A Harborside Press® Publication

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

VOLUME 2, ISSUE 6

APRIL 15, 2011

I never realized when I graduated from nursing school some 20 years ago exactly

where my career as an oncology nurse would take me or the opportunities that would be afforded me. I envisioned working my entire career as a stem cell transplant nurse or a radiation oncology nurse. All I really want-ed to do was care for patients and families with cancer. I didn’t envision that someday I would be asked as a registered nurse to give testimony to the FDA or be in the pres-ence of the President of the United States. I guess it is normal to look back and be in awe of where life has taken us, but my journey speaks as one example of how far our profes-sion has come and how important nurses are to the current health-care system.

Most Trusted ProfessionFor years, Gallup poll results have shown

that nurses are the most trusted profession

continued on page 13

continued on page 54

MORE IN THIS ISSUE

Oncology Meetings CoverageNCCN 16th Annual Conference ................................................ 32011 Genitourinary Cancers Symposium ..........1, 10, 17, 182011 Gastrointestinal Cancers Symposium ......................16, 31

A Conversation with James F. Holland ....... 4Direct from ASCO .......................................16FDA Update ..................................30, 41, 53

Teamwork in Cancer Care:

More Important Than Ever

The massive devastation of Japan by an earth-quake and tsunami is an overwhelming tragedy,

and the world mourns for its victims. The brute de-struction of the sophisticated infrastructure by natu-ral forces and subsequent inclement weather contin-ue to impede rescue efforts. But while the destruction is viewed worldwide, it is what we cannot see—the risks associated with the release of radiation from a damaged nuclear power plant—that has diverted and slowed rescue efforts, and worried the world.

The potential of a disaster occurring from the peaceful use of radiation in Japan more than 65 years after the wartime devastation wrought by nuclear

The Lessons of Japan and Radiation: Recognizing the Good and Ill of a Powerful ToolBy Nora Janjan, MD, MPSA, MBA, and John Goodman, PhD

continued on page 2

NCCN GuidelinesTM updates 3 | Ipilimumab in melanoma 30 | Pain management 36

A large cohort study suggests that an initial prostate-specific

antigen (PSA) level of  3  ng/mL should be the cutoff for biopsy of the prostate and that men with ini-tial PSA values <  2  ng/mL should be screened at substantially longer intervals than is the current prac-tice. Experts agreed that the study’s findings suggest a new cutoff for prostate biopsy and longer screening intervals for men at very low risk of prostate cancer.

Avoids Unnecessary Procedures “These results justify use of a threshold of

≥  3  ng/mL for prostate biopsy,” stated Meelan Bul, MD, Erasmus University Medical Center of Rotterdam, The Netherlands, who presented the findings of a Dutch cohort study that was part of

the European Randomized Study of Screening for Prostate Cancer (ERSPC) at the recent Genitouri-nary Cancers Symposium held in Orlando, Florida. “This means that we can possibly avoid unnecessary testing, diagnosis, and treatment of less aggressive disease, with the accompanying side effects, by fo-cusing biopsies and other follow-up on men with higher initial PSA levels above 3.0 ng/mL.”

Longer Screening Intervals Make Sense in Men with Initial PSA Levels < 2 ng/mLBy Alice Goodman

By Carlton G. Brown, RN, PhD, AOCN President, Oncology Nursing Society

weapons is fateful. While the radiation that caused the wartime devastation could not be seen, the af-termath was viewed worldwide. Seeing the conse-quences of nuclear war struck fear into every world leader. This fear helped foster a mutual détente dur-ing the Cold War, and a line for humanity that could not be crossed. Over the past decade, the world has worried about rogue nations with nuclear weapons, and whether this line protecting humanity will be breached.

Power Plant IncidentsEven when nuclear energy is applied for good in

power plants, questions arise about whether the risks of radiation outweigh its potential benefits to satisfy progress powered by energy. Although there were no deaths and no long-term effects to health or the environment associated with the Three Mile Island incident in 1979,1 the event had a profound impact on public opinion, and the United States turned away from nuclear energy.

Dr. Brown is President of the Oncology Nursing Society and Assistant Professor at the University of Delaware School of Nursing, Newark, Delaware.

■ Men with initial PSA levels < 2 ng/mL do not require annual screening, and the interval for men with initial PSA levels < 1 ng/mL could be adjusted upward to 8 years.

■ The cutoff threshold for biopsy should be PSA of 3 ng/mL or higher, not the current threshold of PSA equal to 4 ng/mL or higher.

‘Game-Changer’ in PSA Screening?

2011 Genitourinary Cancers Symposium

Perspective

The web of our life is of a mingled yarn, good

and ill together. —William Shakespeare

PAGE 2 The ASCO Post | APRIL 15, 2011

Opinion

James  O. Armitage, MD Editor-in-Chief

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

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

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

William T. McGivney, PhD National Comprehensive Cancer Network

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 EDITORSClement Adebamowo, BM, ChB (Hons), ScD University of Ibadan Ibadan, Nigeria

Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina

Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada

Jacek Jassem, MD Medical University of Gdansk Gdansk, Poland

David Khayat, MD Pitie-Salpetriere Hospital Paris, France

Tony Mok, MD The Chinese University of Hong Kong Shatin, Hong Kong

Eliezer Robinson, MD National Council for Oncology Israeli Cancer Association Haifa, Israel

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

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

Conor Lynch, Executive Editor Conor@harborsidepress.com

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

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

Sarah McGullam, Assistant Editor Sarah@harborsidepress.com

Michael Buckley, Graphic Designer Michael@harborsidepress.com

Wendy McGullam, Director of Production Wendy@harborsidepress.com

Leslie Dubin, Vice-President, Director of Sales Leslie@harborsidepress.com

Anthony Cutrone, President Anthony@harborsidepress.com

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

Editorial Board

Harborside Press® Publishing Staff

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

Erratum: In the March 15 print issue of The ASCO Post (2[5]:8, 2011), an article on the interim results of a trial compar-ing intermittent vs continuous androgen suppression in patients with PSA progression after radical therapy for prostate cancer (Klotz L, et al: 2011 Genitourinary Can-cers Symposium, Abstract 3) mis-reported the median survival data. The correct median survival results were 8.8 years in the intermittent androgen suppression arm vs 9.1 years in the continuous androgen deprivation arm.  We regret any confusion this error has caused. The online ver-sion of the article reflects this cor-rection and may be viewed via the 2D barcode here. SEE PAGE 51

in the United States. It is estimated that there are around 3 million nurs-es in our country, so nurses have power in numbers and are well re-spected. But from my vantage point as the 21st President of the Oncol-ogy Nursing Society (ONS), oncol-ogy nurses do not completely recog-nize the influence they have in the health-care arena, nor do they com-pletely realize the awesome effect they have on patients and families living with cancer.

Health-care Reform and Education

As I watched President Obama sign the Patient Protection and Af-fordable Care Act into law on March 30, 2010, I knew this new law would punctuate my own presidency. For patients, this legislation meant they would eventually be protected from losing their insurance by a diagnosis of cancer. Further, there would be protection for participation in clini-cal trials, added research and edu-cation for pain management, and a more important future focus on pre-vention and early detection.

Yet there is a lot of work to be done in reference to the Affordable Care Act. I recently gave a talk on health-care reform to a group of nurses. I asked how many of them would feel comfortable explaining how the new legislation would af-fect patients with cancer. Surpris-ingly, 85% of them said they would not feel comfortable. This tells me that we have much work to do in the area of education and health-care reform law.

Teamwork and Quality Cancer Care

In 2014, approximately 50  mil-lion Americans who currently do not have insurance will have access to coverage, and some of those mil-lions will present with cancer diag-noses. To add insult to injury, it is estimated that by 2020 there will be a significant shortage of oncologists to care for patients with cancer. This situation will equate to increased opportunities for Advanced Practice Nurses, especially Oncology Nurse Practitioners.

In my estimation, there is room for excellent cancer care provided by numerous health-care providers including physicians, nurse prac-

titioners, and physician assistants. Many of us have worked in success-ful teams while caring for patients with cancer. That teamwork will become more important than ever if we are to provide quality cancer care, while eliminating errors, and surviving likely burnout. None of us can do it alone—but together we can provide cancer care more suc-cessfully and safely.

Opportunities and Challenges

So as I enter my final year as Presi-dent of ONS, I look forward to more challenges over the coming year, but also more successes for our Society and members. Health-care reform will continue to be highlighted as we decide what parts of the legislation we can and can’t live without. Nurs-es will find themselves with more opportunities as we are asked to sit in when decisions are made in the area of health care. Oncology nurse researchers will be challenged with verbalizing why they should have a fair amount of federal research fund-ing to conduct research.

It will be a busy year, but an in-credible opportunity to help guide ONS through these turbulent yet incredibly interesting times. I’m up for the challenge mostly because patients with cancer, their families, and the nurses who care for them deserve the best support that there is to provide. Onward! ■

Teamwork in Cancer Carecontinued from page 1

ASCOPost.com | APRIL 15, 2011 PAGE 3

News

The National Comprehensive Cancer Network (NCCN)

Clinical Practice Guidelines in On-cology ™ are among the most widely used guidelines in oncology prac-tice. The Guidelines cover 97% of all patients with cancer and are con-tinually updated by expert panels. The following is a synopsis of the 2011 updates and key points made by panel representatives at the NCCN 16th Annual Conference, held March 10–11 in Hollywood, Florida.

Breast CanCer

“The Panel, in reviewing the data from a single randomized trial, decided to add a footnote to the guidelines that there was no improvement observed in overall survival or local recurrence rates with completion axillary lymph node dissection in women with 1 to 3 involved sentinel lymph nodes and who were treated with breast-conserving surgery and whole breast radiation.”

—Robert W. Carlson, MD, Stanford Comprehensive Cancer Center,

Palo Alto

■ Eribulin (Halaven) was added as a new chemotherapeutic option for treating metastatic disease.

■ Denosumab (Xgeva) was added as an option for preventing skele-tal-related events in patients with bone metastases.

■ Bevacizumab (Avastin), in com-bination with paclitaxel, was reaf-firmed as an option for metastatic disease.

■ Hormonal status and HER2 sta-tus should be determined in met-astatic disease patients.

Myeloid Growth FaCtors

“There is an increase in myelodysplastic syndrome and acute leukemia, but the all-cause mortality analysis shows a significant reduction in risk with growth factors….There clearly is an overall net benefit.”

—Jeffrey Crawford, MD, Duke Cancer Institute, Durham

■ Granulocyte colony-stimulating factors (G-CSF) can prevent fe-brile neutropenia and its compli-cations and improve survival in patients at increased risk for these complications.

■ Outcomes with pegfilgrastim (Neulasta) and filgrastim (Ne-upogen) are similar.

■ Prior to beginning chemotherapy, patients should be assessed for risk, and those with > 20% febrile neutropenia risk should receive G-CSF starting at the first cycle.

■ Risk of myelodysplasia and acute myeloid leukemia is real, but it is small, and is confounded by the increase in chemotherapy dose delivery and offset by a reduc-tion in all-cause mortality in ap-propriate patients treated with G-CSF.

MaliGnant MelanoMa

“Mitotic index is the single most important predictor of survival in the patient with a thin melanoma.”

—Daniel G. Coit, MD, Memorial Sloan-Kettering Cancer Center,

New York

■ Mitotic index replaces Clark level in defining clinical stage IB mela-noma.

■ The presence of any mitosis (mitotic rate ≥  1 mm2) in a thin melanoma (≤ 1 mm) upstages the patient to stage IB and has impli-cations for sentinel lymph node biopsy (SLNB).

■ SLNB should be discussed and offered to patients with stage IA or II melanomas; the threshold for considering SLNB is a risk of recurrence of approximately 7%.

■ For follow-up of patients with ≤  stage IIA disease, there is less emphasis on routine bloodwork and cross-sectional imaging.

■ Newer targeted agents and immu-notherapy strategies are yielding dramatic, and sometimes durable, responses and will change the treatment paradigm.

■ Radiotherapy and genetic analy-sis have a growing role.

sarCoMa

“Patients with resectable desmoid tumors can be considered for observation.”

—Margaret von Mehren, MD, Fox Chase Cancer Center, Philadelphia

The major change to the guide-lines for the treatment of sarcoma pertains to the management of des-moid tumors. ■ Patients with desmoid tumors

can be followed carefully if the tumors are small and not located on the trunk and if surgery would lead to excessive morbidity.

■ Several changes in staging were made; lymph node involvement was reclassified as stage III, rather than IV.

■ Molecular profiles will become increasingly evident in sarcoma, and markers will aid in diagnosis, prognosis, and treatment.

ChroniC MyeloGenous leukeMia

“Oncologists can start new patients on a second-generation tyrosine kinsase inhibitor or stick with imatinib (400 mg), reserving the newer agents for sequential use after imatinib failure since salvage rates are excellent.”

—Susan O’Brien, MD, The University of Texas MD Anderson Cancer Center,

Houston

■ Second-generation tyrosine kinase inhibitors nilotinib (Tasigna) and dasatinib (Sprycel) were added as front-line treatment options.

■ Nilotinib and dasatinib exerted similar improvements in short-term endpoints, as compared with imatinib, in randomized trials; with short follow-up, their impact on event-free and overall survival has not yet been established.

■ Cytogenetic complete response remains the gold standard for re-sponse; molecular responses do not define treatment failure.

■ New agents now in clinical trials show promising activity.

non–sMall Cell lunG CanCer

“Histology matters in non–small cell lung cancer [NSCLC], and NSCLC ‘not otherwise specified’ [NOS] is unacceptable in 2011.”

—David S. Ettinger, MD, Sidney Kimmel Comprehensive Cancer Center

at Johns Hopkins School of Medicine, Baltimore

■ Testing for the epidermal growth factor receptor (EGFR) is a cat-

NCCN Clinical Practice Guidelines™: Important Updates for 2011

continued on page 9

Clinical Oncology

PAGE 4 The ASCO Post | APRIL 15, 2011

Expert’s Corner

James F. Holland, MD, Distin-guished Professor of Neoplastic

Diseases, Mount Sinai School of Medicine, New York, has been at the forefront of cancer research for more than half a century. In a recent interview with The ASCO Post, Dr. Holland looked back at his research at NCI and explained why our ac-complishments over the past several decades reinforce his concept that there are no incurable cancers, just precurable ones.

The Early DaysCombining cytotoxic agents was

a significant conceptual hurdle in the early days of cancer research. Was there an early influence on the direction of your research?

When I went to the NCI in 1953, I was assigned to help Lloyd W. Law, PhD, prepare a lecture he was giving to the research directors of the NIH. It was the beginning of a rich learn-ing experience that had a profound

effect on my  career. Dr. Law was a true pioneer, with two important discoveries to his credit that were instrumental in the development of medical oncology.

First, resistance preexists and represents the selection of a resis-tant cell out of a population rather than developing as a biochemical mechanism to resist chemotherapy. Second, combination chemotherapy is more effective than single drugs given in sequence because a com-bination enhances the potential for eradication. Cells resistant to drug

A might in fact not be resistant to si-multaneously given drug B.

When I was leaving NCI, Clinical Director Gordon Zubrod recruited Emil (Tom) Frei to fill my position. He introduced us, and Tom and I be-came lifelong colleagues and friends. We modified the in-house study that I had been conducting, and out of that friendship came the Cancer and Leukemia Group B (CALGB), originally called the Acute Leukemia Group B. We led the first coopera-tive group study in the United States,

treating patients with acute leukemia with a combination chemotherapy regimen of mercaptopurine and methotrexate. At 55 years, CALGB is the oldest surviving cooperative group in the country. Also out of that friendship came Holland-Frei Cancer Medicine, now in its 8th edition.

