for both local and systemic relapse after partial-breast radiation, an area he pioneered.

“After the symposium, I went back and looked at my research and found an increased local recurrence rate, which may also be true for conventional radiation in ER-negative tumors,” he said. As a result, he added that important information into his data analysis, and the randomized clinical trial NSABP B‑39/RTOG 0413, of which he’s co–principal inves-

Volume 29, Issue 15

May 20, 2011

JOURNAL OF CLINICAL ONCOLOGY Official Journal of the American Society of Clinical Oncology

Tumor-Infiltrating CD8+ Lymphocytes Predict Clinical Outcome in Breast Cancer. S.M.A. Mahmoud et al. Editorial: R. Mouawad et al Coalesced Multicentric Analysis of Patients With Myelodysplastic Syndromes Indicates an Underestimation of Poor-Risk Cytogenetics in the International Prognostic Scoring System. J. Schanz et al Editorial: P.L. Greenberg Phase III Study of First-Line Oxaliplatin-Based Chemotherapy Plus PTK787/ZK 222584 in Patients With Metastatic Colorectal Adenocarcinoma. J.R. Hecht et al. Editorial: A.F. Sobrero et al Phase III Study of Oxaliplatin, Fluorouracil, and Leucovorin With or Without PTK787/ZK 222584 in Patients With Previously Treated Metastatic Colorectal Adenocarcinoma. E. Van Cutsem et al Editorial: A.F. Sobrero et al Phase I Dose-Escalation Study of Stereotactic Body Radiation Therapy for Low- and Intermediate-Risk Prostate Cancer. T.P. Boike et al Editorial: A.V. D’Amico ASCO Special Article: Provisional Clinical Opinion: EGFR Mutation Testing for Patients With Advanced NSCLC Considering First-Line EGFR Tyrosine Kinase Inhibitor Therapy. V.L. Keedy et al. Editorial: P.A. Bunn Jr et al

www.jco.org

tigator, will offer a head-to-head comparison.

‘Science to Survivorship’ The symposium’s theme this year is “The Continuum of Breast Care: Science to Survivorship.” The aim is to foster dialogue between investigators and clinicians to bring the results of research directly into practice. Attendees will be able to be part of discussion-based sessions with faculty from the top cancer institutions.

Topics for sessions will include new approaches in diagnostic pathology, new imaging modalities, current controversies and future prospects in detection, and survivorship aspects such as diet, nutri-

What’s Hot in

JCO

Top 10 most-accessed articles recently published in Journal of Clinical Oncology

JCO.org 1. Considerations in the Management of Patients With Philadelphia Chromosome–Positive Chronic Myeloid Leukemia Receiving Tyrosine Kinase Inhibitor Therapy Hagop Kantarjian, et al 29(12): 1512

6. Is Screening With Magnetic Resonance Imaging in BRCA Mutation Carriers a Safe and Effective Alternative to Prophylactic Mastectomy?

Monika L. Burness, et al 29(13): 1652

2. The War on Cancer: Progress at What Price?

Andre Konski 29(12): 1503

7. Advanced Insights Into the Biology of Malignant Lymphomas Richard I. Fisher 29(14): 1799

3. Circulating Tumor Cells: Not All Detected Cells Are Bad and Not All Bad Cells Are Detected Max S. Wicha, et al 29(12): 1508

8. Are We Making Progress in Curing Advanced Cervical Cancer?

Gillian Thomas 29(13): 1654

4. Long-Term Follow-Up of Women in Trials of Adjuvant Therapy for Breast Cancer: Is It Still Important?

Kathleen I. Pritchard, et al 29(13): 1651

9. Denosumab for Bone Metastases From Breast Cancer: A New Therapy Option?

Matti S. Aapro 29(14): e419

5. Can Quantifying Hormone Receptor Levels Guide the Choice of Adjuvant Endocrine Therapy for Breast Cancer?

John R. Mackey 29(12): 1504

10. Multiple Myeloma and Amyloidosis: An Evolving Treatment Paradigm Toward the Goal of Tailored Therapy Paul Richardson 29(14): 1801

Robert R. Kuske, MD

tion, and ethnic/racial issues. Other topics will include new systemic agents, novel surgical approaches in local/regional management, and radiation and radiobiology.

In addition, this year’s Gianni Bonadonna Breast Cancer Award recipient will be announced at the symposium. The Gianni Bonadonna Breast Cancer Research Fellowship funds an early-career investigator committed to conducting breast cancer research at

Shawna C. Willey, MD

the awardee’s institution and under the mentorship and supervision of the awardee. It consists of a 1-year grant in the amount of $50,000.

This year’s symposium will take place at the San Francisco Marriott Marquis. To register, go to www. breastcasym.org and select “Register for the Symposium.”

■

© 2011. American Society of Clinical Oncology. All rights reserved.

Living Life beyond Cancer: ASCO’s Focus on Survivorship

O

n June 5, National Cancer Survivors Day participants united to celebrate living beyond cancer and focus on the issues facing cancer survivors, an area in which ASCO is increasing its efforts.

ASCO recently developed a new committee focused on survivorship to tackle issues related to cancer survivors and address the needs and concerns of this patient population. With nearly 12 million cancer survivors in the United States alone, ASCO stands ready to lead the cancer community in addressing the needs and concerns of this group. ASCO has a long history of supporting policies to assist cancer survivors as part of its overall commitment to ensuring high-quality care for all patients with cancer and will continue this work through the survivorship committee.

The Cancer Survivorship Committee held its first meeting earlier this year and developed four primary goals, on which members will focus over the next year:

■■ identify the best practices of clinical management of cancer survivors and provide guidelines on common health risks ■■ collaborate with pediatric and medical oncology cooperative groups to establish uniform minimum sets of data related to survivorship for collection as patients are entering treatment ■■ examine models of survivorship care and consider how to best transition and share care between oncology practices and primary care providers ■■ improve the effectiveness and uptake of treatment plans and treatment summaries to help transition survivorship information between providers ASCO has a host of resources available for cancer survivors on its patient website, www.cancer.net/ survivorship. For updates on ASCO’s survivorship work, visit www.asco. org/ascoaction.

■

© 2011. American Society of Clinical Oncology. All Rights Reserved.

Indication HalavenTM is indicated for the treatment of patients with metastatic breast cancer who have previously received at least two chemotherapeutic regimens for the treatment of metastatic disease. Prior therapy should have included an anthracycline and a taxane in either the adjuvant or metastatic setting.

Important Safety Information Neutropenia • Monitor complete blood counts prior to each dose, and

increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days • Severe neutropenia (ANC <500/mm3) lasting more than 1 week occurred in 12% (62/503) of patients. Patients with elevated liver enzymes >3 × ULN and bilirubin >1.5 × ULN experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal levels • Grade 3 and Grade 4 neutropenia occurred in 28% and 29%, respectively, of patients who received Halaven. Febrile neutropenia occurred in 5% of patients and two patients (0.4%) died from complications

Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral motor and sensory neuropathy • Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less • Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new

or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)

Pregnancy Category D • Halaven is expected to cause fetal harm when administered to a pregnant woman and patients should be advised of these risks

QT Prolongation • In an uncontrolled ECG study in 26 patients, QT

prolongation was observed on Day 8, independent of eribulin concentration, with no prolongation on Day 1. ECG monitoring is recommended for patients with congestive heart failure; bradyarrhythmias; concomitant use of drugs that prolong QT interval, including Class Ia and III antiarrhythmics; and electrolyte abnormalities • Correct hypokalemia or hypomagnesemia prior to initiating Halaven and monitor electrolytes periodically during therapy.

Avoid in patients with congenital long QT syndrome

Hepatic and Renal Impairment • For patients with mild (Child-Pugh A) or moderate (ChildPugh B) hepatic and/or moderate (CrCl 30-50 mL/min) renal impairment, a reduction in starting dose is recommended

Please see accompanying brief summary of Halaven full Prescribing Information.

References: 1. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 2.2011. http:NCCN.org. Published January 5, 2011. Accessed February 2, 2011. 2. Halaven [package insert]. Woodcliff Lake, NJ: Eisai Inc; 2010. 3. Saad ED, Katz A, Buyse M. Overall survival and post-progression survival in advanced breast cancer: a review of recent randomized clinical trials. J Clin Oncol. 2010;28(11):1958-1962. 4. Slamon DJ, Leyland-Jones B, Shak S, et al. Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med. 2001;344(11):783-792. 5. Geyer CE, Forster J, Lindquist D, et al. Lapatinib plus capecitabine for HER2-positive advanced breast cancer.

N Engl J Med. 2006;355(26):2733-2743. 6. von Minckwitz G, du Bois A, Schmidt M, et al. Trastuzumab beyond progression in human epidermal growth factor receptor 2–positive advanced breast cancer: a German Breast Group 26/Breast International Group 03-05 study. J Clin Oncol. 2009;27(12):1999-2006. 7. Miller K, Wang M, Gralow J, et al. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666-2676. 8. Robert NJ, Dieras V, Glaspy J, et al. RIBBON-1: randomized, double-blind, placebo-controlled, phase III trial of chemotherapy with or without bevacizumab (B) for first-line treatment of HER2-negative locally recurrent or metastatic breast cancer (MBC). J Clin Oncol. 2009;27(suppl; abstr 1005). 9. Sparano JA, Vrdoljak E, Rixe O, et al. Randomized phase III trial of ixabepilone plus capecitabine versus capecitabine in patients with metastatic breast cancer previously treated with an anthracycline and a taxane. J Clin Oncol. 2010;28(20):3256-3263. 10. Jones SE, Erban J, Overmoyer B, et al. Randomized phase III study of docetaxel compared with paclitaxel in metastatic breast cancer. J Clin Oncol. 2005;23(24):5542-5551. 11. Cortes J, O’Shaughnessy J, Loesch D, et al. Eribulin monotherapy versus treatment of physician’s choice in patients with metastatic breast cancer (EMBRACE): a phase 3 open-label randomised study. Lancet. 2011;377(9769):914-923.

HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA /May 2011 ERI 81

Scan this code to visit www.halaven.com

Included in the NCCN Guidelines1

DISCOVER

OVERALL SURVIVAL

Halaven: The FIRST and ONLY third-line, single-agent therapy proven to significantly extend overall survival in patients with metastatic breast cancer (MBC) 2-10 The Phase III EMBRACE* trial met its primary endpoint of overall survival (OS) 2,11 • In the primary analysis, conducted when ~50% of events had been observed, median OS with Halaven vs Control Arm (Treatment of Physician’s Choice [TPC]) was 13.1 months (95% CI: 11.8, 14.3) vs 10.6 months (95% CI: 9.3, 12.5), HR=0.81 (95% CI: 0.66, 0.99) (P=0.041)† 2,11 UPDATED OVERALL SURVIVAL ANALYSIS (UNPLANNED)†2 Halaven (n=508)

TPC Arm (n=254)

Median OS (months [95% Cl])

13.2 (12.1, 14.4)

10.6 (9.2, 12.0)

Deaths

386

203

1.0 0.9

PROPORTION OF PATIENTS ALIVE

0.8 0.7 0.6

Halaven

0.5

Control Arm

0.4 0.3 0.2 0.1 0.0

0

6

12

18

24

30

36

54 26

11 5

0 0

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Halaven TPC Arm

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2 Results from an updated, unplanned survival analysis of the Phase III, open-label, multicenter, multinational EMBRACE trial of Halaven vs TPC in patients with MBC (N=762). The primary endpoint was OS. Patients were randomized (2:1) to receive either Halaven 1.4 mg/m2 IV for 2 to 5 minutes on Days 1 and 8 of a 21-day cycle, or any single-agent therapy, selected prior to randomization. At baseline, all patients had received ≥2 prior chemotherapeutic regimens for metastatic disease and demonstrated disease progression within 6 months of their last chemotherapeutic regimen.

All patients received prior anthracycline- and taxanebased chemotherapy, unless contraindicated. Therapies in the TPC arm consisted of 97% chemotherapy (26% vinorelbine, 18% gemcitabine, 18% capecitabine, 16% taxane [included paclitaxel, docetaxel, nab-paclitaxel, and ixabepilone], 9% anthracycline, 10% other chemotherapy) and 3% hormonal therapy.2, 11

CI=confidence interval; HR=hazard ratio.

*EMBRACE=Eisai Metastatic Breast Cancer Study Assessing Physician’s Choice vs E7389 (Eribulin). †Conducted in the intent-to-treat (ITT) population.

Halaven: Quick administration • 2- to 5-minute intravenous infusion on Days 1 and 8 of a 21-day cycle2 Halaven: Safety profile • Studied in the Phase III EMBRACE trial2 Most Common Adverse Reactions • Most common adverse reactions (≥25%) reported in patients receiving Halaven were neutropenia (82%), anemia (58%), asthenia/fatigue (54%), alopecia (45%), peripheral neuropathy (35%), nausea (35%), and constipation (25%)

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%) • Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

ADVANCING SURVIVAL

The ASCO Post | JUNE 15, 2011

PAGE 24

Perspective

Planning Survivorship Programs continued from page 2

follow-up with the oncology team, it can include the provision of a shared-care communication plan with the primary care provider, specifically delineating the responsibilities of each provider.

In the United States, a rapidly growing model of care is the integrated care model, where the survivorship provider is a nurse practitioner or physician assistant who is embedded in the oncology team where the patient was treated. This model offers an easy transition for survivors and the

HALAVENTM (eribulin mesylate) Injection BRIEF SUMMARY – See package insert for full prescribing information.