Lessons for TodayWhat can we learn from your early

days of research and how those pursuits differed from research today?

There was less red tape, and I can say assuredly that patient safety did

not suffer for it. We were concep-tually following a logical scientific premise with the idea that we would find useful clinical answers. And in-deed we did, without the regulatory burdens that today’s lawyers in the House of Representatives and Sen-ate have imposed, some of which is well-intentioned legislative overkill that doesn’t expand the boundaries of research or make patients on clini-cal trials any safer.

How would you characterize clini-cal trial accrual then and now?

In those days, acute leukemia was an incurable disease. The clinical trials we designed offered patients their best therapeutic options, of-ten their only option. What parents wouldn’t want that for their child? So entering a clinical trial was not considered risky, it was considered an opportunity to get the newest available therapy. However, as our therapies get closer to success, each incremental benefit is usually less, and perhaps today people worry that entering a clinical trial might limit them from receiving an established treatment with proven efficacy. So, in the 1950s, we did not have that barrier to accrual because we were essentially offering patients their best chance for a positive outcome.

Advances in Cancer BiologyOver the past 2 decades, our un-

derstanding of tumor biology has in-creased at a breakneck pace. However, mortality rates from cancer remain high. Are you optimistic?

Absolutely. However, I personally think the phrases targeted or person-alized therapies are slightly mislead-ing. First off, the concept of specific targeting is not new. Targeting spe-cific enzymes or receptors is simply more intelligent therapy.

Over the past decades we’ve un-earthed the complexity of cancer bi-ology, and as we venture deeper into its molecular components it will un-doubtedly become even more com-

A Conversation with James F. Holland, MDReflections on cancer research, prevention, cure, and the common house mouseBy Ronald Piana

James F. Holland, MD

The ASCO Post (ISSN 2154-3283) is published semi-monthly, except monthly in February, April, June, August, October and December, by Harborside Press, 37 Main Street, Cold Spring Harbor, NY 11724, under a license arrangement with the American Society of Clinical Oncology, Inc. (ASCO®). Application to mail at Periodicals Prices is Pending at Cold Spring Harbor, NY, and additional mailing offices.

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continued on page 8

Spotlight on Research

We are seeing more tumors that are curable, more subcurable tumors being treated

successfully, and several precurable tumors that are showing signs of vulnerability

to chemotherapy.

http://www.xgeva.com

http://www.xgeva.com

PAGE 8 The ASCO Post | APRIL 15, 2011

Expert’s Corner

plex. But for each bit of information we obtain about a particular gene, it clarifies a pathway that is either at-tackable today or that will be attack-able in the near future. Moreover, understanding pathways and how to characterize and classify diseases

is intrinsic to improving our ability to identify and treat the hundreds of different disease states in cancer. The reason for optimism is that we are breaking the cure barrier, albeit slowly. We are seeing more tumors that are curable, more subcurable tumors being treated successfully, and several precurable tumors that

James F. Hollandcontinued from page 4

are showing signs of vulnerability to chemotherapy.

Cure vs Chronic IllnessAnother contemporary concept is

that we need to reach a point at which we manage cancer as a long-term chronic disease. What’s your perspec-tive on that approach?

The prime objective is preven-tion. Once disease is present, the prime objective becomes cure. Longtime survival is meritorious as long as the patient’s quality of life is relatively good. And with some dis-eases this balance can be achieved. In metastatic cancer there are a few dis-eases, such as lymphoma, myeloma, and chronic myelogenous leukemia, where dramatic therapeutic advanc-es have allowed patients to live with-out undo impact on their daily lives. But this is not true for metastatic lung, liver, colon, and other cancers, where the course of the illness is still measured in months or years, not de-cades. And as chronic illness for me carries the concept of decades, that formulation doesn’t work in other than the few cancers I mentioned.

So we do not want to settle for incomplete eradication. A num-ber of cancers—choriocarcinoma, testis cancer, large-cell lympho-mas, Hodgkin disease, and acute lymphocytic leukemia in children, to name a few—are curable with multimodality treatment options. We need to keep our eye on the target—curing people with cancer. The philosophical palliative of liv-ing longer with metastatic disease is not as important or realistic as is the effort at cure.

In 1976, when Bonadonna, Vero-nesi, and colleagues published their report on adjuvant CMF [cyclo-phosphamide, methotrexate, fluoro-uracil] for operable breast cancer in The New England Journal of Medicine, I was asked to write the editorial. I called their findings a monumental change in the treatment of breast cancer. Many in the community excoriated my assessment, calling it hyperbole, but in fact it proved true—we can cure a substantial por-tion of women who retrospectively must have had micrometastatic dis-ease at the time of surgery because their survival is markedly better after chemotherapy than after placebo.

Thus, such women had disease, which at the microscopic level could be cured with adjuvant che-motherapy after surgery (or perhaps radiation) for their primary tumor. This paradigm offers opportuni-ties for many other cancers. So I’m not an advocate of living with your cancer for a long period; I’m an ad-vocate of getting rid of your cancer altogether.

continued on page 17

ASCOPost.com | APRIL 15, 2011 PAGE 9

News

NCCN Guidelinescontinued from page 3

egory  1 recommendation for ad-enocarcinoma, large cell disease, and NSCLC NOS but is not rec-ommended for squamous cell car-cinoma.

■ Mutational status, particularly EGFR, KRAS, and EML4/ALK, is now affecting the choice of effective treatment options.

■ Platinum doublets, chemotherapy with bevacizumab, and newer tar-geted agents are improving out-comes in advanced NSCLC.

■ New pages were added to the 2011 guidelines to discuss the debate surrounding the use of surgery after induction therapy for patients with stage IIIA (N2) disease; the benefit of surgery in this heterogeneous group remains unclear.

■ Patients with a single lymph node < 3 cm can be considered for a mul-timodality approach that includes surgical resection.

non-hodGkin lyMphoMa

“Post-transplant lymphoproliferative disorder has emerged as a significant complication of solid organ and allogeneic bone marrow transplantation.”

—Andrew Zelenetz, MD, Memorial Sloan-Kettering Cancer Center, New York

■ A significant change to the guide-lines is the addition of a new guide-line for post-transplant lymphopro-liferative disorder.

■ Recommended treatment options for post-transplant lymphoprolifer-ative disorder include reduction of immunosuppression, single-agent rituximab (Rituxan), and che-moimmunotherapy.

■ Category 1 recommended treat-ments for follicular lymphoma now include bendamustine (Treanda)/rituximab for first-line treatment, rituximab maintenance, and radio-immunotherapy for treatment after

first remission. ■ Patients with mantle cell lympho-

ma who have a low proliferation fraction and are treated aggressively are potentially curable.

prostate CanCer

“The addition of sipuleucel-T and cabazitaxel into the Guidelines represents a significant advancement in the case of men with advanced prostate cancer.”

—James L. Mohler, MD, Roswell Park Cancer Institute, Buffalo, New York

■ The Guidelines establish a new “very low risk” category that incor-porates the strictest Epstein criteria from all definitions for clinically in-significant prostate cancer.

■ Active surveillance is recommend-ed as the sole initial treatment for men meeting the criteria for very low-risk disease who have a life ex-pectancy of > 20 years.

■ Active surveillance monitoring was made more rigorous for men in the very low-risk category: For men with a life expectancy <  20 years, prostate-specific antigen must be measured at least every 6 months, a prostate exam must be performed at least every 12 months, and repeat prostate biopsies should be consid-ered as often as every 12 months.

■ Men with low-risk prostate cancer and a life expectancy <  10 years should also be recommended for active surveillance.

■ Sipuleucel-T (Provenge) was added as an immunotherapy option for asymptomatic or minimally symp-tomatic castrate-resistant metastat-ic disease and a life expectancy ≥ 6 months.

■ Cabazitaxel ( Jevtana) was added as a new second-line option for castrate-resistant metastatic disease after progression on docetaxel.

■ Denosumab was added as an al-ternative to zoledronic acid for the prevention of skeletal-related events.

head and neCk CanCer

“The guidelines now include a suggestion that the workup for cancer of the oropharynx include testing for human papillomavirus.”

—David G. Pfister, MD, Memorial Sloan-Kettering Cancer Center, New York

■ An algorithm for  mucosal melano-ma was added to the guidelines for malignant melanoma.

■ Human papillomavirus is a growing concern in certain head and neck cancers and is associated with a bet-ter prognosis. Testing for the virus is now suggested for oropharynx cancers, as well as occult primary cancers with a squamous cell or un-differentiated  histology.

■ The therapeutic benefits associated with the integration of chemother-apy with radiation compared with radiation alone continues to be up-held in several disease settings.

■ The concomitant integration of chemotherapy with radiation thera-py is backed by a large body of data.

ovarian CanCer

“Regardless of the type of cancer, the guidelines reflect the importance of stage and grade of disease on prognosis and treatment recommendations.”

—Robert J. Morgan, MD, City of Hope Comprehensive Cancer Center, Duarte

■ Borderline epithelial ovarian cancer of low malignant potential should be primarily managed surgically.

■ For women with borderline epithe-lial ovarian cancer wishing to maintain fertility, surgery should be limited to unilateral salpingo-oophorectomy; standard debulking surgery is rec-ommended for those not concerned about fertility preservation.

■ Stage II, III, or IV epithelial ovarian cancer should be considered for in-traperitoneal chemotherapy first-line; updated recommendations include intravenous dose-dense paclitaxel as a possible treatment option, though this may be more toxic.

■ New language details the Panel’s view that it is premature to recommend the addition of bevacizumab to carbopla-tin/paclitaxel upfront; participation in clinical trials is encouraged.

■ New language supports the discussion of the pros and cons of CA-125 moni-toring, based on data showing a lack of survival benefit when treatment for relapse was initiated based on a rising CA-125 level.

■ Specific recommendations were added on managing infusion drug reactions.

Multiple MyeloMa

“There has been a very rapid bench-to-bedside translation with the targeted agents in multiple myeloma.”

—Kenneth C. Anderson, MD, Dana-Farber Cancer Institute, Boston

■ Bortezomib (Velcade)/cyclophospha-mide/dexamethasone is now a cat-egory 2A option for induction therapy in the transplant setting, and lenalido-mide (Revlimid)/bortezomib/dexa-methasone is a promising category 2B alternative.

■ Lenalidomide maintenance, which has nearly doubled progression-free sur-vival, has been added as a new option after autologous stem cell transplant.

■ Melphalan/prednisone/lenalidomide and bortezomib/dexamethasone are now category 2A options in the non-transplant setting.

■ Cyclophosphamide/bortezomib/continued on page 10

PAGE 10 The ASCO Post | APRIL 15, 2011

2011 Genitourinary Cancers Symposium

Two studies presented at this year’s Genitourinary Cancers Sympo-

sium shed light on treatment of meta-static renal cell carcinoma. The first study confirmed that the approved dosing schedule for sunitinib (Sutent) should be the schedule of choice in metastatic renal cell carcinoma. The second study showed that adding a monoclonal antibody targeted to an-giogenesis did not provide additional efficacy when combined with the VEGF inhibitor sorafenib (Nexavar).

Dosing of SunitinibThe approved dosing schedule for

sunitinib in metastatic renal cell car-cinoma—4 weeks on treatment and 2 weeks off—should be followed to achieve optimal results, according to results of a randomized, phase  II

study.1 Time to progression was su-perior on the approved schedule vs a continuous schedule on lower-dose sunitinib (see Fig. 1 on page 13). The study was supported by Pfizer.

According to lead investigator Rob-ert Motzer, MD, Attending Physician at Memorial Sloan-Kettering Cancer Center, New York, “The message of this study is straightforward and sim-

ple, but the data impact the real-world use of sunitinib. Physicians should have pa-tients adhere to the stan-dard dosing schedule. Some [community] physicians are inventing their own sched-ules, but they should be us-ing the approved schedule.”

The standard schedule of sunitinib (50 mg once daily, 4 weeks on/2 weeks off) was

approved because studies suggested that this was the most effective way to give the drug. “The 2 weeks off gave patients a break from the associated toxicities of fatigue, hand-foot syn-drome, hypertension, and diarrhea,” Dr. Motzer explained.

“There has been interest in an alter-native dosing schedule to reduce side

effects further,” he noted. “We chose to evaluate low-dose continuous suni-tinib 37.5 mg orally once a day.” The continuous schedule is potentially at-tractive because of concerns that the 2-week break could allow the cancer to return and/or compromise compli-ance, he explained.

Study DataThe phase  II study randomly as-

signed 292 patients to the approved schedule (arm A) vs continuous suni-tinib (arm B). Median age was 62 years, and 65% were male. Patients were treated with a median of four cy-cles in arm A and five cycles in arm B.

Median time to progression favored the approved schedule: 9.9 vs 7.1 months for arm A and B, respectively;

Studies Address Schedule of Sunitinib, Novel Agent Added to Sorafenib in Metastatic Renal Cell CarcinomaBy Alice Goodman

continued on page 12

Robert Motzer, MD Brian Rini, MD

Kidney Cancer

dexamethasone and cyclophospha-mide/lenalidomide/dexametha-sone have been added as category 2A salvage treatment options.

■ Carfilzomib, pomalidomide, and panobinostat are promising novel investigational agents for relapsed/refractory disease.

hepatitis B sCreeninG and CheMotherapy

“One-third of the world has been exposed to hepatitis B, making it an enormous problem…Depending on how it’s defined, 5% to 40% of people who have an acute reactivation will die of liver failure.”

—Emmy Ludwig, MD, Memorial Sloan-Kettering Cancer Center, New York

NCCN Guidelinescontinued from page 9

■ Many patients are unaware that they have been exposed to or have active hepatitis B infection.

■ Many patients being treated for cancer with immunosuppressive therapies are at risk of hepatitis B virus (HBV) reactivation.

■ Limited data suggest that antiviral prophylaxis is 100% effective in preventing chemotherapy-related HBV reactivation.

■ Many medical groups recommend universal screening for HBV, al-though ASCO is not one of them.

■ The optimal antiviral agent and duration of prophylaxis remain unresolved issues.

radiation onColoGy

“Many facilities throughout the country are using stereotactic body radiation therapy [SBRT] for tumors in the pancreas, head

and neck, prostate, and spinal cord; however, until further data are available, use of SBRT outside the lungs and liver should be limited to cooperative trials.”

—Michael Kuettel, MD, MBA, PhD, Roswell Park Cancer Institute, Buffalo,

New York

■ Inoperable lung and liver tumors are the only two NCCN-approved

indications for SBRT. ■ Used to treat pediatric tumors,

proton therapy can deliver an increased dose to the target vol-ume while decreasing the dose to normal tissue, thereby reducing morbidity.

■ Intensity-modulated radiation ther-apy has proven benefit in reducing dry mouth in patients with head and neck cancer and in improving associated quality of life. ■

Financial Disclosures: Comprehensive disclosure information relevant to the complete NCCN Clinical Practice Guidelines is available at nccn.org. The following NCCN panel members reported no potential conflicts of interest with the manufacturer(s) of product(s), mentioned in this report: Kenneth C. Anderson; Robert W. Carlson; Daniel G. Coit; Michael Kuettel; Emmy Ludwig; James L. Mohler; Robert J. Morgan; Susan O’Brien; and David G. Pfister.  Other NCCN panel members reported potential conflicts of interest as follows: Jeffrey Crawford has received research funding from Amgen and has served on the advisory board at Amgen. David S. Ettinger has indi-cated serving on an advisory board, speakers bureau, as an expert witness, or consultant for  Boeh-ringer Ingelheim GmbH, Daiichi-Sankyo Co., Eli Lilly and Company, Genentech, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Biodesix, Inc., Poniard Pharmaceuticals, Inc., Pro-metheus, Shin Nippon Biomedical Labs, and Telik, Inc.  Margaret von Mehren disclosed that she has served as a scientific advisor/consultant to Novartis, scientific advisor to Merck, and consultant to Pfizer and Pharma Mar. In addition, she has received research support from Novartis and Merck. Andrew Zelenetz reported receiving clinical research support from Cephalon, Inc., Genentech, Inc., GlaxoSmithKline, Millennium Pharmaceuticals, Inc., Onyx Pharmaceu-ticals, Inc., Allos Pharm., Calistoga, Pharmacyclics, Plexxikon, Roche, and Seattle Genetics. He reported serving on an advisory board, speakers bureau, as an expert witness, or consultant for  Abbott Laboratories, Cephalon, Inc., Genentech, Inc. GlaxoSmithKline, Allos Pharm, Cancer Genetics, Seattle Ge-netics, Roche Laboratories, Inc., and sanofi-aventis U.S. SEE PAGE 51

ALOXI® provides powerful CINV prevention that can’t be ignored.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc.© 2010 Eisai Inc.All rights reserved. Printed in USA. ALO000083A 08/10

STARTS STRONG. LASTS LONG.