2.2 Dose Modification Assess for peripheral neuropathy and obtain complete blood cell counts prior to each dose.

Recommended dose delays • Do not administer HALAVEN on Day 1 or Day 8 for any of the following: – ANC <1,000/mm3 – Platelets <75,000/mm3 – Grade 3 or 4 non-hematological toxicities • The Day 8 dose may be delayed for a maximum of 1 week.

– If toxicities do not resolve or improve to ≤ Grade 2 severity by Day 15, omit the dose.

– If toxicities resolve or improve to ≤ Grade 2 severity by Day 15, administer HALAVEN at a reduced dose and initiate the next cycle no sooner than 2 weeks later.

Recommended dose reductions • If a dose has been delayed for toxicity and toxicities have recovered to Grade 2 severity or less, resume HALAVEN at a reduced dose as set out in Table 1.

• Do not re-escalate HALAVEN dose after it has been reduced.

Table 1 Recommended Dose Reductions Recommended Event Description HALAVEN Dose 2 Permanently reduce the 1.4 mg/m HALAVEN dose for any of the following: ANC <500/mm3 for >7 days ANC <1,000 /mm3 with fever or infection Platelets <25,000/mm3 1.1 mg/m2 Platelets <50,000/mm3 requiring transfusion Non-hematologic Grade 3 or 4 toxicities Omission or delay of Day 8 HALAVEN dose in previous cycle for toxicity Occurrence of any event requiring permanent dose reduction while receiving 1.1 mg/m2 0.7 mg/m2 Occurrence of any event requiring permanent dose reduction while receiving 0.7 mg/m2 Discontinue HALAVEN ANC = absolute neutrophil count.

Toxicities graded in accordance with National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 3.0.

5 WARNINGS AND PRECAUTIONS 5.1 Neutropenia Severe neutropenia (ANC <500/mm3) lasting more than one week occurred in 12% (62/503) of patients in Study 1, leading to discontinuation in <1% of patients. Patients with alanine aminotransferase or aspartate aminotransferase >3 × ULN (upper limit of normal) experienced a higher incidence of Grade 4 neutropenia and febrile neutropenia than patients with normal aminotransferase levels. Patients with bilirubin >1.5 × ULN also had a higher incidence of Grade 4 neutropenia and febrile neutropenia.

Monitor complete blood counts prior to each dose; increase the frequency of monitoring in patients who develop Grade 3 or 4 cytopenias. Delay administration of HALAVEN and reduce subsequent doses in patients who experience febrile neutropenia or Grade 4 neutropenia lasting longer than 7 days. Clinical studies of HALAVEN did not include patients with baseline neutrophil counts below 1,500/mm3.

5.2 Peripheral Neuropathy Grade 3 peripheral neuropathy occurred in 8% (40/503) of patients, and Grade 4 in 0.4% (2/503) of patients in Study 1.

Peripheral neuropathy was the most common toxicity leading to discontinuation of HALAVEN (5% of patients; 24/503).

Neuropathy lasting more than one year occurred in 5% (26/503) of patients. Twenty-two percent (109/503) of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days). Monitor patients closely for signs of peripheral motor and sensory neuropathy. Withhold HALAVEN in patients who experience Grade 3 or 4 peripheral neuropathy until resolution to Grade 2 or less.

5.3 Embryo-Fetal Toxicity There are no adequate and well-controlled studies of HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if a patient becomes pregnant while taking this drug, she should be apprised of the potential hazard to the fetus.

5.4 QT Prolongation In an uncontrolled open-label ECG study in 26 patients, QT prolongation was observed on Day 8, independent of eribulin concentration, with no QT prolongation observed on Day 1. ECG monitoring is recommended if therapy is initiated in patients with congestive heart failure, bradyarrhythmias, drugs known to prolong the QT interval, including Class Ia and III antiarrhythmics, and electrolyte abnormalities. Correct hypokalemia or hypomagnesemia prior to initiating HALAVEN and monitor these electrolytes periodically during therapy. Avoid HALAVEN in patients with congenital long QT syndrome.

6 ADVERSE REACTIONS The following adverse reactions are discussed in detail in other sections of the labeling: • Neutropenia • Peripheral neuropathy • QT interval prolongation The most common adverse reactions (≥25%) reported in patients receiving HALAVEN were neutropenia, anemia, asthenia/ fatigue, alopecia, peripheral neuropathy, nausea, and constipation. The most common serious adverse reactions reported in patients receiving HALAVEN were febrile neutropenia (4%) and neutropenia (2%). The most common adverse reaction resulting in discontinuation of HALAVEN was peripheral neuropathy (5%).

Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice.

In clinical trials, HALAVEN has been administered to 1,222 patients with multiple tumor types, including 240 patients exposed to HALAVEN for 6 months or longer. The majority of the 1,222 patients were women (82%) with a median age of 58 years (range: 26 to 91 years). The racial and ethnic distribution was Caucasian (83%), Black (5%), Asian (2%), and other (5%).

The adverse reactions described in Table 2 were identified in 750 patients treated in Study 1. In Study 1, patients were randomized (2:1) to receive either HALAVEN (1.4 mg/m2 on Days 1 and 8 of a 21-day cycle) or single agent treatment chosen by their physician (control group). A total of 503 patients received HALAVEN, and 247 patients in the control group received therapy consisting of chemotherapy [total 97% (anthracyclines 10%, capecitabine 18%, gemcitabine 19%, taxanes 15%, vinorelbine 25%, other chemotherapies 10%)] or hormonal therapy (3%). The median duration of exposure was 118 days for patients receiving HALAVEN and 63 days for patients receiving control therapy. Table 2 reports the most common adverse reactions occurring in at least 10% of patients in either group.

Table 2 Adverse Reactions with a Per-Patient Incidence of at Least 10% in Study 1 HALAVEN (n=503) Control Group (n=247) MedDRA ver 10.0 All Grades ≥ Grade 3 All Grades ≥ Grade 3 Blood and Lymphatic System Disordersa Neutropenia 82% 57% 53% 23% Anemia 58% 2% 55% 4% Nervous system disorders b Peripheral neuropathy 35% 8% 16% 2% Headache 19% <1% 12% <1% General disorders and administrative site conditions Asthenia/Fatigue 54% 10% 40% 11% Mucosal inflammation 9% 1% 10% 2% Pyrexia 21% <1% 13% <1% Gastrointestinal disorders Constipation 25% 1% 21% 1% Diarrhea 18% 0 18% 0 Nausea 35% 1% 28% 3% Vomiting 18% 1% 18% 1% Musculoskeletal and connective tissue disorders Arthralgia/Myalgia 22% <1% 12% 1% Back pain 16% 1% 7% 2% Bone pain 12% 2% 9% 2% Pain in extremity 11% 1% 10% 1% Investigations Weight decreased 21% 1% 14% <1% Metabolism and nutrition disorders Anorexia 20% 1% 13% 1%

Table 2 (cont’d) MedDRA ver 10.0

oncologist, since the patient continues to be cared for by the team but by someone with expertise in survivorship issues. Communication with the primary care provider using a treatment summary and care plan is a key component of this model.

Although survivorship follow-up

HALAVEN (n=503) All Grades ≥ Grade 3

Control Group (n=247) All Grades ≥ Grade 3

Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders Alopecia 45% NAc 10% NAc Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

Cytopenias: Grade 3 neutropenia occurred in 28% (143/503) of patients who received HALAVEN in Study 1, and 29% (144/503) of patients experienced Grade 4 neutropenia. Febrile neutropenia occurred in 5% (23/503) of patients; two patients (0.4%) died from complications of febrile neutropenia. Dose reduction due to neutropenia was required in 12% (62/503) of patients and discontinuation was required in <1% of patients. The mean time to nadir was 13 days and the mean time to recovery from severe neutropenia (<500/mm3) was 8 days. Grade 3 or greater thrombocytopenia occurred in 1% (7/503) of patients. G-CSF (granulocyte colony-stimulating factor) or GM-CSF (granulocyte–macrophage colonystimulating factor) was used in 19% of patients who received HALAVEN. Peripheral Neuropathy: In Study 1, 17% of enrolled patients had Grade 1 peripheral neuropathy and 3% of patients had Grade 2 peripheral neuropathy at baseline. Dose reduction due to peripheral neuropathy was required by 3% (14/503) of patients who received HALAVEN. Four percent (20/503) of patients experienced peripheral motor neuropathy of any grade and 2% (8/503) of patients developed Grade 3 peripheral motor neuropathy.

Liver Function Test Abnormalities: Among patients with Grade 0 or 1 ALT levels at baseline, 18% of HALAVEN-treated patients experienced Grade 2 or greater ALT elevation. One HALAVEN-treated patient without documented liver metastases had concomitant Grade 2 elevations in bilirubin and ALT; these abnormalities resolved and did not recur with re-exposure to HALAVEN. Less Common Adverse Reactions: The following additional adverse reactions were reported in ≥5% to <10% of the HALAVEN-treated group: • Eye Disorders: increased lacrimation • Gastrointestinal Disorders: dyspepsia, abdominal pain, stomatitis, dry mouth • General Disorders and Administration Site Conditions: peripheral edema • Infections and Infestations: upper respiratory tract infection • Metabolism and Nutrition Disorders: hypokalemia • Musculoskeletal and Connective Tissue Disorders: muscle spasms, muscular weakness • Nervous System Disorders: dysgeusia, dizziness • Psychiatric Disorders: insomnia, depression • Skin and Subcutaneous Tissue Disorders: rash 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Category D There are no adequate and well-controlled studies with HALAVEN in pregnant women. HALAVEN is a microtubule inhibitor; therefore, it is expected to cause fetal harm when administered to a pregnant woman. Embryo-fetal toxicity and teratogenicity occurred in rats that received eribulin mesylate at approximately half of the recommended human dose based on body surface area. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

In a developmental toxicity study, pregnant rats received intravenous infusion of eribulin mesylate during organogenesis (Gestation Days 8, 10, and 12) at doses approximately 0.04, 0.13, 0.43 and 0.64 times the recommended human dose, based on body surface area (mg/m2). Increased abortion and severe external or soft tissue malformations were observed in offspring at doses 0.64 times the recommended human dose based on body surface area (mg/m2), including the absence of a lower jaw, tongue, stomach and spleen. Increased embryo-fetal death/resorption, reduced fetal weights, and minor skeletal anomalies consistent with developmental delay were also reported at or above doses of 0.43 times the recommended human dose.

Maternal toxicity of eribulin mesylate was reported in rats at or above doses of 0.43 times the recommended human dose (mg/m²), and included enlarged spleen, reduced maternal weight gain and decreased food consumption.

8.3 Nursing Mothers It is not known whether HALAVEN is excreted into human milk. No studies in humans or animals were conducted to determine if HALAVEN is excreted into milk. Because many drugs are excreted into human milk and because of the potential for serious adverse reactions in human milk fed infants from HALAVEN, a decision should be made whether to discontinue nursing or to discontinue HALAVEN taking into account the importance of the drug to the mother.

8.4 Pediatric Use The safety and effectiveness of HALAVEN in pediatric patients below the age of 18 years have not been established.

8.6 Hepatic Impairment A study evaluated the PK of eribulin in patients with mild (Child-Pugh A; n=7) and moderate (Child-Pugh B; n=5) hepatic impairment. Compared to patients with normal hepatic function (n=6), eribulin exposure increased 1.8-fold and 2.5-fold in patients with mild and moderate hepatic impairment, respectively. Administration of HALAVEN at a dose of 1.1 mg/m2 to patients with mild hepatic impairment and 0.7 mg/m2 to patients with moderate hepatic impairment resulted in similar exposure to eribulin as a dose of 1.4 mg/m2 to patients with normal hepatic function. A lower starting dose of 1.1 mg/m2 is recommended for patients with mild hepatic impairment (Child-Pugh A) and of 0.7 mg/m2 is recommended for patients with moderate hepatic impairment (Child-Pugh B). HALAVEN was not studied in patients with severe hepatic impairment (Child-Pugh C).

8.7 Renal Impairment No formal PK trials were conducted with HALAVEN in patients with renal impairment. Available data suggests that no dose adjustment is necessary for patients with mild renal impairment (CrCl 50-80 mL/min). However, for patients with moderate renal impairment (CrCl 30-50 mL/min), the geometric mean dose-normalized systemic exposure increased 2-fold compared to patients with normal renal function. A lower starting dose of 1.1 mg/m2 is recommended for patients with moderate renal impairment. The safety of HALAVEN was not studied in patients with severe renal impairment (CrCl <30 mL/min).

10 OVERDOSAGE Overdosage of HALAVEN has been reported at approximately 4 times the recommended dose, which resulted in Grade 3 neutropenia lasting seven days and a Grade 3 hypersensitivity reaction lasting one day.

There is no known antidote for HALAVEN overdose.

12 CLINICAL PHARMACOLOGY 12.2 Pharmacodynamics Cardiac Electrophysiology The effect of HALAVEN on the QTc interval was assessed in an open-label, uncontrolled, multicenter, single-arm dedicated QT trial. A total of 26 patients with solid tumors received 1.4 mg/m2 of HALAVEN on Days 1 and 8 of a 21-day cycle. A delayed QTc prolongation was observed on Day 8, with no prolongation observed on Day 1. The maximum mean QTcF change from baseline (95% upper confidence interval) was 11.4 (19.5) ms.

13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, mutagenesis, impairment of fertility Carcinogenicity studies have not been conducted with eribulin mesylate.

Eribulin mesylate was not mutagenic in in vitro bacterial reverse mutation assays (Ames test). Eribulin mesylate was positive in mouse lymphoma mutagenesis assays, and was clastogenic in an in vivo rat bone marrow micronucleus assay.

The effects of HALAVEN on human fertility are unknown. Fertility studies have not been conducted with eribulin mesylate in humans or animals. However, nonclinical findings in repeated-dose dog and rat toxicology studies suggest that male fertility may be compromised by treatment with eribulin mesylate. Rats exhibited testicular toxicity (hypocellularity of seminiferous epithelium with hypospermia/aspermia) following dosing with eribulin mesylate at or above 0.43 times the recommended human dose (mg/m2) given once weekly for 3 weeks, or at or above 0.21 times the recommended human dose (mg/m2) given once weekly for 3 out of 5 weeks, repeated for 6 cycles. Testicular toxicity was also observed in dogs given 0.64 times the recommended human dose (mg/m2) weekly for 3 out of 5 weeks, repeated for 6 cycles.

17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling • Advise patients to contact their health care provider for a fever of 100.5°F or greater or other signs or symptoms of infection such as chills, cough, or burning or pain on urination.

• Advise women of childbearing potential to avoid pregnancy and to use effective contraception during treatment with HALAVEN. –––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––––– HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA / May 2011 ERI 161

care traditionally has been the responsibility of the treating oncologist, we now have a much greater appreciation for formal communication with other physicians. Today, sharing care with other specialists and the primary care provider is recognized as both necessary and optimal. In addition, there has been a rethinking about who the appropriate provider of care is during the follow-up period, and considerations about staffing the previously mentioned models with both primary care physicians and nonphysician providers (such as nurses and nurse practitioners), depending on the country.

Measuring Success The variety of care models doesn’t signal confusion or chaos, but rather, it offers the oncology community the option of tailoring needed services to the survivor population and the clinical environment. We are beginning to answer critical questions about how cancer survivors should be followed, by whom, and for how long. As these models mature, each should be evaluated using key metrics to ensure that we are providing optimal care for this growing number of individuals. Success will be measured not merely in numbers, but in the quality of the lives of these survivors.

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Financial Disclosure: Ms. McCabe reported no potential conflicts of interest.

Call for Papers The ASCO Post invites readers to share their thoughts and opinions on matters of interest to the oncology community (500 words recommended). All submissions will be acknowledged and considered for publication.

Write to: Editor@ASCOPost.com for more information or to submit your commentary.

ASCOPost.com | JUNE 15, 2011

PAGE 25

Expert’s Corner

Conversation with Dr. Ganz continued from page 4

of the task as simply a clinical note that summarizes the course of treatment, which can be documented at the first follow-up visit after completing adjuvant or curative therapy. However, we don’t have any systematic method for creating treatment plans. To start using universal electronic records, there will have to be agreement on what the variables are and how they are going to be input. The problem in cancer is that there are over 100 different diseases, but we already have a TNM and clinical staging system, so we need to figure out some way to make the preparation of the treatment summary easier. Like anything else, there are things we do in medicine that are now routine, but probably when they started out everyone said, “Why should we do that?”

Ultimately, these plans are tools for better communication and better quality care.

That’s what having a survivorship care plan is all about. It’s not just window dressing.

UCLA-LIVESTRONG Center What’s included in your model of care at the UCLA-LIVESTRONG Survivorship Center of Excellence?

UCLA is a matrix cancer center, so we’re embedded within a university medical center. My Co-director at the LIVESTRONG Center is Jackie Casillas, MD, a pediatric oncologist, and we’ve developed consultative models of care for both childhood/young adult survivors and adult survivors of cancer. After seeing survivors for a consultation, we make sure that they are also being followed by a primary care physician, which may be in addition to seeing a medical or surgical oncologist, depending on their needs after cancer treatment. The key in our strategy for following survivors has been to find primary care physicians who can work collaboratively with the oncologists.

We’ve identified a number of internists and family physicians who can take care of young adult cancer survivors. They can perform gynecologic and routine medical exams and they can also follow survivors for surveillance of cancer late effects. We’ve also cultivated endocrinologists, cardiologists, and neurologists who are not just thinking about specific organs in isolation but about how those organs are affected in the context of the cancer exposure.

During their visit, we also screen all patients for depression, assess diet and physical activity, and measure body mass index. In addition to Dr. Casillas, I work closely with a psychologist from the Simms/Mann–UCLA Center for Inte-

grative Oncology who sees the patient first during our consultation. An adult nurse practitioner also works with me to deliver information about diet, exercise, and lifestyle factors. Incorporating these clinicians into the medical consultation visit indicates to the survivor that this is part of their comprehensive medical care.

Role of Primary Care Physicians How willing are primary care physicians to take on long-term cancer survivorship care?

At UCLA, we try to enhance the ability of the primary care physician to deliver ongoing follow-up care to survivors.

Recently, we did a quality improvement study to evaluate whether our consultations were helpful to the primary care physicians with whom we worked. A physician not involved in our program interviewed these clinicians to see what they liked or didn’t like about our survivorship care plan. We were worried that our consultation notes were too long, for example. But they raved about our consult notes and plans.

Many of the primary care physicians who have received our treatment sum-

The Survivorship Care Plan Document: A Flexible Tool

I

n the Journal of Oncology Practice,1 Erin E. Hahn, MPH, and Patricia A. Ganz, MD, reported a qualitative study of cancer survivorship programs, based on in-depth interviews with teams from four institutions—an academic center, a community hospital, a primary care medical group, and a county hospital.

SEE PAGE 41 “The key finding is that these successful survivorship programs have developed and implemented unique types of [survivorship care plan] documents within their organizations,” the authors noted. They concluded that the survivorship care plan document “is a flexible tool that can be successfully adapted for use in extremely varied settings, from primary care to hospitals to academic centers, to inform and educate patients and providers alike.”

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Reference 1. Hahn EE, Ganz PA: Survivorship programs and care plans in practice: Variations on a theme. J Oncol Pract 7:70-75, 2011.

oncologist. If you are in a three-person practice, you may have to take money out of another budget to pay for preparing a care plan. It’s not seen as a priority.

Then most often the problem is staffing and budget and perhaps not being aware of the importance of survivorship care plans?

Yes. I don’t think the oncologist is intellectually or emotionally opposed

It doesn’t cost a lot of time and effort to implement these plans if one thinks of the task as simply a clinical note that summarizes the course of treatment. maries and care plans over the past 5 years now refer their patients with cancer to us for a consult because they find that having the care plan roadmap allows them to better care for those patients. So we know that the plan is very useful to them.

Creating More Survivorship Plans What can be done to increase the number of survivorship care plans nationwide?

Time and resources need to be set aside to implement care plans. The challenge is developing the infrastructure.

We have a survivorship conference every year, and we do a lot of community outreach, which was part of our first 5-year Lance Armstrong Foundation grant. We had three community-based affiliates as part of our original center of excellence grant, and one focus was to develop a program in the community hospital.

But the big problem is that physicians don’t want to send their patients to the community hospital for a survivorship program. The real barrier is the medical

to preparing a care plan; it’s more a problem of knowing how to do it, how to organize it. If you are an oncologist in a very busy practice, it may not be feasible. So I’m very sympathetic.

Role of Professional Organizations What can the professional societies do to assist their members in developing and implementing survivorship care plans for their patients?

Some tools have already been developed and can be used by members.

ASCO has worked to disseminate treatment summaries and care plans that are available on its website, and we have done several educational programs at its annual meeting. I’ve also been involved with a collaborative project called Journey Forward, which promotes the use of survivorship care plans. Oncology professionals can go to the website at Journeyforward.org/professionals/survivorship-care-plan-builder and download a Survivorship Care Plan Builder,

which also includes free technical support. The plan is adapted from ASCO’s chemotherapy treatment summary templates and surveillance guidelines and is simple to use.

The program includes sample care plan forms that oncologists can customize with their practice logo. It’s fully loaded, easy to install on any computer, and includes resources such as a built-in regimen library and body surface area and body mass index calculators. This is a tool everyone can use.

Journey Forward is a collaborative effort of the National Coalition for Cancer Survivorship, UCLA Cancer Survivorship Center, WellPoint Health Insurance, and Genentech. Recently, the Oncology Nursing Society (ONS) has joined us in this partnership, and I think the collaboration will be very helpful to nurses. Having all these easy-to-use tools available will help decrease the barriers to preparing survivorship care plans, and that’s part of the message. We hope that with ONS joining this collaboration, survivorship care plans will be more widely disseminated to nurses in hospitals and within office practices, and that might make it easier for follow-up survivorship care to be conducted on a consistent basis.

We also need to get the electronic health record vendors onboard, we need to do what we can to break down the paper work, and that’s where ASCO could play a role. I’ve been pushing ASCO to deal with the vendors. Most of the institutional vendors are focused on primary care; they don’t think about oncology, which is not a big part of their market. That’s another area where the cancer centers may be able to help out, by pushing the electronic vendors to do more in this regard.

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Financial Disclosure: Dr. Ganz reported no potential conflicts of interest.

The ASCO Post | JUNE 15, 2011

PAGE 26

Journal Spotlight Hematology

Subcutaneous Bortezomib Offers Improved Safety Profile for Treating Patients with Relapsed Multiple Myeloma

S

ubcutaneous administration of bortezomib (Velcade) was comparably efficacious to intravenous administration in a phase III trial in patients with relapsed multiple myeloma, but the SC route “seemed to have an improved systemic safety profile compared with intravenous delivery,’’ investigators reported in Lancet Oncology. “Subcutaneous administration is a promising alternative to intravenous administration, particularly in patients with poor venous access or at increased risk of side effects,” they concluded.

ropathy risk factors no longer constitute a limiting factor for selection of bortezomib treatment,” they added.

“The increased convenience of subcutaneous administration might also

be relevant for investigation in settings such as maintenance therapy,” the authors commented. This route of administration could facilitate home administration of the drug, “with

substantial cost reduction and greatly improved patient convenience,” they concluded.

■

Moreau P, et al: Lancet Oncol 12:431440, 2011.

An Option for Newly Diagnosed Chronic Phase (CP) Ph+ CML Adult Patients…

Start With SPRYCEL (dasatinib)

Trial Data

SPRYCEL: Superior Response Rates vs Imatinib • Phase III, open-label, international, multicenter, randomized* study of SPRYCEL 100 mg once daily (n=259) vs imatinib 400 mg once daily (n=260) in adults with newly diagnosed Ph+ CML in chronic phase (N=519) at a minimum follow-up of 12 months1,2 — Primary endpoint was confirmed complete cytogenetic response (CCyR)† by 12 months

Major Molecular Response (MMR)‡ at Any Time1 MMR at Any Time

Patients were enrolled at 53 centers in 10 countries in Europe, Asia, and South America. Eligible patients had secretory multiple myeloma, had received one to three previous lines of therapy (excluding previous bortezomib), and had evidence of disease progression since the last therapy. After a median follow-up of 11.8 months for the 145 evaluable patients in the subcutaneous group and 12.0 months for the 73 patients in the intravenous group, there were no significant differences in time to progression (median, 10.4 months for those receiving subcutaneous administration vs 9.4 SEE PAGE 41 months for intravenous administration) and 1-year overall survival (72.6% vs 76.7%). Grade 3 or worse adverse events were reported in 57% of the patients in the subcutaneous group vs 70% in the intravenous group, with 22% of patients in the subcutaneous group vs 27% in the intravenous group discontinuing treatment because of adverse events and 31% in the subcutaneous group and 43% in the intravenous group requiring bortezomib dose reductions due to adverse events.

“Notably, we recorded significantly lower rates of peripheral neuropathy of all grades, grade 2 and higher, and grade 3 and higher with subcutaneous bortezomib than with intravenous bortezomib, despite similar rates of potential risk factors in each group,” the investigators reported. “Subcutaneous administration seems to provide an additional option to reduce bortezomib-related peripheral neuropathy, and in conjunction with dosing or schedule modifications, could further reduce neuropathy side effects to a level such that potential peripheral neu-

52% SPRYCEL (95% CI, 46-58)

P<0.0001§

34%

SPRYCEL (n=259) Imatinib (n=260)

Imatinib (95% CI, 28-40)

0

10

20

30

40

50 60 MMR (%)

70

80

90

100

• Among responders, median time to MMR was 6.3 months with SPRYCEL (n=135) vs 9.2 months with imatinib (n=88)1 • Primary endpoint: A significantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confirmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1 • Among responders, median time to confirmed CCyR with SPRYCEL was 3.1 months (n=199) vs 5.6 months with imatinib (n=177)1

Select Important Safety Information • SPRYCEL is associated with the following warnings and precautions: myelosuppression; bleeding-related events; fluid retention; QT prolongation; congestive heart failure, left ventricular dysfunction, and myocardial infarction; and use in pregnancy • The most frequently reported serious adverse events in patients with newly diagnosed CP CML included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) • The most frequently reported adverse reactions reported in ≥10% of patients with newly diagnosed CP CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash • Please see detailed Important Safety Information on adjacent pages

Indication SPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosomepositive chronic myeloid leukemia (Ph+ CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic and major molecular response rates. The trial is ongoing and further data will be required to determine long-term outcome.