Proven CINV prevention in a single IV dose• Powerful CINV prevention in the fi rst 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

• Lasts long against nausea following moderately emetogenic chemotherapy3

• Powerful acute CINV prevention following highly emetogenic chemotherapy4

• Eisai offers a variety of support programs and resources

IndicationALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information• ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any

of its components

• Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%)

Please see the brief summary of the Full Prescribing Information on the adjacent page.

References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on fi le. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

ALOXI® provides powerful CINV prevention that can’t be ignored.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc.© 2010 Eisai Inc.All rights reserved. Printed in USA. ALO000083A 08/10

STARTS STRONG. LASTS LONG.

Proven CINV prevention in a single IV dose• Powerful CINV prevention in the fi rst 24 hours and up to 5 days following

moderately emetogenic chemotherapy1,2

• Lasts long against nausea following moderately emetogenic chemotherapy3

• Powerful acute CINV prevention following highly emetogenic chemotherapy4

• Eisai offers a variety of support programs and resources

IndicationALOXI® (palonosetron HCl) injection 0.25 mg is indicated in adults for the prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of moderately emetogenic chemotherapy, and acute nausea and vomiting associated with initial and repeat courses of highly emetogenic chemotherapy.

Important Safety Information• ALOXI is contraindicated in patients known to have hypersensitivity to the drug or any

of its components

• Most commonly reported adverse reactions in chemotherapy-induced nausea and vomiting include headache (9%) and constipation (5%)

Please see the brief summary of the Full Prescribing Information on the adjacent page.

References: 1. Gralla R, Lichinitser M, Van der Vegt S, et al. Palonosetron improves prevention of chemotherapy-induced nausea and vomiting following moderately emetogenic chemotherapy: results of a double-blind randomized phase III trial comparing single doses of palonosetron with ondansetron. Ann Oncol. 2003;14:1570-1577. 2. Eisenberg P, Figueroa-Vadillo J, Zamora R, et al. Improved prevention of moderately emetogenic chemotherapy-induced nausea and vomiting with palonosetron, a pharmacologically novel 5-HT3 receptor antagonist: results of a phase III, single-dose trial versus dolasetron. Cancer. 2003;98:2473-2482. 3. Data on fi le. Eisai Inc., Woodcliff Lake, NJ. 4. Aapro MS, Grunberg SM, Manikhas GM, et al. A phase III, double-blind, randomized trial of palonosetron compared with ondansetron in preventing chemotherapy-induced nausea and vomiting following highly emetogenic chemotherapy. Ann Oncol. 2006;17:1441-1449.

PAGE 12 The ASCO Post | APRIL 15, 2011

2011 Genitourinary Cancers Symposium

this difference was not statistically sig-nificant but indicated a strong trend favoring the 4/2 schedule, Dr. Motzer commented. Objective response rates were 32.2% vs 28.1%—a difference that was not statistically significant.

Renal Cell Carcinomacontinued from page 10

Median overall survival was similar between groups: 23.1 vs 23.5 months, respectively.

Interestingly, there was no differ-ence in the side-effect profiles of the two arms. “We saw no benefit for con-tinuous dosing related to side effects,” Dr. Motzer stated. The most common

treatment-related adverse events were fatigue (62% in both arms), nausea (56% in arm A, 49% in arm B), and di-arrhea (56% in arm A, 64% in arm B).

In general, quality of life was not sig-nificantly different in the two study arms. It improved and then plateaued on con-tinuous dosing, and as might be expect-

ed, there was an “on/off” phenomenon with the 4/2 schedule. “We saw no ben-efit on quality of life with the continuous schedule,” Dr. Motzer noted.

“Sunitinib is the most common first-line therapy for metastatic renal cell carcinoma. This study confirms the need to give the standard dosing schedule. There is no benefit for con-tinuous dosing,” he emphasized.

“We’ve been waiting for this infor-mation [on sunitinib] for a long time. The study shows that how you give a drug—the dose and schedule—does matter. It is important to do a study like this, because different patients have different needs,” said Brian Rini, MD, Associate Professor of Medicine, Cleveland Clinic Lerner College of Medicine, Cleveland.

Pazopanib vs SunitinibDr. Motzer mentioned that he

is lead investigator of an ongoing, 900-patient, phase III trial to compare pazopanib (Votrient) vs sunitinib as first-line therapy for metastatic renal cell carcinoma. That study, sponsored by GlaxoSmithKline, has just com-pleted accrual, and Dr. Motzer hopes to present results in 2012.

“Both drugs target angiogenesis, but they have different toxicity profiles,” he said. “Pazopanib may have less toxicity than sunitinib. If this study shows equal efficacy for pazopanib, then we may have another treatment option. One drug may be better than another for cer-tain patients. . . . The main point is to use whatever drug is best for the patient.”

Related StudyDr. Rini was lead author of a related

phase II study designed to evaluate the combination of sorafenib—another

Sunitinib in Renal Cell Carcinoma: Dose and Schedule Matter

■ A phase II trial confirmed the approved 4 weeks on/2 weeks off schedule for sunitinib as the schedule of choice in metastatic renal cell carcinoma. Continuous dosing is similarly effective but does not improve the drug’s side-effect profile.

■ AMG 386, a novel angiogenesis inhibitor, does not provide added benefit when combined with sorafenib in metastatic renal cell carcinoma.

ALOXI® (palonosetron HCl) injection

BRIEF SUMMARY OF PRESCRIBING INFORMATION

INDICATIONS AND USAGE

Chemotherapy-Induced Nausea and VomitingALOXI is indicated for:• Moderately emetogenic cancer chemotherapy – prevention of acute and delayed nausea and vomiting associated with initial and repeat courses• Highly emetogenic cancer chemotherapy – prevention of acute nausea and vomiting associated with initial and repeat coursesDOSAGE AND ADMINISTRATIONRecommended DosingChemotherapy-Induced Nausea and VomitingDosage for Adults - a single 0.25 mg I.V. dose administered over 30 seconds. Dosing should occur approximately 30 minutes before the start of chemotherapy.Instructions for I.V. AdministrationALOXI is supplied ready for intravenous injection. ALOXI should not be mixed with other drugs. Flush the infusion line with normal saline before and after administration of ALOXI.Parenteral drug products should be inspected visually for particulate matter and discoloration before administration, whenever solution and container permit.CONTRAINDICATIONSALOXI is contraindicated in patients known to have hypersensitivity to the drug or any of its components. [see Adverse Reactions (6) in full prescribing information]WARNINGS AND PRECAUTIONSHypersensitivityHypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.ADVERSE REACTIONSBecause 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 refl ect the rates reported in practice.In clinical trials for the prevention of nausea and vomiting induced by moderately or highly emetogenic chemotherapy, 1374 adult patients received palonosetron. Adverse reactions were similar in frequency and severity with ALOXI and ondansetron or dolasetron. Following is a listing of all adverse reactions reported by ≥ 2% of patients in these trials (Table 1).Table 1: Adverse Reactions from Chemotherapy-Induced Nausea and Vomiting Studies ≥ 2% in any Treatment Group

In other studies, 2 subjects experienced severe constipation following a single palonosetron dose of approximately 0.75 mg, three times the recommended dose. One patient received a 10 mcg/kg oral dose in a postoperative nausea and vomiting study and one healthy subject received a 0.75 mg I.V. dose in a pharmacokinetic study.In clinical trials, the following infrequently reported adverse reactions, assessed by investigators as treatment-related or causality unknown, occurred following administration of ALOXI to adult patients receiving concomitant cancer chemotherapy:Cardiovascular: 1%: non-sustained tachycardia, bradycardia, hypotension, < 1%: hypertension, myocardial ischemia, extrasystoles, sinus tachycardia, sinus arrhythmia, supraventricular extrasystoles and QT prolongation. In many cases, the relationship to ALOXI was unclear.Dermatological: < 1%: allergic dermatitis, rash.Hearing and Vision: < 1%: motion sickness, tinnitus, eye irritation and amblyopia.Gastrointestinal System: 1%: diarrhea, < 1%: dyspepsia, abdominal pain, dry mouth, hiccups and fl atulence.

General: 1%: weakness, < 1%: fatigue, fever, hot fl ash, fl u-like syndrome.Liver: < 1%: transient, asymptomatic increases in AST and/or ALT and bilirubin. These changes occurred predominantly in patients receiving highly emetogenic chemotherapy.Metabolic: 1%: hyperkalemia, < 1%: electrolyte fl uctuations, hyperglycemia, metabolic acidosis, glycosuria, appetite decrease, anorexia.Musculoskeletal: < 1%: arthralgia.Nervous System: 1%: dizziness, < 1%: somnolence, insomnia, hypersomnia, paresthesia.Psychiatric: 1%: anxiety, < 1%: euphoric mood.Urinary System: < 1%: urinary retention.Vascular: < 1%: vein discoloration, vein distention.Postmarketing ExperienceThe following adverse reactions have been identifi ed during postapproval use of ALOXI. 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.Very rare cases (<1/10,000) of hypersensitivity reactions and injection site reactions (burning, induration, discomfort and pain) were reported from postmarketing experience of ALOXI 0.25 mg in the prevention of chemotherapy-induced nausea and vomiting.DRUG INTERACTIONSPalonosetron is eliminated from the body through both renal excretion and metabolic pathways with the latter mediated via multiple CYP enzymes. Further in vitro studies indicated that palonosetron is not an inhibitor of CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2D6, CYP2E1 and CYP3A4/5 (CYP2C19 was not investigated) nor does it induce the activity of CYP1A2, CYP2D6, or CYP3A4/5. Therefore, the potential for clinically signifi cant drug interactions with palonosetron appears to be low.Coadministration of 0.25 mg I.V. palonosetron and 20 mg I.V. dexamethasone in healthy subjects revealed no pharmacokinetic drug-interactions between palonosetron and dexamethasone.In an interaction study in healthy subjects where palonosetron 0.25 mg (I.V. bolus) was administered on day 1 and oral aprepitant for 3 days (125 mg/80 mg/80 mg), the pharmacokinetics of palonosetron were not signifi cantly altered (AUC: no change, Cmax: 15% increase).A study in healthy volunteers involving single-dose I.V. palonosetron (0.75 mg) and steady state oral metoclopramide (10 mg four times daily) demonstrated no signifi cant pharmacokinetic interaction.In controlled clinical trials, ALOXI injection has been safely administered with corticosteroids, analgesics, antiemetics/antinauseants, antispasmodics and anticholinergic agents.Palonosetron did not inhibit the antitumor activity of the fi ve chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.USE IN SPECIFIC POPULATIONSPregnancyTeratogenic Effects: Category BTeratology studies have been performed in rats at oral doses up to 60 mg/kg/day (1894 times the recommended human intravenous dose based on body surface area) and rabbits at oral doses up to 60 mg/kg/day (3789 times the recommended human intravenous dose based on body surface area) and have revealed no evidence of impaired fertility or harm to the fetus due to palonosetron. There are, however, no adequate and well-controlled studies in pregnant women. Because animal reproduction studies are not always predictive of human response, palonosetron should be used during pregnancy only if clearly needed.Labor and DeliveryPalonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.Nursing MothersIt is not known whether palonosetron 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 and the potential for tumorigenicity shown for palonosetron in the rat carcinogenicity study, 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 UseSafety and effectiveness in patients below the age of 18 years have not been established.Geriatric UsePopulation pharmacokinetics analysis did not reveal any differences in palonosetron pharmacokinetics between cancer patients ≥ 65 years of age and younger patients (18 to 64 years). Of the 1374 adult cancer patients in clinical studies of palonosetron, 316 (23%) were ≥ 65 years old, while 71 (5%) were ≥ 75 years old. No overall differences in safety or effectiveness were observed between these subjects and the younger subjects, but greater sensitivity in some older individuals cannot be ruled out. No dose adjustment or special monitoring are required for geriatric patients.Of the 1520 adult patients in ALOXI PONV clinical studies, 73 (5%) were ≥65 years old. No overall differences in safety were observed between older and younger subjects in these studies, though the possibility of heightened sensitivity in some older individuals cannot be excluded. No differences in effi cacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI effi cacy in geriatric patients has not been adequately evaluated.Renal ImpairmentMild to moderate renal impairment does not signifi cantly affect palonosetron pharmacokinetic parameters. Total systemic exposure increased by approximately 28% in severe renal impairment relative to healthy subjects. Dosage adjustment is not necessary in patients with any degree of renal impairment.Hepatic ImpairmentHepatic impairment does not signifi cantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.RaceIntravenous palonosetron pharmacokinetics was characterized in twenty-four healthy Japanese subjects over the dose range of 3 – 90 mcg/kg. Total body clearance was 25% higher in Japanese subjects compared to Whites, however, no dose adjustment is required. The pharmacokinetics of palonosetron in Blacks has not been adequately characterized.OVERDOSAGEThere is no known antidote to ALOXI. Overdose should be managed with supportive care. Fifty adult cancer patients were administered palonosetron at a dose of 90 mcg/kg (equivalent to 6 mg fi xed dose) as part of a dose ranging study. This is approximately 25 times the recommended dose of 0.25 mg. This dose group had a similar incidence of adverse events compared to the other dose groups and no dose response effects were observed.Dialysis studies have not been performed, however, due to the large volume of distribution, dialysis is unlikely to be an effective treatment for palonosetron overdose. A single intravenous dose of palonosetron at 30 mg/kg (947 and 474 times the human dose for rats and mice, respectively, based on body surface area) was lethal to rats and mice. The major signs of toxicity were convulsions, gasping, pallor, cyanosis and collapse.PATIENT COUNSELING INFORMATIONSee FDA-Approved Patient Labeling (17.2) in full prescribing informationInstructions for Patients• Patients should be advised to report to their physician all of their medical conditions, any pain, redness, or swelling in and around the infusion site [see Adverse Reactions (6) in full prescribing information].• Patients should be instructed to read the patient insert.

Rx OnlyMfd by OSO Biopharmaceuticals, LLC, Albuquerque, NM, USA or Pierre Fabre, Médicament Production, Idron, Aquitaine, France and Helsinn Birex Pharmaceuticals, Dublin, Ireland.

ALOXI® is a registered trademark of Helsinn Healthcare SA, Switzerland, used under license.Distributed and marketed by Eisai Inc., Woodcliff Lake, NJ 07677.© 2009 Eisai Inc.All rights reserved. Printed in USA. AL449 08/09

EventALOXI

0.25 mg (N=633)

Ondansetron 32 mg I.V. (N=410)

Dolasetron 100 mg I.V.