ASCOPost.com | JUNE 15, 2011

PAGE 27

2011 ASCO Annual Meeting More Than $6 Million Awarded to Promising Cancer Researchers

T

his year ASCO’s Conquer Cancer Foundation will support promising researchers as they pursue studies that explore the anticancer activity of diabetes drugs in prostate cancer, improve the quality of life for elderly patients with colorectal cancer, and examine psycho-

social outcomes of siblings of pediatric stem cell transplant survivors. These are just a few of the research studies being conducted by the 205* gifted recipients who were presented with more than $6 million in grants and awards by the Foundation. The recipients were recog-

nized at ASCO’s Annual Meeting.

“The Conquer Cancer Foundation is committed to supporting cuttingedge cancer research and improving patient care globally,” said Martin J. Murphy Jr, PhD, DMedSc, Chair of the Foundation’s Board of Directors.

for Superior Response vs Imatinib in 1st Line

Start With Convenient Once-Daily Dosing

1 pill 100 mg 1 time per day

One tablet taken consistently, either in the morning or in the evening Tablets should not be crushed or cut; they should be swallowed whole Tablet not actual size.

• In clinical studies, treatment with SPRYCEL was continued until disease progression or until no longer tolerated by the patient1

SPRYCEL Can Be Taken Either With or Without Food1

FASTING

SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in chronic phase with: • No fasting requirements • No need to alter meal schedules • No need to take with food

Important Safety Information About Drug Interactions • Use of concomitant strong CYP3A4 inducers may decrease plasma concentrations of SPRYCEL and should be avoided • Strong CYP3A4 inhibitors may increase plasma concentrations of SPRYCEL and should be avoided • Grapefruit juice may increase plasma concentrations of SPRYCEL and should be avoided • Concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids should be considered instead. Antacids may decrease SPRYCEL drug levels. If antacid therapy is needed, the dose should be given 2 hours before or after SPRYCEL *Stratified by Hasford risk score.2 Confirmed CCyR is defined as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1 ‡ MMR (at any time) was defined as BCR-ABL ratios ≤0.1% by real-time quantitative polymerase chain reaction (RQ-PCR) in peripheral blood samples standardized on the International Scale.1 †

Adjusted for Hasford score and indicated statistical significance at a pre-defined nominal level of significance.1

§

Please see detailed Important Safety Information, including Important Safety Information on Drug Interactions, on adjacent pages.

“We are excited about this year’s class of dedicated recipients who, with help from the Foundation’s grant and award programs, are making great progress in the field of oncology,”

■

*Number as of May 31, 2011.

The ASCO Post | JUNE 15, 2011

PAGE 28

FDA Update

FDA Issues Revised Draft Guidance on Financial Disclosure

by Clinical Investigators

T

he FDA recently issued a draft guidance on financial disclosure by clinical investigators, intended to assist researchers, industry, and FDA staff in

interpreting and complying with regulations found in the Code of Federal Regulations Title 21, Part 54. The draft is being distributed for comment purposes only.

The document is a revision of a guidance issued in March 2001, and can be found in its entirety here: http://www.fda.gov/ downloads/RegulatoryInformation/

Guidances/UCM256525.pdf.

Notice announcing the availability of the draft guidance was published in the Federal Register on May 24, 2011.

Important Safety Information Myelosuppression: • Treatment with SPRYCEL® (dasatinib) can cause severe (NCI CTC Grade 3/4) thrombocytopenia, neutropenia, and anemia. Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities — Perform complete blood counts (CBCs) weekly for the first 2 months and then monthly thereafter, or as clinically indicated — Myelosuppression was generally reversible and usually managed by dose interruption, dose reduction, or discontinuation — Hematopoietic growth factor has been used in patients with resistant myelosuppression Bleeding-Related Events: • SPRYCEL caused platelet dysfunction in vitro and thrombocytopenia in humans — In all clinical trials, severe central nervous system (CNS) hemorrhage, including fatalities, occurred in 1% of patients. Severe gastrointestinal (GI) hemorrhage, including fatalities, occurred in 4% of patients receiving SPRYCEL, which generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients • Most bleeding events were associated with severe thrombocytopenia — Exercise caution in patients required to take medications that inhibit platelet function or anticoagulants Fluid Retention: • SPRYCEL is associated with fluid retention — In clinical trials, fluid retention was severe in up to 10% of patients. Ascites (<1%), generalized edema (<1%), and severe pulmonary edema (1%) were also reported in these trials • Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray • Severe pleural effusion may require thoracentesis and oxygen therapy • Fluid retention was typically managed by supportive care measures that included diuretics or short courses of steroids QT Prolongation: • In vitro data suggest that SPRYCEL has the potential to prolong cardiac ventricular repolarization (QT interval) • In 865 patients with leukemia treated with SPRYCEL in five phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms • In clinical trials of patients treated with SPRYCEL (n=2440), 15 patients (<1%) had QTc prolongation as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms • Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc, including patients with hypokalemia, hypomagnesemia, or congenital long QT syndrome and patients taking anti-arrhythmic drugs, other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy — Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Pregnancy: SPRYCEL may cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled 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 when taking SPRYCEL. Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because of the potential for serious adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or to discontinue SPRYCEL.

ASCOPost.com | JUNE 15, 2011

PAGE 29

FDA Update

Commenters have until July 25, 2011, to submit comments and suggestions, which should be directed to the Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm 1061, Rockville, MD 20852, or electronically, to http://www. regulations.gov. All comments should be

identified with the docket number FDA1999-D-0792.

For questions regarding the document, contact Marsha Melvin, Office of Good Clinical Practice, at 301-796-3340; Leah Ripper, Center for Drug Evaluation and Research, at

301-796- 1282; Sheila Brown, Center for Devices and Radiological Health, at 301-7966563; and Office of Communication, Outreach and Development, Center for Biologics Evaluation and Research, at 800-835-4709 or 301-827-1800.

Drug Interactions: SPRYCEL (dasatinib) is a CYP3A4 substrate and a weak time-dependent inhibitor of CYP3A4.

• Drugs that may increase SPRYCEL plasma concentrations are: — CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided • Drugs that may decrease SPRYCEL plasma concentrations are: — CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided • H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and 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 • Drugs that may have their plasma concentration altered by SPRYCEL are: — CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL Adverse Reactions: The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months).

The majority of SPRYCEL-treated patients experienced adverse reactions at some time. Patients aged 65 years and older are more likely to experience toxicity. In the newly diagnosed chronic phase CML study, SPRYCEL was discontinued for adverse reactions in 6% of patients.

• In newly diagnosed chronic phase CML patients: — The most frequently reported serious adverse reactions included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%) — The most frequently reported adverse reactions (reported in ≥10% of patients) included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash — Grade 3/4 laboratory abnormalities included neutropenia (22%), thrombocytopenia (19%), anemia (11%), hypophosphatemia (5%), hypocalcemia (3%), and elevated bilirubin (1%) • Grade 3/4 elevations of transaminase or bilirubin and Grade 3/4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML — Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption — Patients developing Grade 3/4 hypocalcemia during the course of SPRYCEL therapy often had recovery with oral calcium supplementation

Please see brief summary of full Prescribing Information on adjacent pages.

References: 1. SPRYCEL® (dasatinib) full Prescribing Information. Bristol-Myers Squibb. 2. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2010;362:2260-2270.

SPRYCEL is a registered trademark of Bristol-Myers Squibb Company.

For more information online, visit www.sprycel.com.

© 2011 Bristol-Myers Squibb 729US10AB13506 1/11

■

Send Us Your News Send your news of new appointments, awards, or significant events to The ASCO Post.

Write to editor@ASCOPost.com.

All submissions will be considered for publication.

The ASCO Post | JUNE 15, 2011

PAGE 30

Book Announcements

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SPRYCEL® (dasatinib) Tablet for Oral Use Brief Summary of Prescribing Information. For complete prescribing information consult official package insert.

INDICATIONS AND USAGE SPRYCEL® (dasatinib) is indicated for the treatment of adults with • newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia (CML) in chronic phase. The effectiveness of SPRYCEL is based on cytogenetic response and major molecular response rates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further data will be required to determine long-term outcome.

• chronic, accelerated, or myeloid or lymphoid blast phase Ph+ CML with resistance or intolerance to prior therapy including imatinib.

• Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) with resistance or intolerance to prior therapy.

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS Myelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombocytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CML or Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequently in patients treated with 100 mg once daily than in patients treated with other dosing regimens.

Perform complete blood counts weekly for the first 2 months and then monthly thereafter, or as clinically indicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCEL temporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and Adverse Reactions].

Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib caused platelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, including fatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, including fatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Other cases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severe thrombocytopenia.

Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibit platelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidal anti-inflammatory drugs (NSAIDs) was allowed concurrently with SPRYCEL if the platelet count was >50,000–75,000 per microliter. Exercise caution if patients are required to take medications that inhibit platelet function or anticoagulants.

Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention was reported in up to 10% of patients. Ascites and generalized edema were each reported in <1% of patients.

Severe pulmonary edema was reported in 1% of patients. Patients who develop symptoms suggestive of pleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion may require thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive care measures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention events were reported less frequently with once daily dosing than with other dosing regimens.

QT Prolongation: In vitro data suggest that dasatinib has the potential to prolong cardiac ventricular repolarization (QT interval). Of the 2440 patients with CML treated with SPRYCEL in clinical studies, 15 patients (<1%) had QTc prolongation reported as an adverse reaction. Twenty-two patients (1%) experienced a QTcF >500 ms. In 865 patients with leukemia treated with SPRYCEL in five Phase 2 single-arm studies, the maximum mean changes in QTcF (90% upper bound CI) from baseline ranged from 7.0 ms to 13.4 ms.

Administer SPRYCEL with caution to patients who have or may develop prolongation of QTc. These include patients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients taking anti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-dose anthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration.

Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adverse reactions were reported in 5.8% of 258 patients taking SPRYCEL, including 1.6% of patients with cardiomyopathy, heart failure congestive, diastolic dysfunction, fatal myocardial infarction, and left ventricular dysfunction. Monitor patients for signs or symptoms consistent with cardiac dysfunction and treat appropriately.

Use in Pregnancy Pregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses of dasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. There are no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in Specific Populations].

ADVERSE REACTIONS The following adverse reactions are discussed in greater detail in other sections of the labeling: • Myelosuppression [see Dosage and Administration (2.3) in Full Prescribing Information and Warnings and Precautions].

• Bleeding related events [see Warnings and Precautions].

• Fluid retention [see Warnings and Precautions].

• QT prolongation [see Warnings and Precautions].

• Congestive heart failure, left ventricular dysfunction, and myocardial infarction [see Warnings and Precautions].

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 described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newly diagnosed chronic phase CML and in 2182 patients with imatinib resistant or intolerant CML or Ph+ ALL. In the newly diagnosed chronic phase CML trial, the median duration of therapy was 18 months; the median average daily dose was 99 mg.

In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 years follow-up (starting dosage 100 mg once daily, 140 mg once daily, 50 mg twice daily, or 70 mg twice daily).

Among patients with chronic phase CML and resistance or intolerance to prior imatinib therapy, the median duration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The median duration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) for accelerated phase CML, 3 months (range 0.03–29 months) for myeloid blast phase CML, and 3 months (range 0.1–10 months) for lymphoid blast CML. The majority of SPRYCEL-treated patients experienced adverse reactions at some time. In the newly diagnosed chronic phase CML trial, drug was discontinued for adverse reactions in 6% of SPRYCEL-treated patients.

Among patients with resistance or intolerance to prior imatinib therapy, the rates of discontinuation for adverse reaction were 15% in chronic phase CML, 16% in accelerated phase CML, 15% in myeloid blast phase CML, 8% in lymphoid blast phase CML, and 8% in Ph+ ALL. In a dose-optimization study in patients with resistance or intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reaction was lower in patients treated with 100 mg once daily than in patients treated with other dosing regimens (10% and 16%, respectively).

The most frequently reported adverse reactions reported in ≥10% of patients in newly diagnosed chronic phase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31 patients (see Table 1).

The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance to prior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skin rash, fatigue, nausea, and hemorrhage.

The most frequently reported serious adverse reactions in patients with newly diagnosed chronic phase CML

included pleural effusion (2%), hemorrhage (2%), congestive heart failure (1%), and pyrexia (1%). The most frequently reported serious adverse reactions in patients with resistance or intolerance to prior imatinib therapy included pleural effusion (11%), gastrointestinal bleeding (4%), febrile neutropenia (4%), dyspnea (3%), pneumonia (3%), pyrexia (3%), diarrhea (3%), infection (2%), congestive heart failure/cardiac dysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%).

Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reported in at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML and Table 2 for CML patients with resistance or intolerance to prior imatinib therapy.

Table 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML All Grades Grade 3/4 SPRYCEL (dasatinib) Imatinib SPRYCEL Imatinib (n=258) (n=258) (n=258) (n=258) Preferred Term Percent (%) of Patients Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ 2 1 <1 <1 cardiac dysfunctiona 2 <1 <1 0 Pericardial effusion Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 Musculoskeletal pain 12 16 0 <1 b 11 17 0 1 Rash 21 Nausea 9 0 0 Fatigue 8 11 <1 0 12 Myalgia 6 0 0 6 5 1 1 Hemorrhagec Gastrointestinal bleeding 2 <1 1 0 d 5 5 0 1 Other bleeding CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage.