(N=194)Headache 60 (9%) 34 (8%) 32 (16%)

Constipation 29 (5%) 8 (2%) 12 (6%)Diarrhea 8 (1%) 7 (2%) 4 (2%)Dizziness 8 (1%) 9 (2%) 4 (2%)Fatigue 3 (< 1%) 4 (1%) 4 (2%)

Abdominal Pain 1 (< 1%) 2 (< 1%) 3 (2%)Insomnia 1 (< 1%) 3 (1%) 3 (2%)

ASCOPost.com | APRIL 15, 2011 PAGE 13

2011 Genitourinary Cancers Symposium

standard therapy for metastatic renal cell carcinoma—with AMG 386.2 The goal of that study, which was support-ed by Amgen, was to determine wheth-er the addition of the first-in-class pep-tibody targeted to angiopoietin-1 and -2 would augment VEGF inhibition achieved with sorafenib.

“The rationale for the combination is that these two drugs attack angiogen-esis by two different means,” he said.

The study randomly assigned 152 patients with metastatic renal cell car-cinoma to one of three treatment arms: sorafenib plus placebo; sorafenib plus AMG  386, 10 mg/kg; or sorafenib plus AMG  386, 3 mg/kg. AMG  386 provided no additional benefit over sorafenib alone. For the primary end-point of progression-free survival, all three arms of the study had a median progression-free sur-vival of 9 months. The data showed a hint of a benefit for over-

all response rate when AMG 386 was added, but this was not the primary endpoint of the trial, Dr. Rini said.

At the time the study was initi-ated, it was not clear that sunitinib would become the preferred first-line

therapy for metastatic renal cell carci-noma. “Over the course of the study, sunitinib emerged as the preferred first-line therapy, and ovarian cancer studies suggested that higher doses of AMG 386 would be more effective. In

the future, AMG  386 will be studied in higher doses in combination with sunitinib in metastatic renal cell carci-noma,” Dr. Rini said. ■

Financial Disclosure: Dr. Motzer has received research funding from Pfizer and Wyeth. Dr. Rini disclosed financial ties with Amgen, AVEO, Bayer, GlaxoSmithKline, Novartis, Pfizer, Roche, Celgene, Sanofi-aventis, and Novartis.

References1. Motzer RJ, Hutson TH, Olsen MR,

et al: Randomized phase II multicenter study of the efficacy and safety of suni-tinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial. Genitourinary Cancers Symposium. Ab-stract LBA308. Presented February 19, 2011.

2. Rini BI, Szczylik C, Tannir NM, et al: AMG 386 in combination with sorafenib in patients with metastatic renal cell can-cer: A randomized, double-blind, placebo-controlled, phase II study. Genitourinary Cancers Symposium. Abstract 309. Febru-ary 19, 2011.SEE PAGE 51

0.0

0.2

0.4

0.8

1.0

0 10 20

4/2 schedule (N = 146)Median = 9.9 months(95% CI = 7.0–13.4)

CDD schedule (N = 146)Median = 7.1 months(95% CI = 6.8–9.7)

HR = 0.77(95% CI = 0.57–1.04)P = .090 (unstratified log-rank test)

30

0.6

Time (months)

Prob

abili

ty o

f no

tum

or p

rogr

essi

on

Fig. 1: Time to tumor progression in a trial of sunitinib, standard schedule of 4 weeks on/2 weeks off (4/2) vs continuous dosing (CDD). Courtesy of Robert Motzer, MD.

Speaking at a press telecast where these results were highlighted, study senior author Monique Roobol, PhD, of Erasmus University Medical Center said, “These results can also contribute to risk stratification and management of men in PSA-based screening programs. For example, the favorable outcomes in men with ini-tial PSA values of less than 1 ng/mL support prolongation of the screen-ing interval for these men for up to 8 years.”

Study DetailsThe Dutch cohort study included

42,376 men between the ages of 55 and 74 with an initial PSA value of <  3  ng/mL and no evidence of can-cer from 1997 on. Almost 20,000 men were randomly assigned to serial screening PSA tests, and the thresh-old for biopsy was PSA of 3  ng/mL or higher. The report at the Genito-

urinary Cancers Symposium focused on 15,758 (79%) men with PSA val-ues <  3.0 ng/mL at the first screen-ing test; men were screened every 4 years.

At baseline, men were stratified ac-cording to initial PSA levels <  1  ng/mL (45%), 1 to 1.9  ng/mL (39%), and 1.9 to 2.9 ng/mL (16%). At a me-dian follow-up of 11 years, 915 can-cers were detected in the Dutch co-hort, which represented less than 6% of study participants. Of these, 733 were found at screening and 182 by clinical exam. The risk of cancer was increased—although still very low—with increasing initial PSA level. A total of 23 prostate cancer deaths oc-curred over the course of the study, for a mortality rate of 0.15%.

A fourfold increased risk of can-cer was seen when men with initial PSA levels <  1 ng/mL were com-pared with those who had levels of 1 to 1.9 ng/mL; a tenfold increase was observed between those with initial levels < 1 ng/mL compared with 1.9 to 2.9 ng/mL.

Of the 915 cancers detected dur-ing the study, 138 were deemed ag-gressive (ie, definite clinical stage T2c or higher, Glea-son score ≥  8, and PSA level of 20  ng/mL or higher). A 2.7-fold increase was observed between

Expert Point of View

This study gives us confidence that annual PSA screening will become a thing of the past,” said

Nicholas Vogelzang, MD, US Oncology, Las Ve-gas, who moderated the press telecast at the Geni-tourinary Cancers Symposium. “Initial PSA levels < 1 and < 2 ng/mL could be considered for longer screening intervals. Results also suggest that PSA threshold of  4 ng/mL should be dropped to PSA level of 3 ng/mL for biopsy,” he added.

Dr. Vogelzang said that PSA level is useful, but the future is headed toward personalization of PSA

screening. “The Dutch study is helpful, although it does not speak to the mo-lecular characteristics of the tumor or to genetic characteristic. It does suggest we can reduce the intensity and frequency of screening in men with initial PSA levels < 3 ng/mL,” he said.

“PSA level is good at identifying men at low risk, and a PSA level < 3 ng/mL removes about 50% of men between the ages of 55 and 74. More sophisticated approaches and better biomarkers are needed to determine risk in the other 50% of men,” Dr. Roobol added. ■

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

Nicholas Vogelzang, MD

Monique Roobol, PhD PSA levels < 1 ng/mL and levels of 1 to 1.9 ng/mL, and a 6.2-fold increase of aggressive prostate cancer was ob-served between PSA levels <  1  ng/mL vs 2 to 2.9 ng/mL.

Dr. Roobol said that PSA level was much more predictive than age for future risk of developing prostate cancer. “The difference between risk in men with initial PSA levels < 1 and 2  ng/mL is much more significant than age,” she noted. ■

Financial Disclosure: Dr. Bul reported no potential conflicts of interest. Dr. Roobol disclosed financial relationships with Beckman Coulter, GlaxoSmithKline, and Gen-Probe.

Reference1. Bul M, van Leeuwen PJ, Zhu X, et

al: Prostate cancer incidence and disease-specific survival in men participating in the ERSPC with an initial PSA less than 3.0 ng/mL. Genitourinary Cancers Symposium. Abstract 7. Presented February 17, 2011.

PSA Screening Intervalscontinued from page 1

SEE PAGE 51

Searching for a target in metastatic melanoma?

Begin with BRAFBRAF

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.

EGFREGFR

EGFREGFR

MEKMEK

ERKERK

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

RASRAS

71280ha_b.indd 1 11/17/10 1:11 PM

Searching for a target in metastatic melanoma?

Begin with BRAFBRAF

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.

EGFREGFR

EGFREGFR

MEKMEK

ERKERK

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

RASRAS

71280ha_b.indd 1 11/17/10 1:11 PM

PAGE 16 The ASCO Post | APRIL 15, 2011

2011 Gastrointestinal Cancers Symposium

The movement to relate gene pro-files and protein expression to

tumor aggressiveness is as active in pancreatic cancer as in other more common tumors, according to stud-ies presented at the 2011 Gastroin-testinal Cancers Symposium, held January 20–22 in San Francisco. Two investigations in particular correlated biomarkers with outcomes after sur-gery and/or chemoradiation.

S100A2 and A4 Related to Poor Prognosis

Aberrant expression of two calci-um-binding proteins stratifies pan-creatic cancer into distinct prognostic groups and can be incorporated into nomograms to better select patients for treatment, Australian investigators reported.1

Surgery provides the only poten-tial for cure in pancreatic cancer, but there are no means of predicting who will benefit preoperatively. “Defining clinically and biologically relevant phenotypes in other cancers has led to substantial improvements in over-all outcomes, but none have been defined for pancreatic cancer,” said David Chang, MD, of the Cancer Research Program at the Garvan In-stitute of Medical Research in Sydney, Australia, who is part of a team led by Professor Andrew Biankin.

Dr. Chang and colleagues evalu-ated the expression of two biologi-cally relevant proteins, S100A4 and S100A2,2 which are known to be re-lated to metastatic potential, chemo-resistance, and poor-prognosis cancer phenotypes. They associated the ex-pression of these proteins with sur-vival in a cohort of 372 patients who underwent surgical resection for pan-creatic cancer and incorporated this information, along with clinicopatho-

logic variables, into a nomogram to guide decision-making.

“A preoperative nomogram using only variables that could be measured preoperatively, such as tumor size and molecular biomarkers, predicted sur-vival better than nomograms derived from using clinicopathologic vari-ables, which are only determined af-ter examination of the resected speci-

men,” said Dr. Chang. “Integration of S100A4 and S100A2 stratified the cohort into three distinct prognostic groups.”

Patients who lacked aberrant expression of both markers had a median survival of 34.3  months af-ter pancreatectomy, compared with 15.6  months for those who were S100A2-negative but S100A4-pos-itive and just 11.9  months for the S100A2-positive subset (P  <  .0001, see Fig. 1).

“The development and application of such nomograms in routine clinical practice has the potential to improve patient selection and, as a conse-quence, overall outcomes for pancre-atic cancer,” Dr. Chang concluded. The investigators are now refining means of assessing biomarker status preoperatively, to put this informa-tion into clinical use.

RecQ1 A159C Polymorphism Associated with Survival

RecQ1, a DNA helicase, has been implicated in cancer and chromosome instability, and its depletion results in mitotic catastrophe and mitotic death in cancer cells. The RecQ1 A159C poly-morphism was associated with a sig-nificantly reduced overall survival in pa-tients with resectable pancreatic cancer.3

The study included 154 patients with resected pancreatic cancer en-rolled on the Radiation Therapy On-cology Group (RTOG) 9704 trial of fluorouracil (5-FU)-based chemoradi-ation, preceded and followed by 5-FU or gemcitabine. Investigators evalu-ated the association between genotype (RecQ1 A159 AA, AC, and CC) and overall survival, and found the AA gen-otype to be protective.

The RecQ1 variant AC/CC geno-type carriers were more likely to have node-positive disease than the AA carriers (P  =  .03) and more likely to die (P  =  .032). Carriers of this allele had a 52% increased risk of death, compared to AA. Risk was increased by 57% for AC carriers (P  =  .027) and by 49% for CC carriers (P = .11), compared with the AA genotype, reported Donghui Li, PhD, of The University of Texas MD Anderson

Cancer Center, Houston. The RecQ1 effect (AA vs AC/CC) is more defini-tive for patients on the 5-FU arm than for patients on the gemcitabine arm, she added.

“Our results suggest that the RecQ1 A159C genotype is a prog-nostic or predictive factor for patients with resectable pancreatic cancer who are treated with adjuvant 5-FU before and after 5-FU-based chemoradia-tion,” Dr. Li commented.

“The value of the current study is that it confirmed our pre-vious finding that the RecQ1 A159C vari-ant was associated with significantly reduced overall sur-vival in patients with resectable pan-creatic cancer,” Dr. Li told The ASCO Post. “The current study was conduct-ed in patients with resected pancreatic cancer. So the chemoradiation was given before surgery in our previous study but after surgery in the current study, and the genotype effect was the same,” she noted. ■References

1. Chang DK, Colvin EK, Scarlett CJ, et al: A molecular prognostic nomogram for resectable pancreatic cancer. Gastro-intestinal Cancers Symposium. Abstract 154. Presented January 21, 2011.

2. Biankin AV, Kench JG, Colvin EK, et al: Expression of S100A2 calcium-binding protein predicts response to pancreatectomy for pancreatic cancer. Gastroenterology 137:558-68, 568 e1-11, 2009

3. Li D, Moughan J, Crane CH, et al: Association of RecQ1 A159C polymor-phism with overall survival of patients with resected pancreatic cancer: A repli-cation study in RTOG 9704. Gastrointes-tinal Cancers Symposium. Abstract 156. Presented January 21, 2011.

Biomarkers Can Assess Recurrence Risk in Patients with Resected Pancreatic CancerBy Caroline Helwick

Median survival:34.3 vs 15.6 vs 11.9 months

n = 318P < .0001

85Patients at risk Months

Cum

mul

ative

sur

viva

l

54 28 11 5 4 2 0185 62 24 9 6 2 1 148 7 2 0

0

20 400 60 80

S100A2– / A4–S100A2– / A4+

S100A2+

100 120 140

0.2

0.4

0.6

0.8

1.0

S100A2+

S100A2– / A4+

S100A2– / A4–

Fig. 1: S100A2/S100A4 expression as predictors of survival after pancreatectomy in patients with re-sectable pancreatic cancer. Courtesy of David Chang, MD.

SEE PAGE 51

David Chang, MD

Donghui Li, PhD

Pancreatic Cancer

ASCOPost.com | APRIL 15, 2011 PAGE 17

2011 Genitourinary Cancers Symposium

Although guidelines for the man-agement of muscle-invasive

bladder cancer recommend cisplatin-based neoadjuvant chemotherapy based on level 1 evidence showing a survival advantage, only a small per-centage of patients undergoing radi-cal cystectomy who were eligible for this treatment received it in a recent study, which was presented at the 2011 Genitourinary Cancers Sym-posium.1 Surprisingly, these findings emerged from a survey of academic centers, where one would expect state-of-the-art treatment to be im-plemented.

“Our study showed that practice patterns varied considerably among the 15 academic institutions we sur-veyed in this first phase of our study.

Among all patients treated with perioper-ative chemotherapy, only 9% received neo-adjuvant cisplatin-based chemotherapy;

31% of those treated with neoadju-vant chemotherapy did not receive cisplatin,” stated Andrew Feifer, MD, Memorial Sloan-Kettering Cancer

Center, New York. The overwhelm-ing majority of patients included in the study received pelvic lymph node dissection as per recommendations.

Study DetailsThe survey was conducted among

15 academic centers and included 4,972 patients who underwent radi-cal cystectomy for nonmetastatic muscle-invasive bladder cancer from 2003 to 2008. The retrospective study sought to determine current baseline practice patterns regarding four qual-ity care indicators at academic cen-ters. A second part of the study will explore the reasons for practice varia-tions found during the first phase, Dr. Feifer explained.

The four quality indicators were: referral to medical oncology for mul-timodality therapy; if neoadjuvant therapy was recommended, use of cis-platin for at least three cycles; if adju-vant therapy was recommended, use of adjuvant cisplatin for at least three cycles; and bilateral pelvic lymphad-enectomy of at least the iliac, hypo-gastric, and obturator lymph nodes.