Table 2:

Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy 100 mg Once Daily

Preferred Term

Fluid Retention Superficial localized edema Pleural effusion Generalized edema Pericardial effusion Congestive heart failure/ cardiac dysfunctiona Pulmonary edema Headache Diarrhea Fatigue Dyspnea Musculoskeletal pain Nausea Skin rashb Myalgia Arthralgia Infection (including bacterial, viral, fungal, and non-specified) Abdominal pain Hemorrhage Gastrointestinal bleeding CNS bleeding Vomiting Pyrexia Febrile neutropenia

Chronic (n=165) All Grade Grades 3/4

140 mg Once Daily Myeloid Blast Accelerated (n=74) (n=157) All Grade All Grade Grades 3/4 Grades 3/4 Percent (%) of Patients 35 8 34 7 18 1 14 0

34 18

4 0

18 3 2 0

2 0 1 0

21 1 3 0

7 0 1 0

20 3 0 4

0 33 27 24 20 19 18 17 13 12 12

0 1 2 2 2 2 1 2 0 1 1

1 27 31 19 20 11 19 15 7 10 10

0 1 3 2 3 0 1 0 1 0 6

12 11 2 0 7 5 1

1 1 1 0 1 1 1

6 26 8 1 11 11 4

0 8 6 1 1 2 4

Lymphoid Blast (n=33) All Grade Grades 3/4 21 3

6 0

7 0 0 0

21 0 0 0

6 0 0 0

4 18 20 20 15 8 23 16 7 5 14

3 1 5 1 3 1 1 1 1 1 7

0 15 18 9 3 0 21 21 3 0 9

0 3 0 3 3 0 3 0 0 0 0

8 19 9 0 12 18 12

3 9 7 0 0 3 12

3 24 9 3 15 6 12

0 9 3 3 0 0 12

a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythema multiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rash follicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skin irritation, urticaria vesiculosa, and rash vesicular.

Laboratory Abnormalities Myelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4 neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronic phase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratory values as well as in patients with pre-existing laboratory abnormalities.

In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption or reduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phase CML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions].

ASCOPost.com | JUNE 15, 2011

PAGE 31

Book Announcements

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of prostate cancer.…This will be highly recommended reading for all my patients who have an interest in prostate cancer.”

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Note to Readers If you have a book you would like to recommend to readers of The ASCO Post, or if you are interested in writing a review of a newly published book for oncology professionals and/or patients with cancer, contact editor@ ASCOPost.com.

Contact

The ASCO Post Editorial Correspondence James O. Armitage, MD Editor-in-Chief e-mail: Editor@ASCOPost.com

Cara H. Glynn

Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, and hypophosphatemia were reported in patients with all phases of CML but were reported with an increased frequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin were usually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia during the course of SPRYCEL (dasatinib) therapy often had recovery with oral calcium supplementation.

Laboratory abnormalities reported in patients with newly diagnosed chronic phase CML are shown in Table 3.

There were no discontinuations of SPRYCEL therapy in this patient population due to biochemical laboratory parameters.

Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed Chronic Phase CML SPRYCEL (n=258)

Imatinib (n=258)

Percent (%) of Patients Hematology Parameters Neutropenia 22 20 Thrombocytopenia 19 10 Anemia 11 7 Biochemistry Parameters Hypophosphatemia 5 24 Hypokalemia 0 2 Hypocalcemia 3 2 Elevated SGPT (ALT) <1 1 Elevated SGOT (AST) <1 1 Elevated Bilirubin 1 0 Elevated Creatinine <1 1 9 9 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 10 /L, Grade 4 <0.5 × 10 /L); thrombocytopenia (Grade 3 ≥25–<50 × 109/L, Grade 4 <25 × 109/L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0– 1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0–2.5 mmol/L, Grade 4 <2.5 mmol/L).

Laboratory abnormalities reported in patients with CML resistant or intolerant to imatinib who received the recommended starting doses of SPRYCEL are shown by disease phase in Table 4.

Table 4: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance or Intolerance to Prior Imatinib Therapy Chronic Phase CML 100 mg Once Daily (n=165)

Advanced Phase CML 140 mg Once Daily Accelerated Myeloid Phase Blast Phase (n=157) (n=74) Percent (%) of Patients

Lymphoid Blast Phase (n=33)

Hematology Parameters Neutropenia 36 58 77 79 Thrombocytopenia 23 63 78 85 Anemia 13 47 74 52 Biochemistry Parameters Hypophosphatemia 10 13 12 18 Hypokalemia 2 7 11 15 Hypocalcemia <1 4 9 12 Elevated SGPT (ALT) 0 2 5 3 Elevated SGOT (AST) <1 0 4 3 Elevated Bilirubin <1 1 3 6 Elevated Creatinine 0 2 8 0 CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/L); thrombocytopenia (Grade 3 ≥25–<50 × 9 9 10 /L, Grade 4 <25 × 10 /L); anemia (hemoglobin Grade 3 ≥65–<80 g/L, Grade 4 <65 g/L); elevated creatinine (Grade 3 >3–6 × upper limit of normal range (ULN), Grade 4 >6 × ULN); elevated bilirubin (Grade 3 >3–10 × ULN, Grade 4 >10 × ULN); elevated SGOT or SGPT (Grade 3 >5–20 × ULN, Grade 4 >20 × ULN); hypocalcemia (Grade 3 <7.0–6.0 mg/dL, Grade 4 <6.0 mg/dL); hypophosphatemia (Grade 3 <2.0–1.0 mg/dL, Grade 4 <1.0 mg/dL); hypokalemia (Grade 3 <3.0– 2.5 mmol/L, Grade 4 <2.5 mmol/L).

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia (Ph+ ALL) A total of 135 patients with Ph+ ALL were treated with SPRYCEL 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 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; <0.1% – protein losing gastroenteropathy. 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: 1%–<10% – cough, 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, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, 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; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <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).

Postmarketing Experience The following additional adverse reactions have been identified during post approval use of SPRYCEL (dasatinib).

Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Cardiac disorders: atrial fibrillation/atrial flutter. Vascular disorders: thrombosis/embolism (including pulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitial lung disease.

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. 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. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL 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 well-controlled 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: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 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. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity.

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 given appropriate supportive treatment.

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).

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

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The ASCO Post | JUNE 15, 2011

PAGE 32

Survivorship

Explaining the Survival Gap continued from page 1

unknown, clues are starting to emerge.

One key factor, say experts, may be that the biology of cancers in young adults is different from the biology of the same diseases in either children or older patients, especially when it comes to the most common cancers diagnosed in young adults, including lymphomas, leukemias, sarcomas, melanoma, and testicular, ovarian, thyroid, colorectal, and breast malignancies.

In 2009, the NCI and the Lance Armstrong Foundation launched a workshop to examine the possible biologic differences in three of those diseases—ALL, breast cancer, and colon cancer—and to discuss ways to improve prognosis and treatment outcomes. The findings were published earlier this year in the Journal of the National Cancer Institute.1 They showed startling differences in the features of these diseases in

adolescents and young adults, bolstering the suggestion that tumor biology in these cancers is different compared to the same cancers in the younger and older age groups. For example, young adults diagnosed with colon cancer have more advanced disease and poorer prognosis at diagnosis compared with older adults, are less responsive to treatment, and have a greater frequency of microsatellite instability.

“Some of the microsatellite instability is due to the inherited, familial forms of colon cancer, but what we’ve learned is that microsatellite instability is also found in the nonfamilial types and, therefore, young adults who have no inherited predisposition to cancer who get colon or rectal cancer probably often have a different molecular type than occurs in older persons. That a majority of young adults who develop colon cancer have sporadic disease and the microsatellite instability type

is a clear illustration that a distinctly different biologic type is involved,” said Archie W. Bleyer, MD, Clinical Research Professor, Oregon Health & Science University, and Co-Chair of the Research Task Force of the LIVESTRONG Young Adult Alliance.

Different Standards of Care?

The clinical features of breast cancer and ALL in young adults are also worse, including more aggressive disease and less favorable outcomes, which may mean that cancers in this age group need different treatment protocols. The NCI’s Adolescent and Young Adult Oncology Progress Review Group has recommended the development of standards of care for young adults, and both the National Comprehensive Cancer Network and the LIVESTRONG Young Adult Alliance are working on developing standards of care. However, the availability of clinical trials for this

Archie W. Bleyer, MD

age group is limited and participation in clinical trials by adolescent and young adult patients is lacking—only 5% of 15 to 25 year olds are entered into clinical trials compared to 60% to 65% of younger patients. Given the resulting insufficiency of tissue specimens, these factors make it difficult to study the possible molecular differences of young adult tumors and how those differences impact treatment effectiveness.

Body composition, size, organ maturity, and hormonal status may also

A Conversation with Brad Zebrack, PhD, MSW, MPH How to help young adults cope with cancer

By Jo Cavallo

E

ach year in the United States, ap- how oncologists and other medical proximately 70,000 providers can help young people between the ages adults cope with cancer. of 15 and 40 are diagnosed Watching for with cancer. And while Psychosocial Issues getting a cancer diagnoWhat can oncologists sis at any age can be devdo to spot psychosocial isastating, for adolescents sues their young adult paand young adults (AYAs) tients with cancer may be grappling with sexuality, experiencing? body image, peer pressure, You have to specifidating, marriage, family Brad Zebrack, PhD, MSW, MPH cally ask them how they planning, education, and career goals, making the adjustment of are coping with cancer. Are they having having a life-threatening disease can be pain, sexual problems, emotional probespecially difficult. Although all cancer lems, or treatment-related side effects? survivors share some common con- Knowing that young adults experience cerns, studies show that young adults more psychological distress compared suffer more cancer pain and distress with older adults with cancer, docthan older patients and experience tors need to ask them specifically what more sleeping difficulties, sadness, they’re struggling with and then determine how the health-care team can help worry, irritability, and sexual issues.

Diagnosed with Hodgkin lympho- them and what psychosocial support ma at 26, Brad Zebrack, PhD, MSW, interventions might be necessary.

MPH, Associate Professor, University of Michigan School of Social Work, Population-specific Needs How unique is this population comand Adjunct Associate Professor, University of Michigan School of Public pared to children and older cancer surviHealth in Ann Arbor, has devoted his vors in the types of psychosocial support career to researching the impact of services they may need?

The tricky thing that makes AYAs cancer on adolescent and young adult cancer survivors. Recently, The ASCO unique is that they need to know that Post talked with Dr. Zebrack about the support services are available to

them when they want them. Adolescents and young adults don’t want to be told what to do. They want to get there on their own, but they’re still kids, so the approach has to be different. Chances are an oncologist may be seeing a young person with a drug or alcohol problem, and those issues need to be addressed in the context of care. But if the doctor asks, ‘How much alcohol do you drink?’ or ‘Do you take drugs?’ that young person will likely say, ‘No, I don’t.’ The oncologist can then make the point about the importance of not taking drugs or drinking when on active treatment and say, ‘If these are issues you need help with, there are people I can refer you to.’

Oncologists are becoming more aware of the fertility issues and do raise those concerns with patients. However, when a young adult gets a cancer diagnosis, often the only thing she hears is that she has cancer, so these issues have to be revisited throughout the continuum of care. It’s not enough to say, ‘This might impact your fertility.’ The next week, when the patient comes back for staging, say, the doctor needs to raise the issue again. The research I’m doing seems to show that those first few months following a diagnosis is when psychosocial information is critical for young adults.

Role of Social Media Since this is a population that grew up in the digital age, would using social media like Twitter help keep patients treatment compliant?

The research hasn’t been done yet to show to what extent all the social media applications can be used to promote adherence to therapy, but it’s a great question. For young adults, it’s all about maintaining a lifestyle they can be okay with while they’re going through cancer treatment. Young people have little experience in dealing with life-threatening issues, so they’re at risk for choosing quality of life over cancer treatment, because they want to deny or ignore the fact that they have cancer.

Cognitively, these young patients haven’t yet developed fully functioning reasoning capabilities. So when they do something stupid like go to a party on a Friday afternoon instead of coming in for their chemotherapy treatment, it’s best to avoid the punitive approach and instead reinforce the positive message of how important it is to stick to the therapy, which is going to improve their chances for survival.

■

Financial Disclosure: Dr. Zebrack reported no potential conflicts of interest.

ASCOPost.com | JUNE 15, 2011

PAGE 33

Survivorship

be contributing factors in stagnating survival rates among young adults.

“There’s probably a biologic reason; age is just a surrogate,” said Karen H. Albritton, MD, Director, Adolescent and Young Adult Oncology Program, Cook Children’s Medical Center and University of North Texas Health Science Center in Fort Worth. “It may

Karen H. Albritton, MD

be the biology of the tumor, the biology of the host, hormonal differences, or that adolescents and young adults are using substances that affect their drug metabolism. It’s just a hypothesis, but these patients may be different because of their changing body metabolism and fat distribution, and we may be missing the mark a lot.”

Compliance Issues Lack of treatment compliance may also play a role in worse survival outcomes. According to research published last year in the Journal of Clinical Oncology,2 as many as 27% to 60% of young people may have poor adherence to cancer treatment. And those percentages are expected to rise with the advent of more oral cancer drugs.

“Anecdotally, we all recognize that there could be a major issue with com-

pliance, but I think the problem is underrecognized. We don’t have enough data to point to how common and critical the problem is. I know that for chronic myelogenous leukemia, for which the treatment is the oral medication imatinib (Gleevec), studies have looked at the degree to which patients of all ages aren’t able to adhere to a regular schedule, as well as the fact that missing just a handful of doses a month can lead to differences in cytogenetic outcomes,” said Dr. Hayes-Lattin.