Results showed that 33.6% of pa-

tients received any perioperative che-motherapy: 12.4% received any neo-adjuvant therapy and 21.7% received any adjuvant chemotherapy. An analysis of time trends during 2003 to 2008 showed that the use of neo-adjuvant therapy increased while the use of adjuvant therapy was slightly reduced. In a subset of 3,298 patients, among those who received any neo-adjuvant chemotherapy, 69.4% re-ceived cisplatin; among those who received any perioperative chemo-therapy, 63.5% received cisplatin. Overall, 80% of patients treated with perioperative chemotherapy received

three cycles. Almost 95% of patients underwent bilateral lymph node dis-section. The reasons for which pa-tients were treated with or without systemic therapy are speculative. ■

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

Reference1. Feifer A, Taylor JM, Shouery M,

et al: Multi-institutional quality-of-care initiative for nonmetastatic, muscle in-vasive, transitional cell carcinoma of the bladder: Phase I. Genitourinary Cancers Symposium. Abstract 240. Presented February 18, 2011.

Expert Point of View

These results show that even in highly experienced academic centers, the vast majority of patients did not receive neoadjuvant cisplatin-based

chemotherapy, which based on high-level prospective evidence is the stan-dard of care,” said Maha A. Hussain, MD, Program Chair of the 2011 Genito-urinary Cancers Symposium and Professor and Associate Director for Clini-cal Research at the University of Michigan, Ann Arbor. “Interestingly the use of bilateral lymph node dissection, which is not supported by the same level of evidence, appears to be widely used,” she stated. Clearly the phase II part of this project is critical to shed light on what factors contribute to the observed practices. “Although patients’ related health factors could be one of the con-tributors, this in my experience does not explain the low rate of neoadjuvant/perioperative chemotherapy use. It will be important to gauge other factors such as physician-related factors,” Dr. Hussain added

Integration of evidence into practice is critical to improve patient care, and barriers to that should be carefully assessed, she continued. Patients with bladder cancer need multidisciplinary care. They should be evaluated for the appropriateness and counseled on the pros and cons of perioperative chemo-therapy by a medical oncologist. ■

Financial Disclosure: Dr. Hussain receives research funding from Celgene, Abbott Laboratories, Millennium, and Pfizer (through the University of Michigan). She has served as a consultant (compensated) to Sanofi-aventis, Lilly, Merck, Bristol-Myers Squibb, and (uncompensated) to Exelixis.

Most Patients with Muscle-invasive Bladder Cancer Did Not Receive Optimal Multimodality Care at 15 Academic CentersBy Alice Goodman

■ A retrospective survey of 15 academic centers found that only 9% of patients with muscle-invasive bladder cancer received standard of care with cisplatin-based neoadjuvant therapy.

■ This was the first phase of a two-part study on quality care indicators; the second phase will explore the reasons why patients were not offered standard of care.

■ Considerable variation exists among centers regarding adherence to use of neoadjuvant cisplatin as recommended.

Practice Patterns in Bladder Cancer

SEE PAGE 51

Preventive ApproachesWhat are your thoughts on the ad-

vances we’ve seen in preventive vaccines such as that for human papillomavirus (HPV)?

The rate of cervical carcinoma in the United States has been de-creasing for many years based on sexual hygiene, behavioral changes, and treatment of HPV infections. The concept of HPV immunization is valid (as is true for hepatitis B, particularly in Africa and countries

without the advantages of the U.S. community), but I don’t know what impact it has had on cervical cancer rates. The incubation period from the time of infection to the develop-ment of cervical cancer might be 20 years. So we’ll have to wait for the data before we come to conclusions about immunization against can-cer. Until then, increased awareness about known risk factors for devel-oping cancer such as tobacco prod-ucts, various pollutants, and dietary habits must still command medical attention.

Ongoing ResearchWhat is a day in the life of James

Holland like?I still see patients a couple of days a

week and go to clinic to teach Fellows, but my primary motivation is my re-search. My research partner, Dr. Bea-triz Pogo, our colleagues, and I have identified a human mammary tumor virus (HMTV) in breast cancer that is 95% homologous to the mouse mam-mary tumor virus (MMTV) known to cause breast cancer in mice. The viral sequences are not in adjacent normal tissues, and thus are not genetically

inherited, but rather, acquired. The vi-rus is present in 30% to 40% of breast cancers in the Western world, where Mus domesticus (the common house mouse) is indigenous, with abundant MMTV in its genome. In Asia, where breast cancer is much less common, and different mouse species are indig-enous, only 1% to 12% of breast can-cers contain viral sequences. These data are consistent with a causal role for the virus, but we have not proven that postulate as yet. We are hard at work in this endeavor, however, and that is what keeps me going. ■

James F. Hollandcontinued from page 8

PAGE 18 The ASCO Post | APRIL 15, 2011

2011 Genitourinary Cancers Symposium

Despite research efforts, an ef-fective salvage treatment for

metastatic urothelial cancer that has relapsed following first-line chemo-therapy for metastatic disease remains an unmet need. Three different ab-stracts presented at the recent Genito-urinary Cancers Symposium evaluated therapies in this setting. A randomized phase II study was negative for the ad-dition of vandetanib to docetaxel in patients with advanced urothelial can-cer. Two separate phase II studies had reported favorable results for single-agent nab-paclitaxel (Abraxane) and cetuximab (Erbitux) plus paclitaxel, respectively, in this setting, although both studies were small and not defini-tive. At best, “cautious optimism” is the watchword regarding these two strate-gies. Both require further study.

Vandetanib plus DocetaxelIn a multi-institutional, double-

blind, randomized phase  II trial in 142 patients with previously treated, platinum-resistant advanced urothelial cancer, the addition of the investiga-tional agent vandetanib to docetaxel failed to improve progression-free sur-vival, overall response rate, or overall survival and incurred greater toxicity compared with docetaxel alone.1

A total of 37 patients whose dis-ease progressed on the docetaxel arm crossed over to vandetanib. Vande-tanib had no benefit in these patients.

“There is no standard of care for metastatic urothelial cancer that pro-gresses after platinum-containing che-motherapy. The study sought to evalu-

ate whether the addition of vandetanib, a dual antiangiogenesis inhibitor which blocks VEGF and EGFR simultane-ously, would provide added benefit to

docetaxel. The study was negative, and new treatments are urgently needed,” stated lead author Toni Choueiri, MD, Dana-Farber Cancer Institute, Boston.

Single-agent Nab-paclitaxelA phase II trial evaluated single-

agent nab-paclitaxel, the albumin-bound nanoparticle formulation of

Salvage Therapies Show Mixed Results for Metastatic Urothelial Cancer in Preliminary StudiesBy Alice Goodman

In Search of Treatment for Relapsed

Urothelial Cancer ■ Effective salvage therapy for

metastatic urothelial cancer is an area of unmet medical need.

■ A study of vandetanib added to docetaxel found no benefit to the combination.

■ Two preliminary studies, one with nab-paclitaxel and one with cetuximab/paclitaxel, appear to have activity in this setting, but further studies are needed.

GU Cancer Roundup

INDICATIONSXELODA monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defi ned as progressive disease while on treatment, with or without initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fl uoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fl uorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination therapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent XELODA in the adjuvant treatment of Dukes’ C colon cancer.

Boxed WARNING and Additional Important Safety Information

Boxed WARNINGWarfarin Interaction—Coagulopathy

>> Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.

>> A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial.

>> Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.

>> Clinically signifi cant increases in prothrombin time (PT) and INR have been observed in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy, and infrequently within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases.

>> Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Contraindications

XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components or to 5-fl uorouracil. XELODA is also contraindicated in patients with known dihydropyrimadine dehydrogenase (DPD) defi ciency, or severe renal impairment.

Most Common Adverse ReactionsThe most common adverse reactions (≥30%) reported with XELODA were diarrhea, hand-and-foot syndrome, nausea,vomiting, abdominal pain, fatigue/weakness, and

hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported.

Important Safety Information – Monotherapy in MBCIn a single arm study of XELODA monotherapy in metastatic breast cancer, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving XELODA (%) were lymphopenia (59), diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia (11), fatigue (8), stomatitis (7), and dehydration (5). The most common adverse events for all grades occurring in ≥30% of patients receiving XELODA were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), fatigue (41), dermatitis (37), and vomiting (37).

Important Safety Information – Combination Therapy with Docetaxel in MBCIn a phase 3 study of XELODA combination therapy (XELODA plus docetaxel) in metastatic breast cancer, serious adverse events (grade 3/4) occurring at a ≥2% higher incidence in patients receiving XELODA plus docetaxel vs docetaxel alone (%;%) were lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail disorder (2;0). The most common adverse events for all grades occurring at a ≥5% higher incidence in patients receiving XELODA plus docetaxel vs docetaxel alone were diarrhea (67;48), stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), thrombocytopenia (41;23), vomiting (35;24), abdominal pain (30;24), hyperbilirubinemia (20;6), weakness (16;11), dyspepsia (14;8), lacrimation increase (12;7), and appetite decrease (10;5).

Important Safety Information – Monotherapy in Adjuvant Colon CancerIn a phase 3 study of XELODA monotherapy in colon cancer in the adjuvant setting, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/LV (%;%) were increase in bilirubin (20;7), hand-foot syndrome (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), decrease in neutrophils/granulocytes (3;27), decrease in neutrophils (3;27), stomatitis (2;14), and neutropenia (<1;5). The most common adverse events for all grades occurring in ≥30% of patients receiving either XELODA or 5 FU/LV were hand-foot syndrome (60;9), diarrhea (47;65), nausea (34;47), and stomatitis (22;60). A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV

Please see following brief summary of full Prescribing Information, including Boxed WARNING, for additional Important Safety Information.

©2011 Genentech USA, Inc. All rights reserved. 01/11 XEL000021580

RxBIN: 610524

RxPCN: Loyalty

RxGRP:

ISSUER: (80840)

ID:

Co-pay Ass is tance CardCo-pay Card

XXXXXXXX

XXXXXXXXX

GENEXL-1043_Card_FM.indd 1 11/30/10 2:11 PM

XELO0D0011_B_CopayJrnlAd_r6.indd 1 2/14/11 11:43 AM

Program benefi t Pays up to 80% of XELODA co-pay toward each prescription and refi ll.

Program limit Up to $4000 in XELODA co-pay support, which must be used within 1 year after card activation. There is a coverage limit for each 30-day supply. Enrolled patients whose annual household income is $100,000 or more can receive only up to $1500 in benefi ts per calendar year. (Proof of income is required.)

Eligibility >> Covered by a private (nongovernmental) insurance>> 18 years of age or older

Patients covered under Medicare, Medicaid, Medigap, VA, DoD, Tricare, or any other government-funded health care program, patients currently residing or receiving services in Massachusetts, and patients who are already participating in Genentech® Access to Care Foundation (GATCF) are not eligible.

The XELODA Co-pay Card helps reduce eligible patient out-of-pocket costs—up to $4000 a year

Terms and conditionsNo person or entity may seek reimbursement from any third-party payer for any amount provided using the card program. Genentech USA, Inc. reserves the right to deny payment under the card to anyone deemed ineligible in accordance with the stated program criteria. For full terms and conditions, questions about enrollment in other XELODA patient support programs, including nurse call support, call 1-877-987-2487 or visit www.xelodasupport.com. If your patients are not eligible, they may qualify for support offered by XELODA Access Solutions. To learn more call 1-888-249-4918.

Call 1-877-344-7774, from 8 AM–8 PM (EST),

Monday–Friday, or visit www.XELODAASSIST.com.

REACH OUT TO YOUR PATIENTS ON XELODA THERAPY TODAY.

For full terms and conditions, questions regarding enrollment, claim transmission, patient eligibility or other issues, contact XELODA ASSIST:

XELO0D0011_B_CopayJrnlAd_r6.indd 2 2/14/11 11:43 AM

ASCOPost.com | APRIL 15, 2011 PAGE 19

2011 Genitourinary Cancers Symposium

paclitaxel, in 48 patients with urothelial cancer that progressed on or after plat-inum-based first-line chemotherapy.2

Among 47 patients evaluable for response, partial responses were achieved in 15 patients (32%) and stable dis-ease in 10 (21%); 22

patients (47%) had progressive disease.Thus, the clinical benefit rate (re-

sponse or stable disease) was 53%, re-ported Srikala S. Sridhar, MD, Princess Margaret Hospital, Toronto. “This is the highest reported single-agent response rate to date in the second-line setting for urothelial cancer, and further study is clearly warranted,” she concluded.

Cetuximab plus PaclitaxelA multicenter, randomized, phase

II study of 39 evaluable patients with metastatic urothelial cancer previously treated with one line of chemotherapy suggests that cetuximab augments the antitumor activity of paclitaxel in this setting.3 This combination requires fur-

Srikala S. Sridhar, MD continued on page 20SEE PAGE 51

INDICATIONSXELODA monotherapy is indicated for the treatment of patients with metastatic breast cancer resistant to both paclitaxel and an anthracycline-containing chemotherapy regimen or resistant to paclitaxel and for whom further anthracycline therapy is not indicated, eg, patients who have received cumulative doses of 400 mg/m2 of doxorubicin or doxorubicin equivalents. Resistance is defi ned as progressive disease while on treatment, with or without initial response, or relapse within 6 months of completing treatment with an anthracycline-containing adjuvant regimen.

XELODA in combination with docetaxel is indicated for the treatment of patients with metastatic breast cancer after failure of prior anthracycline-containing chemotherapy.

XELODA is indicated as a single agent for adjuvant treatment in patients with Dukes’ C colon cancer who have undergone complete resection of the primary tumor when treatment with fl uoropyrimidine therapy alone is preferred. XELODA was non-inferior to 5-fl uorouracil and leucovorin (5-FU/LV) for disease-free survival (DFS). Although neither XELODA nor combination chemotherapy prolongs overall survival (OS), combination therapy has been demonstrated to improve disease-free survival compared to 5-FU/LV. Physicians should consider these results when prescribing single-agent XELODA in the adjuvant treatment of Dukes’ C colon cancer.

Boxed WARNING and Additional Important Safety Information

Boxed WARNINGWarfarin Interaction—Coagulopathy

>> Patients receiving concomitant capecitabine and oral coumarin-derivative anticoagulant therapy should have their anticoagulant response (INR or prothrombin time) monitored frequently in order to adjust the anticoagulant dose accordingly.

>> A clinically important XELODA-Warfarin drug interaction was demonstrated in a clinical pharmacology trial.

>> Altered coagulation parameters and/or bleeding, including death, have been reported in patients taking XELODA concomitantly with coumarin-derivative anticoagulants such as warfarin and phenprocoumon.

>> Clinically signifi cant increases in prothrombin time (PT) and INR have been observed in patients who were stabilized on anticoagulants at the time XELODA was introduced. These events occurred within several days and up to several months after initiating XELODA therapy, and infrequently within 1 month after stopping XELODA. These events occurred in patients with and without liver metastases.

>> Age greater than 60 and a diagnosis of cancer independently predispose patients to an increased risk of coagulopathy.

Contraindications

XELODA is contraindicated in patients with known hypersensitivity to capecitabine or to any of its components or to 5-fl uorouracil. XELODA is also contraindicated in patients with known dihydropyrimadine dehydrogenase (DPD) defi ciency, or severe renal impairment.

Most Common Adverse ReactionsThe most common adverse reactions (≥30%) reported with XELODA were diarrhea, hand-and-foot syndrome, nausea,vomiting, abdominal pain, fatigue/weakness, and

hyperbilirubinemia. Other adverse reactions, including serious adverse reactions, have been reported.

Important Safety Information – Monotherapy in MBCIn a single arm study of XELODA monotherapy in metastatic breast cancer, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving XELODA (%) were lymphopenia (59), diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia (11), fatigue (8), stomatitis (7), and dehydration (5). The most common adverse events for all grades occurring in ≥30% of patients receiving XELODA were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), fatigue (41), dermatitis (37), and vomiting (37).

Important Safety Information – Combination Therapy with Docetaxel in MBCIn a phase 3 study of XELODA combination therapy (XELODA plus docetaxel) in metastatic breast cancer, serious adverse events (grade 3/4) occurring at a ≥2% higher incidence in patients receiving XELODA plus docetaxel vs docetaxel alone (%;%) were lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail disorder (2;0). The most common adverse events for all grades occurring at a ≥5% higher incidence in patients receiving XELODA plus docetaxel vs docetaxel alone were diarrhea (67;48), stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), thrombocytopenia (41;23), vomiting (35;24), abdominal pain (30;24), hyperbilirubinemia (20;6), weakness (16;11), dyspepsia (14;8), lacrimation increase (12;7), and appetite decrease (10;5).

Important Safety Information – Monotherapy in Adjuvant Colon CancerIn a phase 3 study of XELODA monotherapy in colon cancer in the adjuvant setting, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/LV (%;%) were increase in bilirubin (20;7), hand-foot syndrome (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), decrease in neutrophils/granulocytes (3;27), decrease in neutrophils (3;27), stomatitis (2;14), and neutropenia (<1;5). The most common adverse events for all grades occurring in ≥30% of patients receiving either XELODA or 5 FU/LV were hand-foot syndrome (60;9), diarrhea (47;65), nausea (34;47), and stomatitis (22;60). A total of 18 deaths due to all causes occurred either on study or within 28 days of receiving study drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV

Please see following brief summary of full Prescribing Information, including Boxed WARNING, for additional Important Safety Information.

©2011 Genentech USA, Inc. All rights reserved. 01/11 XEL000021580

RxBIN: 610524

RxPCN: Loyalty

RxGRP:

ISSUER: (80840)

ID:

Co-pay Ass is tance CardCo-pay Card

XXXXXXXX

XXXXXXXXX

GENEXL-1043_Card_FM.indd 1 11/30/10 2:11 PM

XELO0D0011_B_CopayJrnlAd_r6.indd 1 2/14/11 11:43 AM

Program benefi t Pays up to 80% of XELODA co-pay toward each prescription and refi ll.

Program limit Up to $4000 in XELODA co-pay support, which must be used within 1 year after card activation. There is a coverage limit for each 30-day supply. Enrolled patients whose annual household income is $100,000 or more can receive only up to $1500 in benefi ts per calendar year. (Proof of income is required.)

Eligibility >> Covered by a private (nongovernmental) insurance>> 18 years of age or older

Patients covered under Medicare, Medicaid, Medigap, VA, DoD, Tricare, or any other government-funded health care program, patients currently residing or receiving services in Massachusetts, and patients who are already participating in Genentech® Access to Care Foundation (GATCF) are not eligible.

The XELODA Co-pay Card helps reduce eligible patient out-of-pocket costs—up to $4000 a year

Terms and conditionsNo person or entity may seek reimbursement from any third-party payer for any amount provided using the card program. Genentech USA, Inc. reserves the right to deny payment under the card to anyone deemed ineligible in accordance with the stated program criteria. For full terms and conditions, questions about enrollment in other XELODA patient support programs, including nurse call support, call 1-877-987-2487 or visit www.xelodasupport.com. If your patients are not eligible, they may qualify for support offered by XELODA Access Solutions. To learn more call 1-888-249-4918.

Call 1-877-344-7774, from 8 AM–8 PM (EST),

Monday–Friday, or visit www.XELODAASSIST.com.

REACH OUT TO YOUR PATIENTS ON XELODA THERAPY TODAY.

For full terms and conditions, questions regarding enrollment, claim transmission, patient eligibility or other issues, contact XELODA ASSIST:

XELO0D0011_B_CopayJrnlAd_r6.indd 2 2/14/11 11:43 AM

PAGE 20 The ASCO Post | APRIL 15, 2011

2011 Genitourinary Cancers Symposium

ther study to establish its role in the treatment of urothelial cancer, said lead author Yu-Ning Wong, MD, Fox Chase Cancer Center, Philadelphia.

The two-armed study was non-comparative. The goal was to study the effect of cetuximab with or with-

Urothelial Cancercontinued from page 10

out paclitaxel in this setting. The in-vestigators decided to close the cetux-imab-alone arm after 9 of the first 11 patients showed disease progression by 8 weeks. A total of 28 patients com-pleted accrual to the cetuximab/pa-clitaxel arm. Median progression-free survival of the combination arm was 115 days (16.4 weeks) overall. The

overall survival was 9.5 months. The overall response rate of the combina-tion arm was 28.5% (eight patients had a complete or partial response); unconfirmed partial responses were seen in an additional four patients. ■

Financial Disclosure: Dr. Choueiri received research funding for his study from AstraZeneca. Dr. Sridhar disclosed financial Yu-Ning Wong, MD

ASCOPost.com | APRIL 15, 2011 PAGE 21

2011 Genitourinary Cancers Symposium

ties to Sanofi-aventis and Pfizer. Dr. Wong received funding for this study from Bristol-Myers Squibb. She has also served as a paid and unpaid consultant to Bristol-Myers Squibb.

References1. Choueiri TK, Vaishampayan UN,

Yu EY, et al: A double-blind, randomized

trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pre-treated advanced urothelial cancer. Geni-tourinary Cancers Symposium. Abstract LBA239. Presented February 18, 2011,

2. Sridhar SS, Canil CM, Mukherjee SM, et al: Results of a phase II study of single-agent nab-paclitaxel in platinum-refractory second-line metastatic urothe-

lial carcinoma. Genitourinary Cancers Symposium. Abstract 241. Presented February 18, 2011.

3. Wong YN, Litwin S, Plimack ER, et al: Effect of EGFR inhibition with cetux-imab on the efficacy of paclitaxel in previ-ously treated metastatic urothelial cancer. Genitourinary Cancers Symposium. Ab-stract 243. Presented February 18, 2011.

Expert Point of View

In an interview with The ASCO Post, Maha A. Hussain, MD,

Professor of Medicine and Urol-ogy and Associate Director for Clinical Research at the University of Michigan, Ann Arbor, and Pro-gram Chair of the 2011 Genito-urinary Cancers Symposium, dis-cussed these three presentations on metastatic urothelial cancer. She said metastatic urothelial can-cer is a terminal disease and de-spite relatively high response rates to chemotherapy (about 50%), the vast majority of patients, including responders, will relapse and die.

“We have no standard second-line systemic therapy for relapsed patients. This remains an area of unmet need, and it is thus a very important area for more research,” she noted.

In general, three lines of re-search have been pursued: che-motherapy, targeted therapy, and the combination of the two. Dr. Sridhar’s abstract focused on che-motherapy, and the other two ab-stracts evaluated targeted therapy plus chemotherapy with drugs that have a biologic rationale in urothe-lial cancer, she continued.

“The vandetanib trial was nega-tive, but the other two trials sug-gest that both nab-paclitaxel and the combination of cetuximab/paclitaxel are potentially promis-ing. Ultimately, however, larger tri-als will be needed to better assess the magnitude of the observed ef-fects,” Dr. Hussain concluded. ■

Financial Disclosure: Dr. Hussain receives research funding from Celgene, Abbott Laboratories, Millennium, and Pfizer (through the University of Michigan). She has served as a consultant (compensated) to Sanofi-aventis, Lilly, Merck, Bristol-Myers Squibb, and (uncompensated) to Exelixis.

Maha A. Hussain, MD

PAGE 22 The ASCO Post | APRIL 15, 2011

Direct from ASCO

W ith the theme “Patients, Pathways, Progress,” the 2011 ASCO Annual Meeting, to be held June 3–7 in Chicago, offers a wide variety of educa-

tional opportunities for oncology professionals to discover and discuss clinical and translational research and innovations.

The four sessions described here are examples of the Annual Meeting’s cover-age of practice-changing science and directions for the future.

WHAT: Customized Cancer Treatment: A Systems Biology Approach to Drug Selection

WHO: John Mendelsohn, MD, President, MD Anderson Cancer Center; Jeffrey M. Trent, PhD, TGen; Andrea Califan, PhD, Columbia University

This Education Session will cover ad-vances in knowledge, technology, and new drug development in customizing cancer treatment. The speakers will also discuss the challenges facing clinicians and researchers in selecting targets:

• How do we distinguish aberrant genes that are “drivers” from those that are “passengers?”

• Should we measure gene mutations and copy number, gene regulation, tran-scription of genes, or the protein products of genes, or are all of these param-eters required?

• How do we balance patient risks and benefits in dealing with necessarily im-precise gene sequencing assays, in allowing patients with advanced incurable disease access to experimental drugs in an N = 1 experiment, and in rapidly moving forward with combinations of targeted therapies?

WHAT: Direct-to-Consumer Genetic Testing for Cancer: What Physicians Need to Know

WHO: Sancy Leachman, MD, PhD, Huntsman Cancer Institute; Daniel B. Vorhaus, JD, Editor, Genomics Law Report; Stacy W. Gray, MD, AM, Dana-Farber Cancer Institute; Angela R. Bradbury, MD, Fox Chase Cancer Center.

Genetic testing available directly to consumers is one of the most rapidly advancing areas of personalized ge-nomics. This Education Session will address the evolution and current state of technology, analysis, and reporting of test results to patients. Presenters will update clinicians about genetic

tests now available to consumers, how consumers are using the tests, and how regulation of the tests is changing.

Attendees will learn about some of the specific tests that physicians are likely to see, how DNA is collected, whether testing requires a physician intermediary, costs involved, and how understandable the results are to laypersons.

WHAT: How to Participate in Clinical Research across Borders

WHO: Eduardo Cazap, MD, PhD, President, International Union Against Cancer; Martine J. Piccart-Gebhart, MD, PhD, Jules Bordet Institute; Edward Lloyd Trimble, MD; National Cancer Institute; Jean-Yves Blay, MD, PhD, Centre Leon Bérard; Henry Leonidas Gomez, MD, Instituto Nacional de Enfermedades Neoplasicas

This Extended Education Session will address how to improve and facilitate global research in light of the barriers and challenges faced by researchers in developing countries. Presenters will discuss the importance of developing and promoting independent and public funding of clinical trials internationally.

In contrast to industry-supported clinical trials in the developed world that aim to determine the effectiveness of a new product in preparation for marketing, the most important objective of a publicly supported system of cancer clinical trials is identifying optimal therapies.

The presenters will describe teams of cancer care professionals in developing countries and the tools and knowledge needed to conduct clinical research in such environments. They will also discuss opportunities for oncology fellows, junior faculty, and basic and clinical researchers in developed countries to be-come involved in cancer research internationally.

WHAT: PARP Inhibitors, DNA Repair, and Beyond: Theory Meets Reality in the Clinic

WHO: Michael B. Kastan, MD, PhD, St. Jude Children’s Research Hospital; Alan Ashworth, PhD, FRS, Institute of Cancer Research; Judy Garber, MD, MPH, Dana-Farber Cancer Institute

Presenters of this Education Session will address how gene products that are critical in responding to DNA damage in normal cells provide new targets for research efforts to enhance the efficacy of DNA-targeted therapy.

Synergistic possibilities arise because these genes are important in both tu-mor development and tumor thera-py—many tumors are defective in one or more DNA repair genes because

Just a Taste of What’s in Store at the ASCO Annual MeetingEducation Sessions cover the latest advances in oncology practice and research, challenges facing researchers and clinicians, and new directions in cancer care.

Selecting treatment for each cancer patient on the basis of genetic abnormalities in his or her cancer is an achievable goal, but many questions remain.

— John Mendelsohn, MD, MD Anderson Cancer Center

It’s likely direct-to-consumer tests will become part of the frontline armamentarium for personalized medicine in the future.

— Sancy Leachman, MD, PhD, Huntsman Cancer Institute

In the global fight against cancer, it’s critical to develop new research groups in developing countries and to foster long-term research collaborations.

— Eduardo Cazap, MD, PhD, President, International Union Against Cancer

Targeting these repair pathways is advantageous because it provides the type of “therapeutic index” that we are always looking for in cancer therapies—maximizing toxicity to the tumor cells while minimizing toxicity to normal cells.

— Michal B. Kastan, MD, PhD, St. Jude Children’s Research Hospital

continued on page 24

ASCOPost.com | APRIL 15, 2011 PAGE 23

Direct from ASCODirect from ASCO

In recent years, ASCO and Cancer.Net have joined television-driv-

en, sports-related cancer campaigns under the Society’s Champions Against Cancer initiative. Mil-lions of viewers tuned in to these events—Frosted Pink with a Twist, Skate America, and Kaleidoscope—and while being wowed by athletic feats and all-star performances, they also learned about women’s cancers and valuable cancer information re-sources from Cancer.Net.

Following in the same vein, Cham-pions Against Cancer has expanded to include two new collaborations. Most recently, ASCO and the Atlantic Coast Conference (ACC) joined forces to highlight cancer awareness at this sea-

Champions Against Cancer Initiative Grows to Include the Atlantic Coast Conference and ON THE LINE

ASCO Prostate Cancer Advisory PanelBruce J. Roth, MD, Panel Chair Washington University School of Medicine

Anthony V. D’Amico, MD, PhD Dana-Farber Cancer Institute and Brigham and Women’s Hospital, Harvard Medical School

Paul A. Godley, MD, PhD, MPP University of North Carolina at Chapel Hill

Maha Hussain, MD, FACP University of Michigan Comprehensive Cancer Center

Philip W. Kantoff, MD Harvard Medical School, Dana-Farber Cancer Institute

John F. Mahoney, MD Carolinas Hematology-Oncology Associates, Carolinas Medical Center

Derek Raghavan, MD, PhD, FACP, FRACP Levine Cancer Institute, Carolinas HealthCare System

Mack Roach, III, MD University of California, San Francisco

Howard M. Sandler, MD Cedars-Sinai Medical Center

Peter T. Scardino, MD, FACS Memorial Sloan-Kettering Cancer Center

Paul F. Schellhammer, MD Virginia Prostate Center

Eric J. Small, MD UCSF Helen Diller Family Comprehensive Cancer Center

Andrew J. Stephenson, MD, FRCSC Cleveland Clinic

Nicholas J. Vogelzang, MD Comprehensive Cancer Centers of Nevada

Carlton G. Brown, RN, PhD, AOCN Oncology Nursing Society, University of Delaware

Selected portions reprinted from ASCO Connection. © American Society of Clinical Oncology. “ON THE LINE Prostate Cancer Awareness Campaign Draws on Expertise of ASCO.” ASCO Connection, January 2011: Page 35. All rights reserved.

son’s ACC Men’s Basketball Tourna-ment, which took place last month in Greensboro, North Carolina. ASCO member William Blackstock, MD, of North Carolina’s Wake Forest Univer-sity was at the tournament along with ACC Commissioner John Swofford to announce the launch of the new col-laboration. Information was provided to ACC fans through a booth at Fan-Fest, online at Cancer.Net and the of-ficial website of the ACC, and on-air during the game telecasts.

A second initiative called ON THE LINE also launched earlier this year. Created by Edge Health, ON THE LINE is an awareness campaign that strives to engage men through sports and educate them about prostate can-cer. Through primary media vehicle ESPN, athletes, commentators, celeb-rities, and legendary sports coaches are encouraging a dialogue between men and their families, friends, and physicians about risk factors and treat-ment options for prostate cancer. ON THE LINE draws on the expertise of ASCO; a panel of ASCO prostate can-cer experts provided the core clinical prostate cancer information, which serves as the basis for the campaign content and focuses on the following topics: ■ Risk factors ■ Testing/screening ■ Diagnosis ■ Staging

■ Treatment ■ Survivorship

Visit ontheline.com to learn more about this campaign, or check out

www.Cancer.Net/Champions for more on ASCO’s Champions Against Cancer program and collaboration with the ACC. ■

ASCO member William Blackstock, MD, (cen-ter), Professor and Chairman of the Depart-ment of Radiation Oncology at the Wake For-est University School of Medicine, and Atlantic Coast Conference (ACC) Commissioner John Swofford (right) announce the launch of a new collaboration between ASCO and the ACC dur-ing the ACC basketball tournament in Greens-boro on March 11. This effort is the latest ad-dition to ASCO’s Champions Against Cancer initiative, which uses sports-oriented collabo-rations and platforms to educate and empow-er people about cancer and their health. At left is sportscaster Mike Hogwood.