Although no definitive data have shown cause and effect, delays in seeking medical treatment and getting an accurate diagnosis may also be sabotaging survival rates. “We think a couple of things could be contributing to these differences in survival. One is basic biology. The second is how people react to the health-care system, and that includes a delayed diagnosis, which can be quite common in young adult cancers, in part because the patients themselves don’t consider cancer when they have a nagging medical condition, but also because providers don’t consider cancer in young patients either,” said Dr. Hayes-Lattin. While a delayed diagnosis may not ultimately alter the outcome of disease for young adult patients, it may mean that they need more intense treatment, which could result in more late and long-term effects, including secondary cancers, infertility, fatigue, depression, and cognitive problems, hindering quality of life for a population with potentially decades more to live.

“We have to think about the definition of quality of life for young adults and balance treatment toxicity [accordingly],” said Dr. Albritton. “We

Making a Connection The following websites can help young adults learn about their cancer, find support services, and connect with peers:

■■ ASCO’s Cancer.Net (www.cancer.net) ■■ CancerCare (www.cancercare.org) ■■ I’m Too Young for This! Cancer Foundation (www.stupidcancer.com) ■■ LIVESTRONG Young Adult Alliance (www.livestrong.org) ■■ Planet Cancer (www.planetcancer.org) ■■ 15-40 Connection (www.15-40.org) have to meet young adults where they’re at. The field of oncology has moved to a place where we are curing more people, and we were trained to go for the cure, assuming that patients would do anything for that. We imagined they would come back to us 20 years later and say, ‘I don’t care if I can’t have kids and I can’t have a normal life—I’m alive.’ But those days are gone. We owe more to our patients. We can do more than just cure them, and I think we have to take into account these quality-of-life issues, especially for adolescents and young adults who, hopefully, have 50 years ahead of them, not 5.”

Raising Awareness To help educate medical professionals—especially those at the front line of care for young adults, including primary care physicians and nurses—on the challenges of diagnosing and treating young adult patients with cancer, ASCO partnered with LIVESTRONG to launch a new ASCO University ® program called Focus Under Forty™ (http://university. asco.org/focusunder40). To improve

survival rates in this population, adolescents and young adults themselves will also need to be educated on the risks and symptoms of cancer.

“Educating young people about cancer is hard because twenty-somethings don’t want to hear about cancer. They’re invincible at that age, and education has to be done smartly and nonthreateningly,” said Dr. Albritton. “ASCO members can look for opportunities to do this type of education, to speak to high school and college students, for example, and at medical conferences for primary care physicians [to alert them to the risks and symptoms of cancer in this age group].”

■

Financial Disclosure: Dr. Bleyer is on the speakers bureau and a consultant for SigmaTau Pharmaceuticals. Dr. Albritton reported no potential conflicts of interest.

Reference 1. Tricoli JV, Seibel NL, Blair DG, et al: Unique characteristics of adolescent and young adult acute lymphoblastic leukemia, breast cancer and colon cancer. J Natl Cancer Inst 103:628-635, 2011.

2. Butow P, Palmer S, Pai A, et al: Review of adherence-related issues in adolescents and young adults with cancer. J Clin Oncol 28:4800-4809, 2010.

Coming in the July 2011 Issues of Comprehensive coverage of the 2011 ASCO Annual Meeting, including reports on this year’s plenary program:

■■ Abstract LBA1: Twelve versus 36 months of adjuvant imatinib (IM) as treatment of operable GIST with a high risk of recurrence: Final results of a randomized trial (SSGXVIII/AIO). H. Joensuu, author/speaker.

■■ Abstract 2: Busulphan-melphalan as a myeloablative therapy (MAT) for high-risk neuroblastoma: Results from the HR-NBL1/SIOPEN trial. R. L. Ladenstein, author/speaker.

■■ Abstract 3: Comparison of high-dose methotrexate (HD-MTX) with Capizzi methotrexate plus asparaginase (C-MTX/ASNase) in children and young

adults with high-risk acute lymphoblastic leukemia (HR-ALL): A report from the Children’s Oncology Group Study AALL0232. E. C. Larsen, author/speaker.

■■ Abstract LBA4: Phase III randomized, open-label, multicenter trial (BRIM3) comparing BRAF inhibitor vemurafenib with dacarbazine (DTIC) in patients with V600EBRAF-mutated melanoma. P. B. Chapman, author/speaker.

■■ Abstract LBA5: Phase III randomized study of ipilimumab (IPI) plus dacarbazine (DTIC) versus DTIC alone as first-line treatment in patients with unresectable stage III or IV melanoma. J. D. Wolchok, author/speaker.

Plus much more from the Annual Meeting, along with Important columns, features, and clinical departments.

Visit The ASCO Post online at ASCOPost.com.

EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

Š 2010 Genentech USA, Inc. All rights reserved. BRF000012770 Printed in USA.

Oncogenic BRAF: A new potential therapeutic target1,2 The RAS-RAF pathway, a type of MAPK pathway, is a key regulator of diverse biologic functions such as cell proliferation and survival.1,3,4 One of the key intermediaries of this pathway is the BRAF protein.4 Mutations in BRAF may cause the protein to become oncogenic. Oncogenic BRAF signaling triggers overactive downstream signaling via the protein kinases MEK and ERK and can potentially result in tumorigenesis.1,2 The majority of mutations that result in constitutively active oncogenic BRAF are BRAFV600E, which is implicated in diverse malignancies1,2: ~50% of melanoma tumors4 ~40% of papillary thyroid tumors4,5 ~30% of serous ovarian tumors5 ~10% of colorectal tumors6 ~10% of prostate tumors6 In metastatic melanoma, oncogenic V600 BRAF is a readily detectable biomarker and diagnostics to detect this biomarker are currently in development.2 Genentech, a member of the Roche Group, is actively researching the potential of oncogenic BRAF as a novel therapeutic target and as a personalized approach for BRAF-driven tumors. For more information about oncogenic BRAF inhibition, please visit www.ResearchBRAF.com.

References: 1. Wong KK. Recent developments in anti-cancer agents targeting the Ras/Raf/MEK/ERK pathway. Recent Pat Anticancer Drug Discov. 2009;4:28-35. 2. Wellbrock C, Hurlstone A. BRAF as therapeutic target in melanoma. Biochem Pharmacol. 2010;80:561-567. 3. Wan PT, Garnett MJ, Roe SM, et al. Mechanism of activation of the RAF-ERK signaling pathway by oncogenic mutations of B-RAF. Cell.

2004;116:855-867. 4. McCubrey JA, Steelman LS, Abrams SL, et al. Roles of the RAF/MEK/ERK and PI3K/PTEN/AKT pathways in malignant transformation and drug resistance. Adv Enzyme Regul.

2006;46:249-279. 5. Pritchard C, Carragher L, Aldridge V, et al. Mouse models for BRAF-induced cancers. Biochem Soc Trans. 2007;35:1329-1333. 6. Cho NY, Choi M, Kim BH, Cho YM, Moon KC, Kang GH. BRAF and KRAS mutations in prostatic adenocarcinoma. Int J Cancer. 2006;119:1858-1862.

The ASCO Post | JUNE 15, 2011

PAGE 36

In the Literature

Emerging Clinical Data on Cancer Management PROSTATE CANCER Death Rates Significantly Reduced for Men Having Radical Prostatectomy vs Watchful Waiting Estimated 15-year results from the Scandinavian Prostate Cancer Group Study (SPCG-4) show that men diagnosed with early prostate cancer and randomly assigned to radical prostatectomy continued to have significantly reduced rates of death from prostate cancer, death from any cause, and risk of metastases than did men randomly assigned to watchful waiting. “The benefit is obvious among men younger than 65 years of age, but it is still unclear whether the benefit extends to older men,” the investigators reported in The New England Journal of Medicine.

“The finding that the effect of radical prostatectomy is modified by age has not been confirmed in other studies of radical prostatectomy or externalbeam radiation, the authors added.

During a median of 12.8 years, 201 of the 348 men randomly assigned to the watchful waiting group died (81 due to prostate cancer) and 166 of the 347 men in the radical prostatectomy group died (55 due to prostate cancer). The risk of death from prostate cancer after radical prostatectomy was 7 times higher among men who had tumors with extracapsular growth. “Although extracapsular growth is not a

perfect predictor of lethal disease, our findings indicate that these men could be a group for which adjuvant local or systemic therapy would be beneficial,” the authors stated.

“The finding that some low-risk tumors will progress and become lethal emphasizes the importance of protocols with well-defined end points at which men in active surveillance switch to curative treatment,” the authors concluded. “With continued follow-up, data from the SPCG-4 study may allow us to identify prognostic markers in men assigned to watchful waiting that can serve as trigger points for active treatment; the prognostic value of these markers can then be validated in cohorts that are under active surveillance.”

Bill-Axelson A, et al: New Engl J Med 364:1708-1717, 2011.

CERVICAL CANCER Adding Gemcitabine to Chemoradiation Improves Survival Outcomes for Locally Advanced Cervical Cancer A phase III, open-label, randomized trial found that adding gemcitabine to concurrent cisplatin chemoradiotherapy and using gemcitabine as adjuvant chemotherapy with cisplatin improved survival outcomes in women with locally advanced cervical cancer. Toxicity was increased compared to standard

© David Sipress/The New Yorker Collection/www.cartoonbank.com

treatment but clinically manageable.

The 515 study patients, aged 18 to 70, with stage IIB to IVA cervical cancer not previously treated with chemotherapy or radiotherapy, were randomly assigned to one of two treatment arms. Patients in arm A received treatment consisting of gemcitabine plus cisplatin chemoradiotherapy followed by brachytherapy and adjuvant gemcitabine and cisplatin. Patients in arm B received treatment consisting of cisplatin chemoradiotherapy followed by brachytherapy only. At a median follow-up of 46.9 months, the investigators found a statistically significant improvement for arm A over arm B in the three main survival endpoints: 3-year progression-free survival (74.4% in arm A vs 65.0% in arm B; P = .029), overall progression-free survival, and overall survival.

“To our knowledge, the data from this trial represent the first finding of significantly improved survival outcomes” for patients with locally advanced cervical cancer “with combination multimodality therapy compared with single-agent cisplatin chemotherapy,” the authors wrote. The results were reported in the Journal of Clinical Oncology.

Grade 3 and 4 toxicities were seen more frequently in arm A than in arm B (86.5% vs 46.3%, respectively; P < .001), including two deaths possibly related to treatment toxicity in arm A, the investigators reported. There were also more discontinuations in arm A than arm B, mostly a result of the adverse events.

An accompanying editorial noted that the study was “remarkable for many reasons,” including being conducted at sites in the developing world, where the majority of patients with advanced disease live and where access to basic medical care is limited or absent. “This study represents clear evidence that large phase III randomized controlled trials can be conducted in a rapid fashion in the developing world if sufficient commitment, expertise, and financial support are available in countries where the disease is so rampant,” the editorial stated. “This study highlights the importance of the use of therapies accessible and affordable to the developing world.”

Duenas-Gonzalez, et al: J Clin Oncol 29:1678-1685, 2011.

Thomas G: J Clin Oncol 29:1654-1656, 2011.

LUNG CANCER Statistically Significant Decline in Lung Cancer Incidence and Death Rates among Women More than a decade after lung cancer incidence and death rates began to decline in men, a statistically significant decrease in the rates are occurring among women. The Annual Report to the Nation on the Status of Cancer, 1975 to 2007, is the first to document these decreases, the report’s authors noted. Published as a special article in the Journal of the National Cancer Institute, the report is a collaborative effort of the American Cancer Society, the Centers for Disease Control and Prevention, the National Cancer Institute, and the North American Association of Central Cancer Registries.

“The decrease in lung cancer rates in women that we are seeing now reflects the later uptake of cigarette smoking among women,” according to the report and “can be expected to continue for at least two decades as women in the older generations with higher lung cancer risk are replaced by the subsequent younger generations with lower risk. But trends may be interrupted as women born around 1960, who have higher lung cancer and smoking rates, enter the high-risk age groups.” Cancers of the lung and bronchus are the number one cause of cancer deaths among men and women.

Overall cancer incidence rates decreased by approximately 1% per year. This decrease was statistically significant (P < .05) in women, but not in men, because of a recent increase in prostate cancer incidence.

Prostate cancer is the most frequently diagnosed cancer in men and the second leading cause of cancer deaths. In women, breast cancer is the most frequently diagnosed cancer and the second leading cause of cancer deaths.

Cancer death rates continued to decline for both sexes. While childhood cancer incidence rates continued to increase, the death rates continued to decrease.

This year’s report also includes an assessment of central nervous system tumors, including nonmalignant brain tumors, which began being reported nationally in 2004. From then through

ASCOPost.com | JUNE 15, 2011

PAGE 37

In the Literature

2007, more than 213,500 primary brain and other nervous system tumors were diagnosed, and 35.8% were malignant.

Kohler BA, et al: J Natl Cancer Inst 103:714-736, 2011.

RENAL CELL CARCINOMA Sunitinib-induced Hypertension May Be Efficacy Biomarker in Patients with Metastatic Renal Cell Carcinoma A retrospective exploratory analysis of pooled efficacy data from more than 500 patients with metastatic renal cell carcinoma treated with sunitinib (Sutent) “support the hypothesis that hypertension may be a viable biomarker of antitumor efficacy in this patient population,” according to a report in the Journal of the National Cancer Institute. Patients with sunitinib-induced hypertension, defined by a maximum systolic blood pressure of 140 mm Hg or higher, had better outcomes than those without treatment-induced hypertension, including objective response rate (54.8% vs 8.7%); median progression-free survival (12.5 vs 2.5 months); and median overall survival (33.7 vs 7.2 months).