PAGE 24 The ASCO Post | APRIL 15, 2011

Direct from ASCO

The first edition of the ASCO Global Express was delivered

in January to the more than 8,000 international ASCO members. This new electronic newsletter is de-

ASCO Global Express Launches as New Resource for International Memberssigned to serve and inform these clinicians, who practice outside the United States and deliver cancer care in more than 100 countries worldwide.

Published every other month, the ASCO Global Express provides commentary from ASCO’s leader-ship on topics of international pri-ority, information about ASCO’s

upcoming educational and scientific meetings around the world, links to selected articles in the Journal of Clinical Oncology and ASCO Con-nection, and overall insights into ASCO’s efforts to improve cancer care globally.

Created in response to mem-ber requests for a communications channel devoted to the concerns of the international cancer commu-nity, in part for the recognition and appreciation of international mem-bers, ASCO Global Express will also fulfill a growing need for the Society by regularly sharing educational, scientific, and quality initiatives to a steadily growing number of inter-national members. Increasingly, in-ternational volunteers are playing an important role in ASCO, from mak-ing up over half of the attendees at the Annual Meeting in recent years to serving on the ASCO Board of Di-rectors and numerous committees, including the vibrant International Affairs Committee.

In addition to the ASCO Global Express, international members will continue to receive the stan-dard ASCO Express—the electronic newsletter for all ASCO members—every other week.

Questions or comments about the newsletter should be sent to in-ternational@asco.org. ■© 2011. American Society of Clinical Oncology. All Rights Reserved.

Annual Meetingcontinued from page 22the gene mutation contributed to the development of the tumor itself.

The presenters will describe how these mutations serve as a potential Achilles’ heel of the tumor, in that tumors with a defect in one repair pathway are particularly sensitive to inhibition of a different repair path-way, presumably because that second repair pathway compensates for the loss of function associated with the first mutation.

To learn more about the 2011 Annual Meeting and to register, visit chicago2011.asco.org. ■© 2011. American Society of Clinical Oncology. All rights reserved.

PHASE III TRIAL CURRENTLY RECRUITING

ASCOPost.com | APRIL 15, 2011 PAGE 25

Direct from ASCODirect from ASCO

1. Survivorship Programs and Care Plans in Practice: Variations on a Theme Erin E. Hahn, et al 7(2): 70

2. Off-Label Use of Rituximab in a Multipayer Insurance System By Eliezer M Van Allen, et al 7(2): 76

3. Ontario Protocol Assessment Level: Clinical Trial Complexity Rating Tool for Workload Planning in Oncology Clinical Trials By Bobbi Smuck, et al 7(2): 80

4. Implementation in a Large Health System of a Program to Identify Women at High Risk for Breast Cancer By William L. Owens, et al 7(2): 85

5. American Society of Clinical Oncology Clinical Practice Guideline Update Recommendations on the Role of Bone-Modifying Agents in Metastatic Breast Cancer Catherine H. Van Poznak, et al 7(2): 117

What’s Hot in

JOPjop.ascopubs.org

Filling the Gap: Development of theOncology Nurse PractitionerWorkforce

“Developing new strategies for oncology care delivery by increasing thenumbers and expanding the roles of nonphysician practitioners, such asnurse practitioners (NPs) and physician assistants (PAs), is criticallyimportant to meet the current and potential cancer care needs of theUS population.”

By Brenda Nevidjon, MSN, RN, FAAN, et al

Ensuring Quality Cancer CareThrough the OncologyWorkforce“There is a crisis in the oncology workforce. Health professionals . . . areexperiencing significant workforce shortages . . . because of the rapidlygrowing population of Americans requiring cancer care, an aging oncologyworkforce, and inadequate numbers of newly trained workers. This mis-match between supply and demand for cancer care could threaten patientcare, safety, and quality.”

By Laura Levit, JD, et al

Role of Advanced Nurse Practitionersand Physician Assistants inWashington State

By Jonathan C. Britell, MD

Practical Model for Psychosocial CareBy Susan S. Hendrick, PhD, et al

Physician Assistant Perspective on theASCO Workforce Study Regarding theUse of Physician Assistants andNurse Practitioners

By Maura Polansky, MS, PA-C, et al

Georgia Society of Clinical OncologyForms a Patient Navigator Affiliate

Basic Steps to Building a ResearchProgram

By Allison Baer, RN, BSN, et al

A m e r i c a n S o c i e t y o f C l i n i c a l O n c o l o g y

Journal ofOncology

PracticeT H E A U T H O R I T A T I V E R E S O U R C E F O R O N C O L O G Y P R A C T I C E S

V O L U M E 6 I S S U E 1 J A N U A R Y 2010

http://jop.ascopubs.org

I f you are unable to attend the ASCO Annual Meeting, you

Can’t Go to the 2011 ASCO Annual Meeting?  Attend a Best of ASCO® Meeting.can still have access to the most relevant science in oncology with

Best of ASCO. Attendees of Best of ASCO meetings can view presentations and join discussions regarding 50 of the premier abstracts from the 2011 ASCO Annual Meeting. 

Selected by ASCO lead-ership, the science pre-sented at Best of ASCO will highlight the most timely research on a wide array of oncology disciplines in-cluding breast cancer, de-velopmental therapeutics,

lung cancer, gastrointesti-nal cancers, genitourinary cancers, gynecologic can-cers, head and neck cancer, malignant hematology, and more. ■

Housing and Registra-tion for Best of ASCO Mi-ami and Best of ASCO Seattle will open in early April 2011.  Please check boa2011.asco.org for ad-ditional information and a complete program agenda.

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

Direct your patients to Cancer.Net, ASCO’s patient information

website, where they will find the first two videos in a new series on clinical trials (www.cancer.net/videos). One describes the types of cancer clinical tri-als, and the other explains the process of

New Video Series Helps Patients Understand Cancer Clinical Trials

informed consent. They can check back in May and June for the final two install-ments in the series, which address how clinical trials are reviewed to ensure safety and why patients should consid-er clinical trials as a treatment option. Other articles on the topic can be found at www.cancer.net/clinicaltrials. ■© 2011. American Society of Clinical Oncology. All Rights Reserved.

Vol 28, No 34 December 1, 2010

OURNAL OFLINICALNCOLOGY

Official Journal of the American Society of Clinical Oncology www.jco.org

JCO

JCO

Impact of Androgen-Deprivation Therapy on Cognitive Function in Men WithNonmetastatic Prostate Cancer. S.M.H. Alibhai et al

Impact of Androgen-Deprivation Therapy on Physical Function and QOL inMen With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al

Optimizing Collection of Adverse Event Data in Cancer Clinical TrialsSupporting Supplemental Indications. L.D. Kaiser et alEditorial: D.J. Sargent et al

Availability of Experimental Therapy Outside of Randomized Clinical Trials inOncology. E.P. Hamilton et al

Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-ExistingAutoimmune Disease. O. Landgren et al

Prospective Analysis of Hepatitis B Virus Reactivation in Patients With DiffuseLarge B-Cell Lymphoma After Rituximab Combination ChemotherapyN. Niitsu et al

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by ContinuousTreatment With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: ARandomized Controlled Trial. A. Palumbo et al

Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab inPatients With Metastatic Breast Cancer Pretreated With TrastuzumabF. Andre et al

Review Article: Strategies for Prolonged Therapy in Patients With AdvancedNon–Small-Cell Lung Cancer. P. Fidias et al

Art of Oncology: Stand and Wait. G.F. Blackall

What’s Hot in

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

1. Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralat-eral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214) R. Timothy D. Oliver, et al 29(8): 957

2. Carboplatin in Clinical Stage I Seminoma: Too Much and Too Little at the Same Time George J. Bosl, et al 29(8): 949

3. Future Directions in the Treatment of Neuroendocrine Tumors: Consensus Report of the National Cancer Institute Neuroendocrine Tumor Clinical Trials Planning Meeting Matthew H. Kulke, et al 29(7): 934

4. Safety and Efficacy of TG101348, a Selective JAK2 Inhibitor, in Myelofibrosis Animesh Pardanani, et al 29(7): 789

5. Should Oncologists Be Aware in Their Clinical Practice of KRAS Molecular Analysis? Daniele Santini, et al 29(8): e206

6. Supporting Clinical Practice De-cisions With Real-Time Patient-

Reported Outcomes Ethan Basch JCO March 10, 2011 vol. 29 no. 8 954-956

7. Janus-Activated Kinase 2 In-hibitors: A New Era of Targeted Therapies Providing Significant Clinical Benefit for Philadelphia Chromosome–Negative Myelo-proliferative Neoplasms Srdan Verstovsek 29(7): 781

8. Durable Remission of Metastatic Renal Cell Carcinoma With Gem-citabine and Capecitabine After Failure of Targeted Therapy Stephen L. Richey, et al 29(8): e203

9. Treatment of Low-Risk Gesta-tional Trophoblastic Neoplasia Carol Aghajanian 29(7): 786

10. Phase III Comparison of Standard Doxorubicin and Cyclophosphamide Versus Weekly Doxorubicin and Daily Oral Cyclophosphamide Plus Granulocyte Colony-Stimulating Factor As Neoadjuvant Therapy for Inflammatory and Locally Advanced Breast Cancer: SWOG 0012 Georgiana K. Ellis, et al 29(8): 1014

JCO.org

PAGE 26 The ASCO Post | APRIL 15, 2011

Direct from ASCO

On February 22, 2011, the Journal of Clinical Oncology released its

first podcast online, making it possible for busy readers to now access impor-tant JCO content on the go at JCO.org.

JCO Editor-in-Chief designate

JCO Launches Podcast ProgramStephen A. Cannistra, MD, expects the podcast program to enhance read-ers’ experiences by providing both a summary of and further insights into high-profile JCO articles in short, con-venient audio files.

“One of our goals is to ensure that high-profile publications in JCO are packaged as efficiently as possible,” Cannistra explains. “It is becoming in-creasingly clear that many readers do not have time to delve into the details

of an article and yet still wish to under-stand how the results will impact their practice or clinical research.” JCO pod-casts, which will generally be presented in conjunction with an editorial, will enable readers to stay current on the latest research while placing the results into a clinically useful context.

In the first JCO podcast, David Avigan, MD, from the Beth Israel Dea-coness Medical Center, comments on a recently published article entitled “Randomized, Double-Blind Study of Denosumab versus Zoledronic Acid in the Treatment of Bone Metastases in Patients with Advanced Cancer (Ex-cluding Breast and Prostate Cancer) or Multiple Myeloma,” by David H. Hen-ry, MD, et al (J Clin Oncol 10.1200/JCO.2010.31.3304) and an editorial by Howard West, MD (J Clin Oncol 10.1200/JCO.2010.33.5596).

Upcoming podcasts will feature highly anticipated research on a wide variety of disease sites, including results of recent phase III trials in bladder can-cer, breast cancer, and colorectal can-cer. In these podcasts, leading experts will continue the discussion of these articles and their implications for JCO readers. In addition, Cannistra plans to incorporate an interview format, as the program develops, to involve the lead authors of featured articles.

As with Journal of Oncology Practice podcasts, readers now have the op-portunity to play JCO podcasts di-rectly on a desktop computer or to download them to a portable device for later listening. To obtain the latest podcasts, readers may subscribe free of charge via iTunes or an RSS feed, or they may visit www.JCO.org and www.jop.ascopubs.org. The most re-cent audio commentaries are located on the home page of each journal with the current issues; a full archive is also available in the Podcasts section of each journal’s website. ■© 2011. American Society of Clinical Oncology. All Rights Reserved.

Stephen A. Cannistra, MD

Bringing the Latest Science from the World’s premier Oncology Event Close to You

A program licensed by the American Society of Clinical Oncology

Best of ASCO® Germany June 10 – 11 German Cancer Society (DKG) and Working Group for Clinical Studies in Oncology and Hematology Practices (AKS) – Frankfurt

Best of ASCO® Croatia June 12 – 15 Croatian Society of Oncology – Opatija

Best of ASCO® France June 15 – 16 Association Francaise des Cancerologues – Paris

Best of ASCO® Lebanon July 1 – 2 Lebanese Society of Medical Oncology – Beirut

Best of ASCO® Turkey July 2 Tibbi Onkologi Dernegi – Istanbul

Best of ASCO® Japan July 9 – 10 Japanese Society of Medical Oncology – Yokohama

Best of ASCO® China July 15 – 16 Chinese Society of Clinical Oncology – Hangzhou

Best of ASCO® India July 16 – 17 Indian Society of Medical and Paediatric Oncology (ISMPO) – Pune

Best of ASCO® Panama July 22 – 23 Panamanian Society of Oncology – Panama City

Best of ASCO® Ecuador July 29 – 30 Ecuadorian Society of Oncology – Salinas

Best of ASCO® Australia August 13 Medical Oncology Group of Australia – Adelaide

Best of ASCO® Mexico September 2 – 3 Instituto Nacional de Cancerologia and SLACOM – Cancun

Best of ASCO® Singapore September 2 – 4 Singapore Society of Oncology – Singapore

Best of ASCO® Czech Republic September 10 Czech Oncology Society – Prague

Best of ASCO® Serbia September 10 Serbian Society of Medical Oncology – Belgrade

Best of ASCO® Peru September 10 – 11 Peruvian Society of Medical Oncology – Lima

Best of ASCO® Brazil September 16-17 SLACOM – Porto Alegre

Best of ASCO® Egypt September 29 – 30 Egyptian Cancer Society – Cairo

Best of ASCO® Slovakia October 8 Slovak Oncology Society – Bratislava

For more information and updates visit: asco.org/boaintl

Mark Your Calendar

ASC11168 BOA International Print Ad V4.indd 1 3/10/11 11:07 AM

THE 5-YEAR SURVIVAL RATEIS 17% FOR PATIENTS WITHMETASTATIC SOFT TISSUE SARCOMA,YET SIGNIFICANT THERAPEUTICADVANCEMENTS ARE LAGGING.1

NEW TREATMENTS ARE URGENTLY NEEDED.

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

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

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46323Alt_M06DR_Tab_v1 1 5/12/10 10:46 AM

ASCOPost.com | APRIL 15, 2011 PAGE 27

XXXXDirect from ASCO

THE 5-YEAR SURVIVAL RATEIS 17% FOR PATIENTS WITHMETASTATIC SOFT TISSUE SARCOMA,YET SIGNIFICANT THERAPEUTICADVANCEMENTS ARE LAGGING.1

NEW TREATMENTS ARE URGENTLY NEEDED.

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

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

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE

46323Alt_M06DR_Tab_v1 1 5/12/10 10:46 AM

PAGE 28 The ASCO Post | APRIL 15, 2011

Appointments

Howard C. Bauchner, MD, from Boston University School of

Medicine, will become the next Editor-in-Chief of JAMA: The Journal of the American Medical Association on July 1, 2011, according to an announcement made by Michael D. Maves, MD, the Executive Vice President and Chief Ex-ecutive Officer of the American Medi-cal Association. Dr. Bauchner will be the 16th editor in the journal’s 127-year history.

Current CredentialsDr. Bauchner is currently the Editor-

in-Chief of the Archives of Disease in Childhood, the official publication of the Royal College of Paediatrics and Child Health in the United Kingdom. He is the first U.S.-based editor of that journal and has held that position since 2003. He is Professor of Pediatrics and Com-munity Health Sciences at Boston Uni-versity Schools of Medicine (BUSM) and Public Health. He is also the Vice Chairman of the Department of Pediat-rics and Assistant Dean, Alumni Affairs and Continuing Medical Education at BUSM. He has served on many editorial boards, including currently for the Brit-ish Medical Journal and Journal Watch. Dr. Bauchner is also an accomplished researcher. He has published more than 125 papers in peer-reviewed journals.