“The overall incidence of cardiovascular, cerebrovascular, and ocular adverse events was low, and it was similar between patients in both groups,” the authors reported, although patients with hypertension had more renal adverse events (5% vs 3%, and 3% vs 2% for grade 3 or higher). “These data and

the potential for renovascular complications underscore the importance of monitoring patients with metastatic renal cell carcinoma for sunitinib-induced hypertension and treating them as necessary with antihypertensive medication, as recently recommended by an expert panel of the National

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treatment-induced hypertension is prospectively validated, it “may best meet the criteria for a desirable biomarker in patients with advanced renal cell carcinoma treated with sunitinib,” they concluded.

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Rini BI, et al: J Natl Cancer Inst 103:763773, 2011.

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“Although several potential biomarkers have been recently investigated in renal cell carcinoma,” the authors pointed out, “none has been consistently associated with patient outcomes as demonstrated here.” If

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PAGE 38

Opinion Drug Development

FDA–Pharmaceutical Industry Complex continued from page 1

FDA’s Perspective Since the enactment of the Kefauver-Harris Amendment to the Federal Food, Drug, and Cosmetic Act in 1962, the FDA has had a legal responsibility to ensure the safety and effectiveness of all new drug development in the country. In addition to its responsibility for protecting the public from drugs that were unsafe or ineffective, the agency acquired a new responsibility for ensuring that the processes of drug development were also safe and effective. The result was the investigational new drug (IND) application.

Over the next 49 years, the FDA requirements for awarding INDs have progressively escalated. The reason for this is clearly that any new drug that causes an unfavorable outcome— whatever it might be—would certainly be to the strong detriment of the FDA official who approved the IND. In contrast, if a new drug is highly effective and saves many lives, the FDA official reviewing and approving such an application would benefit not at all. Thus, the regulator is motivated to disapprove applications. But even better is the strategy of delay, ie, to require additional information that must be provided by the sponsor.

Pharma’s Perspective On the pharmaceutical side, since the business goal is to develop treatments that can be marketed and produce profits for shareholders, industry executives clearly want to bring potential treatments to the marketplace as quickly as possible. Toward that end, and recognizing the important role of the FDA regulators, industry has acquired a mirror-image group of

professional regulatory experts, many of whom have served in the FDA. These experts shepherd new treatments through the regulatory process to bring them to the market. Of course, this excessive regulation results in progressively escalating costs and progressively escalating delay in the time necessary to bring new treatments to patients who are in desperate need of them.

Recognizing this time factor and seeking to facilitate the process, the regulatory employees in the pharmaceutical industry design all of the stud-

safety for subjects participating in early clinical investigations of new treatments, its consequence has been to exclude the most talented and capable members of the scientific community from the drug development process.

Even worse is the fact that virtually no one benefits from the IND process as it is currently practiced. It greatly escalates the cost for industry and patients. It greatly escalates the cost for the FDA to conduct these regulatory activities. Those who are harmed the most, of course, are the patients, who suffer from delays in the development

Highly knowledgeable, highly effective, experienced physician scientists should play the leadership role in the drug development process. ies in collaboration with the regulatory officials at the FDA. The consequence of all this is that the scientific and professional decisions are made by people who have the least expertise in the area of drug development and therapy. At the same time, the individuals with the greatest achievement, knowledge, resources, and capability to design, develop, and implement new therapies—the academic physician scientists—are excluded entirely from the process. When the regulatory officials in the pharmaceutical industry and those in the FDA reach an agreement that an IND should be issued, specific protocols are often presented to senior investigators as a fait accompli.

Intent vs Consequence Thus, while the intent of the Kefauver-Harris Amendment was to provide

of potential cures for their illnesses.

Solutions The solution is obvious. The IND process is an extremely useful concept that should be effective without increasing delay or cost. Over the past 49 years, clinical investigation of new drugs has become more sophisticated.

The major academic institutions involved in cancer research and the network of comprehensive cancer centers are staffed with highly knowledgeable, highly effective, experienced physician scientists who should play the leadership role in the drug development process, advising both FDA and industry.

The other change since 1962 is the implementation of patient safety laws, which require institutional review boards (IRBs) for all protocols. In the comprehensive cancer centers, all

The ASCO Post

Wants to Hear from You

proposals for novel procedures to be transferred from the laboratory to the clinic require formal protocols, which are formally reviewed within the departmental structure, approved by the head of the department, and reviewed by clinical research committees staffed by all the disciplines that support development of new drugs and therapies.

Ultimately, such proposals must be reviewed and approved by the IRB to ensure that every effort is made to ensure patient safety for any new therapeutic approach.

That being the case, we are long past the point where the FDA–pharmaceutical industry complex needs to be decentralized. Authority for both designing and implementing new drug studies should be the responsibility of institutions that are regularly inspected to have the necessary regulatory processes in place, to ensure patient safety, and to establish objective methods of evaluating effectiveness. Transferring authority in this way would bring the academic physician scientist back into the business of developing new therapies, which will benefit all parties involved.

Finally, it is time to move away from outdated toxicology studies to guide new agent development, and move to more appropriate new techniques for the development of targeted therapy and personalized medicine.

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Financial Disclosure: Dr. Freireich reported no potential conflicts of interest.

References 1. Freireich EJ: Should terminally ill patients have the right to take drugs that pass phase I testing? Yes. BMJ 335:478 2007.

2. Freireich, EJ: The investigational new drug application—who benefits? Nature Clinical Practice Oncology 3:62-63, 2006.

We encourage readers to share their opinions and thoughts on issues of interest to the oncology community.

Write to The ASCO Post at editor@ASCOPost.com. All correspondence will be acknowledged and considered for publication in “Letters to the Editor.”

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724 Phone: 631.692.0800; Fax: 631.692.0805 www.ASCOPost.com

The ASCO Post | JUNE 15, 2011

PAGE 40

In the News Gynecologic Oncology

Hormone Replacement and Ovarian Cancer: Competing Risks in Decisions about Bilateral Salpingo-oophorectomy

By Charlotte Bath

In the News focuses on media reports that your patients may have questions about at their next visit.

This continuing column will provide summaries of articles in the popular press that may prompt such questions, as well as comments from colleagues in the field.

R

ecently reported findings that bilateral salpingo-oophorectomy and hysterectomy decreased the risk of ovarian cancer compared to ovarian conservation and hysterectomy, without increasing cardiovascular, fracture, and other cancer risks, should “challenge” current thinking about bilateral salpingo-oophorectomy and broaden its use among women concerned about ovarian cancer

Robert A. Burger, MD

risk, according to Robert A. Burger, MD. He is Director of the Women’s Cancer Center at Fox Chase Cancer Center in Philadelphia, and Professor in the Department of Surgical Oncology, Section of Gynecologic Oncology. Based on data from the Women’s Health Initiative (WHI) observational study, bilateral salpingo-oophorectomy need not be limited to women at high risk of ovarian cancer, Dr. Burger said, “because there is a risk reduction in ovarian cancer even for low-risk women.”

Reported in the Archives of Internal Medicine,1 the prospective study followed 25,448 postmenopausal women aged 50 to 79 years, with no family history of breast cancer, but with a history of hysterectomy with bilateral salpingo-oophorectomy (56% of the total) or with ovarian conservation (44%). Most women (78.6%) were current or past users of estrogen and/ or progestin. As expected, the women who underwent the bilateral surgi-

cal procedure had a decreased rate of ovarian cancer, 0.02% vs 0.33% in the ovarian conservation group, at a mean follow-up of 7.6 years. Although previous studies have shown increased rates of adverse effects, including coronary heart disease and fractures following bilateral salpingo-oophorectomy, in the current analyses the procedure was not associated with an increased risk of cardiovascular disease, hip fractures, or breast, colorectal, or lung cancer.

Already Low Risk “It is important to point out,” Dr. Burger said, that “in women without a family history of ovarian cancer, even though there is a significant decrease in the risk of developing ovarian cancer with bilateral oophorectomy vs not, the absolute risk level is extremely low.” The overall lifetime risk of developing ovarian cancer is presently estimated to be 1.4%, but that includes women at elevated risk based on family history, while the study included only those with no family history. Despite the low risk, Dr. Burger said, “I think it is worth maximizing your level of prevention for ovarian cancer because the consequences of the disease are so grave.”

With a mean follow-up of 7.6 years, the study results cannot indicate how bilateral salpingo-oophorectomy affected lifetime risk of ovarian cancer for the study participants. “We can learn from the hereditary breast ovarian cancer syndrome studies because we have a fairly accurate assessment of the risk of developing ovarian cancer with or without bilateral salpingo-oophorectomy,” Dr. Burger said.

“We know that the protective effect is greater than 90% for women in those populations who have their ovaries and tubes removed. It is not 100%.

Because of the way ovarian cancer develops, we think that probably there are women who have preexisting cancers or high-grade precancerous lesions that develop into primary peritoneal cancers even after the ovaries and tubes are removed. Some of these cases can be explained by evidence of disease in the ovaries or fallopian tubes not recognized at the time of preventive surgery.”

Expect Questions from Your Patients and Colleagues

P

atients of the Women’s Cancer Center at Fox Chase Cancer Center in Philadelphia often ask about ovarian cancer risk, the center’s Director, Robert A. Burger, MD, told The ASCO Post. Moreover, the recent study showing that bilateral salpingo-oophorectomy reduced that risk generated discussion among colleagues about how to advise patients.

“Up to this point, we have counseled them that having their ovaries and tubes removed is probably the operation that makes most sense, because it is the only operation that well-done studies have shown a risk reduction for, even though we know that hysterectomy may also be an independent protective factor against ovarian cancer,” Dr. Burger said.

Prevention, Treatment, and Survivorship “In our population of women who are at high risk of ovarian cancer, about half of them elect to have a hysterectomy at the time of their bilateral salpingo-oophorectomy and the other half elect just to have their ovaries and tubes removed,” Dr Burger said. But women who have a bilateral salpingo-oophorectomy and want to have hormone replacement therapy because of menopausal symptoms will need to receive progestins as well as estrogen, he explained. “So based on this large population study, the issue becomes this: If they have preventive surgery, should we be counseling them to have their uterus removed if there is a good chance they are going to need to be on hormone replacement? Because if the uterus is removed, we can simplify the hormone replacement regimen and not include progestin and also not expose them to a potential risk of endometrial cancer if they need to be on a medication like tamoxifen to reduce the risk of breast cancer,” Dr. Burger said.

“We are as actively involved in prevention as we are in treatment,” Dr. Burger stated. “We believe that the cancer centers of this millennium basically should be involved in all the points of care that deal with cancer, from primary prevention though survivorship.” He noted that the Women’s Cancer Center staff works closely with an ovarian and breast cancer advocacy group called Facing Our Risk of Cancer Empowered (www.facingourrisk.org).

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Educated Decisions The study authors noted that historically, estrogen and progesterone were commonly prescribed to treat menopausal symptoms that may result from an abrupt decline in ovarian hormone levels caused by bilateral salpingo-oophorectomy.

“However, since the Women’s Health Initiative randomized trials demonstrated more harm than benefit associated with postmenopausal therapy, there has been a dramatic decline in the use of [hormonal therapy],” the authors stated. Data from those earlier WHI trials were first reported in 2002.

Those trials “reported adverse outcomes related to the use of estrogen with progestin, and there was a

reluctance for women to use hormone replacement even if they were symptomatic,” Dr. Burger said. “But now it is becoming clearer that if ovarian hormone replacement is used in the setting of menopausal symptoms as a consequence of SEE PAGE 41 these surgeries and these women are monitored, there is a reasonable safety profile. That, together with this study, should make women a little more comfortable with the idea of having prophylactic bilateral salpingo-oophorectomy at the time of the hysterectomy,” he said.

A woman who is familiar with ovarian cancer risk and the potential of

ASCOPost.com | JUNE 15, 2011

PAGE 41

In the News

bilateral salpingo-oophorectomy to reduce that risk “can make an educated decision” about whether to have the procedure, Dr. Burger said. She can consider whether she would be “comfortable with the idea of hormone replacement” should she develop menopausal symptoms following the surgery.

“When a woman is faced with a decision as to whether her ovaries and tubes should be removed and she appears to be at low risk based on family history, the main issue is the competing risk of hormone replacement for maybe up to 5 years vs the risk of ovarian cancer,” Dr. Burger said. “Those are the two balancing factors.”

Combined Surgery Women who are having abdominal surgery and the surgeons performing the procedures should consider including bilateral salpingo-oophorectomy, Dr. Burger advised. The surgeons “need to be aware of the potential of bilateral salpingo-oophorectomy for risk reduction of ovarian cancer and integrate that into their counseling,”

Using

2D Barcodes The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading. Using the ScanLife application (see below), scan these codes with your camera phone, and see where they bring you.

Getting the Application There are three ways to download the ScanLife applicatiton:

1

Simply text the word “scan” to 43588.

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”.

3

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

Dr. Burger said.

Those surgeons could also refer a patient to her gynecologist for advice about whether to have a bilateral salpingo-oophorectomy at the same time as the abdominal surgery. “I would hope that they would have the gynecologist come in and do that part of

the surgery,” Dr. Burger added. “There are general surgeons who are certainly trained to be able to do that, but generally speaking, it would probably be a better decision to have a gynecologist who does those surgeries all the time to maximize the expertise in the room.”

Financial Disclosure: Dr. Burger reported no potential conflicts of interest.

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Reference 1. Jacoby VL, Grady G, WactawskiWende J, et al: Oophorectomy vs ovarian conservation with hysterectomy. Arch Intern Med 171:760-768, 2011.

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The ASCO Post | JUNE 15, 2011

PAGE 42

Letters to the Editor

Adjuvant Therapy in Cutaneous Melanoma: The Need for a New Approach

M

elanoma of the skin remains a fatal disease, and its incidence continues to rise, mostly in young adults during their prime. Surgery remains the most effective therapeutic modality, but patients’ survival depends on the stage of the disease at the time of diagnosis. Various therapeutic agents have been administered systemically as adjuvant therapy following complete surgical elimination of the disease to improve survival. However, most of these approaches have either failed or met with very limited success, and new approaches are needed.

Allogeneic vs Autologous Vaccines Cutaneous melanoma is potentially a chemoresistant disease, but it is an immunogenic tumor, and several melanomaspecific antigens, epitopes, peptides, and gangliosides have been identified. Nevertheless, it is also a heterogeneous tumor, and targeting any of these molecules singly or in combinations for therapeutic use has failed to produce meaningful results.

Theoretically, even if there is an initial response, heterogeneity of the tumor can overcome this response. In addition, adjuvant therapy with allogeneic melanoma cell vaccines or their extracts have failed to show any benefit. This clearly indicates that the use of nonautologous melanoma cells or their antigens is not effective.

Theoretically, autologous whole cell tumor vaccine includes all the patient’s own tumor-specific antigens and could be more effective as adjuvant therapy.

However, autologous tumor cells are not always available for clinical use. A small amount of tumor cells can be identified postoperatively in the lymph nodes in fixed tissues, but this would be too late to use them for vaccination. If a large metastatic deposit is resected, special laboratory facilities to safely process tumor cells for vaccination are usually lacking. Even if the vaccination process is completed, the results of such an approach have been equivocal, and this could be due to ex vivo processing of the melanoma cells.

It has also been shown that systemic administration of biotherapy or vaccines in metastatic disease can induce high levels of immune response in the peripheral blood, but the tumor continues to grow.

Cytokine Administration The intralesional administration of granulocyte-macrophage colony-stimulating factor (GM-CSF, Leukine) or interleukin-2 (IL-2, Proleukin) in satellitosis and in-transit metastases each gave

over 60% complete responses of long Suggested Readings sized skin reaction at the injection site).

Dehesa LA, Vilar-Alejo J, Valeron-Almaduration. Biologically, GM‑CSF adminThis strategy results in complete tuzon P, et al: Experience in the treatment of cuistration activates dendritic cells, which mor necrosis at the primary site with taneous in-transit melanoma metastases and are very efficient antigen-presenting overexpression of CD8-positive, CD25satellitosis with intralesional interleukin-2. Accells capable of processing tumor antipositive, and CD83-positive cells at the tas Dermosifiliogr 100:571-585, 2009. gens and crosstalk to T lymphocytes, primary site and regional lymph nodes.

Haanen JB, Baars A, Gomez R, et al: creating potentially efficient cytotoxic T The administration of GM-CSF/IL-2 Melanoma-specific tumor-infiltrating lymcells. Dendritic cells are rich in costimucan activate and stimulate dendritic cells phocytes but not circulating melanoma-spelatory factors such as B7-1, B7-2, and and T cells in the presence of tumor cells, cific T cells may predict survival in resected others that are essential to complete the regardless of the amount of tumor presadvanced-stage melanoma patients. Cancer second immunologic signal. Dendritic ent. This forms a triad of actions that can Immunol Immunoth 55:451-458, 2006. cells also increase IL-2 receptors on T potentially initiate tumor-specific cytoKreiter S, Selmi A, Diken M, et al: intranodal vaccination with naked antigencells and enhance the efficacy of IL-2– toxic T cells. The two biologic agents and encoding RNA elicits potent prophylactic induced cytotoxic T cells. The administhe induced antitumor immune cells can and therapeutic antitumor immunity. Cantration of GM-CSF flow to the regional cer Res 70: 9031-9040, 2010. at the primary site lymph nodes and Nasi ML, Lieberman P, Busam KJ, et al: induced dendritic systemically induce The method of Intradermal injection of granulocyte-maccells in the paracorthe same effects. administration can rophage colony stimulating factor (GMtical zone of sentiSuch an apCSF) in patients with metastatic melanoma play a major role in nel lymph nodes— proach is easily availrecruits dendritic cells. Cytokine, Cellular ie, the agent can able to all practitio& Molecular Therapy 5:139-144, 1999. initiating antitumor travel to the reners, less expensive Radny P, Caroli UM, Bauer J, et al: immunity. gional lymph nodes than preparing an Phase II trial of intralesional therapy with and is biologically autologous vaccine interleukin-2 in soft tissue melanoma metastases. Br J Cancer 89:1620-1626, 2003. active. In addition, ex vivo, and does not Rosenberg SA, Sherry RM, Morton the administration of IL-2 can stimulate utilize the addition of adjunct agents that KE, et al: Tumor progression can occur natural killer cells, CD8-positive cells, cause a massive inflammatory reaction at despite the induction of very high levels of and tumor-infiltrating lymphocyte prothe vaccination sites. Standard operative self/tumor antigen-specific CD8+ T cells liferation and function. However, while procedure is then carried out a week later, in patients with melanoma. J Immunol the systemic administration of these two as wide excision of the primary with either 175:6169-6176, 2005. cytokines in patients with metastatic sentinel lymph node(s) biopsy or regional Si Z, Hersey P, Costes AS: Clinical redisease was safe, well tolerated, and inlymph node dissection, depending on the sponses and lymphoid infiltrates in metaduced T-cell activation and elevated stage. Postoperatively, patients with no static melanoma following treatment with serum level of IL-2 receptors, they prometastases to their regional lymph nodes intralesional GM-CSF. Melanoma Res duced no clinical response. would have no major side effects from this 6:247-255, 1996.

Of interest, the method of adminisapproach and can be observed with no Vanquerano JE, Cadbury P, Treseler P, et al: Regression of in-transit melatration can play a major role in initiating further therapy. On the other hand, those noma of scalp with intralesional recomantitumor immunity. It was recently rewith metastases to their regional lymph binant human granulocyte-macrophage ported that the administration of naked nodes should be considered for additional colony-stimulating factor. Arch Dermatol antigen-encoding RNA vaccine in the systemic adjuvant therapy postoperatively 135:1276-1277, 1999. skin, subcutaneous tissue, or near a groin in the form of the same low-dose of GMVuylsteke RJCLM, Molenkamp BG, lymph node in an animal model did not CSF/IL-2 given subcutaneously to mainGietema HA, et al: Local administration initiate antigen-specific T cells. Only tain and magnify the immune response. of granulocyte/macrophage colony-stimwhen the vaccine was injected intranodThis approach can initially be evaluatulating factor increases the number and acally did it induce an immune response. ed in a phase I clinical trial prior to being tivation state of dendritic cells in the sentiassessed for survival benefit in a prospecnel lymph node of early-stage melanoma.

New Approach tive, controlled randomized study.

Cancer Res 64:8456-8460, 2004.

A new approach to adjuvant therapy —E. George Elias, MD, PhD Vuylsteke RJCLM, Molenkamp BG, van Leeuven PAM, et al: Tumor-specific for melanoma utilizes what is available Molecular Oncology Program CD8+ T cell reactivity in sentinel lymph to us clinically. Applying the aforemenGeorgetown Lombardi Comprehensive node of GM-CSF treated stage I melationed results to early-stage disease, Cancer Center noma patients is associated with high-mynewly diagnosed high-risk patients such Washington, DC eloid dendritic cell contents. Clin Cancer Financial Disclosure: Dr. Elias reported no as those with deeply invasive primary Res 12:2826-2833, 2006. potential conflicts of interest. melanoma measuring over 1.0 mm deep, mitosis, ulceration, and/or regional lymph node metastases, can have their Erratum: In the article “From Cairo to Brussels: An International Perspective,” which primary sites put to use for immune maappeared in the May 1st issue of The ASCO Post (2[7]:17, 2011), a sidebar on Egyptian nipulation, prior to the excision. The precancer epidemiology erroneously stated, “There is no population-based cancer registry operative intradermal administration of in Egypt. . . .” In fact, Egypt has established the Gharbiah Population-Based Cancer Reglow doses of GM-CSF (500 µg on day 1) istry, with support from the Middle East Cancer Consortium (MECC) Cancer Registry followed by IL-2 (11 million IU/d on Project, which was initiated in 1998. The registry is affiliated with the Ministry of Health days 2 and 3) at the primary site is safe and Population of Egypt and is located in Tanta, capital of the Gharbiah Governorate. and well tolerated (except for moderate-

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AVASTIN® (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).]

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 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 Specific 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: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

• Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

• Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

• Non‑Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).]

• Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).]

• Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).]

• Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).]

• Proteinuria [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 healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

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 The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor 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 3–4 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 chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus 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 Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was 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 ≥ 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 of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared 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 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

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‑fluorouracil–based chemotherapy.

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) 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.

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 in adult patients 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 ≥ 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 non–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%–5.93%).

Intracranial hemorrhage occurred in 8 of 163 patients with previously treated glioblastoma; two patients had Grade 3–4 hemorrhage.

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 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 ≤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 ≥ 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 Specific 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 3−4 Adverse Events in Study 1 appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 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.

IFL + Placebo IFL + Avastin 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 Body as a Whole 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 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. dipstick reading should undergo further assessment with a 24‑hour urine collection.

71819ge_c 1

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving Table 4 bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2.

NCI‑CTC Grades 1−5 Adverse Events in Study 9 Grade 1–4 adverse events were collected for the first approximately 100 patients in each of (Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo) the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI‑CTC Grade 1‑4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole 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 Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1.

Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN‑α 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 and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin 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 4–5 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 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under‑estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

(3% vs. 0%).

In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to Metastatic Breast Cancer (MBC) Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in be a difference in the mean exposure of either carboplatin or paclitaxel when each was Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving administered alone or in combination with Avastin. However, 3 of the 8 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0. bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% In Study 9, there was no difference in the mean exposure of interferon alfa administered in vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation combination with Avastin when compared to interferon alfa alone.

(3% vs. 0.3%) and proteinuria (3% vs. 0%).

8 USE IN SPECIFIC POPULATIONS Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in 8.1 Pregnancy the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.

Pregnancy Category C Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. There are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/ with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in abdominal, and pain/weakness/hypotension (2). teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations.

Avastin is not approved for use in combination with capecitabine or for use in second or third Adverse fetal outcomes were observed at all doses tested. Other observed effects included line treatment of MBC. The data below are presented to provide information on the overall decreases in maternal and fetal body weights and an increased number of fetal resorptions. safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, [See Nonclinical Toxicology (13.3).] controlled study in which all adverse events were collected for all patients. All patients in Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for from the mother to the developing fetus, and has the potential to cause fetal harm when metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients administered to pregnant women. Because of the observed teratogenic effects of known inhibitors receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential in Table 3. benefit to the pregnant woman justifies the potential risk to the fetus.

8.3 Nursing Mothers Table 3 It is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk.

NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone) substantial amounts. Because many drugs are secreted in human milk and because of the potential for Capecitabine serious adverse reactions in nursing infants from bevacizumab, a decision should be made whether to discontinue nursing or discontinue drug, taking into account the half‑life of the bevacizumab Capecitabine + Avastin (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical (n = 215) (n = 229) Pharmacology (12.3).]

Body as a Whole 8.4 Pediatric Use Asthenia 47% 57% The safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not Headache 13% 33% been established.

Pain 25% 31% Antitumor activity was not observed among eight children with relapsed glioblastoma treated Cardiovascular with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.

Hypertension 2% 24% Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 Digestive to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and Stomatitis 19% 25% exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially Metabolic/Nutrition reversible upon cessation of treatment.

Weight loss 4% 9% 8.5 Geriatric Use Musculoskeletal In Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 Myalgia 8% 14% years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, Respiratory hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, Dyspnea 18% 27% leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall Epistaxis 1% 16% survival was similar in elderly patients as compared to younger patients.

Skin/Appendages In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk Exfoliative dermatitis 75% 84% as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.

Urogenital In Study 4, patients aged ≥ 65 years receiving carboplatin, paclitaxel, and Avastin had a greater relative risk for proteinuria as compared to younger patients. [See Warnings and Albuminuria 7% 22% Precautions (5.8).]

In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether Glioblastoma All adverse events were collected in 163 patients enrolled in Study 7 who either received the overall adverse events profile was different in the elderly as compared with younger patients.

Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated severity that occurred at a higher incidence in the elderly as compared to younger patients, in addition to those described above, were dyspepsia, gastrointestinal hemorrhage, edema, epistaxis, increased with Avastin alone.

In patients receiving Avastin alone (N=84), the most frequently reported adverse events of cough, and voice alteration. any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two incidence of arterial thromboembolic events was increased in all patients receiving Avastin with deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one chemotherapy as compared to those receiving chemotherapy alone, regardless of age. However, the increase in arterial thromboembolic events incidence was greater in patients aged ≥ 65 years neutropenic infection.

In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions Avastin‑related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (5.5).]

(26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), 10 OVERDOSAGE arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), The highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 16 patients and with severe headache in three of 16 patients.

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 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma).

1 DNA Way Avastin® is a registered trademark of Genentech, Inc. Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus South San Francisco, CA 94080‑4990 ©2011 Genentech, Inc. Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

3/8/11 11:24 PM

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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