“We are pleased that Dr. Bauchner will be the new editor of JAMA,” Dr. Maves said. “JAMA is a world-class medical journal and we’re confident the journal will continue to grow and pros-per under his leadership. The future of JAMA—one of the AMA’s most trea-sured assets—is in great hands.”

Departing EditorDr. Bauchner is following Catherine

D. DeAngelis, MD, MPH, who is leav-ing the post after 11 years to return to Johns Hopkins School of Medicine in Baltimore.

“I have tremendous respect for JAMA and the prestige and stature it has achieved under Dr. DeAngelis,” Dr. Bauchner said. “JAMA is among the elite medical journals in the world, and I am excited and honored by the oppor-tunity to be its new editor.”

Dr. Bauchner graduated from Boston University School of Medicine in 1979. He completed his internship and junior-year residency at Boston City Hospital, his senior-year residency at Yale-New

Haven Hospital, and then returned to be Chief Resident at Boston City Hospital. He received additional train-ing in epidemiology and statistics as a

Robert Wood Johnson General Pediat-rics Academic Development Scholar at Yale-New Haven Hospital and has been on sabbatical twice, first as a Scholar in

Residence at the David and Lucile Pack-ard Foundation and then as a Scholar in Residence at the Agency for Healthcare Research and Quality. ■

American Medical Association Names New JAMA Editor-in-Chief Professor of Pediatrics and noted researcher to become 16th editor in journal’s 127-year history

DRAFT FCB HealthCareFile Name: 10574_CLL_JA.inddLocation: PrePressClient: CEPHALONProduct: TREANDAJob #: 2CEP-TREA-I0574Live Area: 7"W x 10"H EACHSmall Trim: 7.75”W x 10.5”H EACHBleed: 17.25”W x 11.125”H Gutter: .25 EACH SIDE OF GUTTERColors: 4C

CAD RouterArt Director: Ella (x3506)

Carl Affarian (x3988)Production: Jim Palazzolo (x2446)Traffi c Person: Miles (x2306)Mac Operator: PCDate: 3/1/11Time: 1:15 pmRound: 19

SIGN-OFF Date Time OK Correx QueryStudio ManagerTraffi cVisual QCEditorCopywriterCopy SupervisorArt DirectorArt SupervisorAcct. ExecutiveAcct. ExecutiveProduction

COMMENTSROB — RELEASES AS PDFX1A.2/24/11 • corrections, update hi-res • PL2/24/11 • PdfX1a, Proofi ng • sc

FILE 1 of 2

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Effi cacy relative to fi rst-line therapies other than chlorambucil has not been established.

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

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve 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

• 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)

TREANDA® is his chemo. This is his therapy.

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

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

Discover the elements of effi cacy and safety

Built for Action™

LEARN MORE AT TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

Single-agent TREANDA tripled median PFS in patients with CLL*

20100 30 4025155

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

35

TREANDA(n=153)

Chlorambucil(n=148)

18 monthsmedian PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

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

6 monthsmedian PFS

S:14.5”

S:10”

T:15.5”

T:10.5”

B:17.25”

B:11.125”

F:7.75”

FS:7”

F:7.75”

FS:7”

I0574_CLL_JA.indd 1 3/1/11 1:18 PM

ASCOPost.com | APRIL 15, 2011 PAGE 29

News

In a decision memo released March 30, the Centers for Medicare and

Medicaid Services (CMS) proposed that “the evidence is adequate to con-clude that the use of autologous cellular immunotherapy treatment sipuleucel-T [Provenge] improves health outcomes

for Medicare beneficiaries with asymp-tomatic or minimally symptomatic metastatic castrate-resistant (hormone refractory) prostate cancer, and thus is reasonable and necessary for that in-dication under 1862(a)(1)(A) of the Social Security Act.” The memo calls for

public comments on the proposed de-termination, after which a final decision on the drug will be made.

Sipuleucel-T was approved by the FDA in April 2010, after controversial delays and resulting protests by pa-tients, advocates, and other supporters

of approval. Adding to the controversy is the drug’s $93,000 cost for a complete course of therapy, which leads to a me-dian 4.1-month survival benefit. The unusual decision by CMS to formally study the drug prior to granting cover-age stirred further debate. ■

CMS Issues Proposed Decision Memo for Sipuleucel-T

DRAFT FCB HealthCareFile Name: 10574_CLL_JA.inddLocation: PrePressClient: CEPHALONProduct: TREANDAJob #: 2CEP-TREA-I0574Live Area: 7"W x 10"H EACHSmall Trim: 7.75”W x 10.5”H EACHBleed: 17.25”W x 11.125”H Gutter: .25 EACH SIDE OF GUTTERColors: 4C

CAD RouterArt Director: Ella (x3506)

Carl Affarian (x3988)Production: Jim Palazzolo (x2446)Traffi c Person: Miles (x2306)Mac Operator: PCDate: 3/1/11Time: 1:15 pmRound: 19

SIGN-OFF Date Time OK Correx QueryStudio ManagerTraffi cVisual QCEditorCopywriterCopy SupervisorArt DirectorArt SupervisorAcct. ExecutiveAcct. ExecutiveProduction

COMMENTSROB — RELEASES AS PDFX1A.2/24/11 • corrections, update hi-res • PL2/24/11 • PdfX1a, Proofi ng • sc

FILE 1 of 2

TREANDA is indicated for the treatment of patients with chronic lymphocytic leukemia (CLL). Effi cacy relative to fi rst-line therapies other than chlorambucil has not been established.

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

• TREANDA was compared with chlorambucil in a randomized, open-label, phase 3 trial in treatment-naïve 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

• 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)

TREANDA® is his chemo. This is his therapy.

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

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

Discover the elements of effi cacy and safety

Built for Action™

LEARN MORE AT TREANDA.COM

Please see accompanying brief summary of full Prescribing Information.

Single-agent TREANDA tripled median PFS in patients with CLL*

20100 30 4025155

PROGRESSION-FREE SURVIVAL (PFS): CHRONIC LYMPHOCYTIC LEUKEMIA (CLL)

35

TREANDA(n=153)

Chlorambucil(n=148)

18 monthsmedian PFS

45

0.10.20.30.40.5

Surv

ival

dis

tribu

tion

func

tion

0.60.70.80.91.0

Months

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

6 monthsmedian PFS

S:14.5”

S:10”

T:15.5”

T:10.5”

B:17.25”

B:11.125”

F:7.75”

FS:7”

F:7.75”

FS:7”

I0574_CLL_JA.indd 1 3/1/11 1:18 PM

PAGE 30 The ASCO Post | APRIL 15, 2011

FDA Update

On March 25, the FDA approved Bristol-Myers Squibb’s ipilim-

umab (Yervoy) for the treatment of unresectable or metastatic melanoma. The last agent to be approved for mela-noma, interleukin-2 (Proleukin), only

benefits 10% to 15% of those with ad-vanced melanoma.

“Late-stage melanoma is devastat-ing, with very few treatment options for patients, none of which previ-ously prolonged a patient’s life,” said

Richard Pazdur, MD, Director of the Office of Oncology Drug Products in the FDA’s Center for Drug Evaluation and Research. “Yervoy is the first ther-apy approved by the FDA to clearly demonstrate that patients with meta-

static melanoma live longer by taking this treatment.”

Ipilimumab is a monoclonal anti-body that blocks cytotoxic T-lympho-cyte antigen 4, which may play a role in slowing down or turning off the body’s immune system, affecting its ability to fight off cancerous cells. The drug may work by allowing the body’s immune system to recognize, target, and attack cells in melanoma tumors.

International TrialIpilimumab’s effectiveness was es-

tablished in a single international study of 676 patients with melanoma. All study patients had stopped responding to other commonly used treatments for melanoma. In addition, partici-pants had disease that had spread or that could not be surgically removed.

The randomly assigned patients received ipilimumab plus an experi-mental tumor vaccine called gp100, ipilimumab alone, or the vaccine alone. Median overall survival for those who received the combina-tion of ipilimumab plus the vaccine or ipilimumab alone was about 10 months, compared with 6.4 months for those who received only the ex-perimental vaccine.

Potential Side EffectsCommon side effects that can result

from autoimmune reactions associated with ipilimumab use include fatigue, diarrhea, skin rash, endocrine deficien-cies, and colitis. Severe to fatal autoim-mune reactions were seen in 12.9% of patients treated with ipilimumab. Due to the unusual and severe side ef-fects associated with ipilimumab, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health-care professionals about these serious risks. ■

Ipilimumab Receives Approval for Late-stage MelanomaSkin Cancer

Projected CostAccording to a report in The Wall Street Journal, “The progress comes with a substantial price tag. Bristol-Myers Squibb. . . says it will charge $120,000 for the four infusions of ipilimumab given over three months that will be the standard course of treatment.”

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 post-marketing 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 3/4Total number of patients with at least 1 adverse reaction 121 (79) 52 (34) 96 (67) 25 (17)Gastrointestinal disordersNausea 31 (20) 1 (<1) 21 (15) 1 (<1)Vomiting 24 (16) 1 (<1) 9 (6) 0 Diarrhea 14 (9) 2 (1) 5 (3) 0General disorders and administration site conditionsPyrexia 36 (24) 6 (4) 8 (6) 2 (1)Fatigue 14 (9) 2 (1) 8 (6) 0Asthenia 13 (8) 0 6 (4) 0Chills 9 (6) 0 1 (<1) 0Immune system disordersHypersensitivity 7 (5) 2 (1) 3 (2) 0Infections and infestationsNasopharyngitis 10 (7) 0 12 (8) 0Infection 9 (6) 3 (2) 1 (<1) 1 (<1)Herpes simplex 5 (3) 0 7 (5) 0Investigations Weight decreased 11 (7) 0 5 (3) 0Metabolism and nutrition disorders Hyperuricemia 11 (7) 3 (2) 2 (1) 0Respiratory, 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

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)

Laboratory Abnormality All Grades Grade 3/4 All Grades Grade 3/4 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 post-approval 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 LD50 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 non-hematologic 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.

Manufactured by: Manufactured for:Pharmachemie B.V. Cephalon, Inc.The Netherlands Frazer, PA 19355TREANDA is a trademark of Cephalon, Inc., or its affiliates.©2008-2010 Cephalon, Inc., or its affiliates. TRE-2074 March 2010(Label Code: 00016287.03) All rights reserved.This brief summary is based on TREANDA full Prescribing Information.

S:7”

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ASCOPost.com | APRIL 15, 2011 PAGE 31

2011 Gastrointestinal Cancers Symposium

Visit The ASCO Post website at: ASCOPost.com

An analysis of epidermal growth factor receptor (EGFR) immuno-

histochemistry in the MRC COIN trial has revealed that patients with KRAS wild-type advanced colorectal cancer whose disease stains ≥ 10% positive for EGFR have a progression-free survival benefit from the addition of cetuximab (Erbitux) to standard oxaliplatin-based chemotherapy. Yet <  10% EGFR-pos-itive immunohistochemistry was not prognostic for either progression-free survival, overall survival, or overall response among patients with KRAS

wild-type tumors. EGFR-positive pa-tients with KRAS mutations also did worse on cetuximab than those who received just standard therapy. The re-sults of the EGFR analysis of the MRC COIN trial were presented in January at the Gastrointestinal Cancers Sympo-sium in San Francisco.1

“Although this effect in patients with KRAS mutant disease was not statisti-cally significant, it was a strong trend in keeping with other studies, said Richard Adams, MD, a Senior Lectur-er at Cardiff University School of Medi-

cine in the United Kingdom. The addi-tion of cetuximab to standard therapy had little effect on the outcomes of pa-tients with KRAS mutant tumors who were negative for EGFR, he added.

“These findings are consistent with the as yet unexplained variation of the biologic characteristics of colorectal cancer carrying the KRAS mutation,” Dr. Adams said. “EGFR-positive tu-mors do provide some prognostic val-ue with progression-free survival and overall survival in univariate analysis, but this statistical significance is lost in the multivariate analysis when assess-ing overall survival,” he added.

Additional Insight into Prognosis

In the MRC COIN trial, 2,445 pa-tients were randomly assigned to three arms that included treatment with ox-aliplatin plus a fluoropyrimidine with or without cetuximab. EGFR immuno-histochemistry was assessed for 1,621 patients—22% were EGFR-negative and 78% were EGFR-positive, and these results were balanced across the arms of the trial, Dr. Adams said. Al-though the study on cetuximab was negative, analyzing results in terms of EGFR biomarker status can provide additional insight into prognosis, Dr. Adams noted.

Although EGFR was not prognos-tic for progression-free survival within KRAS wild-type patients at the stan-dardized cutoff point, it was prognos-tic at the 10% mark. The investigators’ analysis indicated that patients who had at least 10% EGFR staining had better progression-free survival outcomes (< 10% vs ≥ 10%, HR = 1.27, 95% CI = 1.07–1.52, P = .008).

Dr. Adams noted that the results of the MRC COIN analysis indicate that there could be a role for EGFR im-munochemistry as a prognostic variable in patients with KRAS wild-type advanced colorectal cancer. Yet the extensive assess-ment of samples available in the trial suggests that the predictive value of these factors for cetuximab used in combination with chemotherapy in first-line colorectal cancer therapy does not hold true, he said. ■Reference

1. Adams RA, James MD, Smith CG, et al: Epidermal growth factor receptor (EGFR) as a predictive and prognostic marker in patients with advanced colorectal cancer: The MRC COIN trial experience. Gastrointestinal Cancers Symposium. Ab-stract 359. Presented January 22, 2011.

MRC COIN Substudy Suggests Prognostic Role for EGFR Immunohistochemistry in Advanced Colorectal Cancer By Barbara Boughton

Expert Point of View

The findings from the EGFR analysis of the MRC COIN trial are significant because they un-

derline the importance of KRAS status in deciding whether or not to add cetuximab to standard therapy in advanced colorectal cancer, said Morton Kahlen-berg, MD, a surgical oncologist and Medical Director of the Baptist Cancer Center in San Antonio, Texas.

“KRAS status is clearly of major importance in treatment decision-making for patients with meta-static colorectal cancer. We know that it very reliably predicts response to EGFR inhibition, specifically the

use of cetuximab,” he said. “By looking at EGFR, the investigators of the MRC COIN trial asked a novel question retrospectively,” Dr. Kahlenberg said.

Although EGFR staining provided information on prognosis in the study, the results probably will not change the standard of care, Dr. Kahlenberg said. “It’s a meaningful study in that they showed that if KRAS is mutated, then EGFR sta-tus does not predict response to therapy. Yet with more EGFR staining in KRAS wild-type patients, progression-free survival was enhanced,” he said.

Provocative QuestionAlthough EGFR testing might add an additional layer of information to oncol-

ogists treating patients with advanced colorectal cancer, the question is whether it would truly be valuable in KRAS wild-type patients. “We know that cetuximab will work in these patients, but the question is how much will it work—and that will now be the provocative question,” Dr. Kahlenberg said.

If EGFR testing in a patient with KRAS wild-type disease stains at less than 10%, the MRC COIN trial indicates that there would be little benefit in adding cetuximab to therapy. “Would one use EGFR staining as a means of deciding, for instance, to withhold therapy in a KRAS wild-type patient who stains at less than 10%?” Dr. Kahlenberg asked. In the clinical setting and in the era of cost containment, this is a provocative question. ■

Financial Disclosures: Dr. Kahlenberg reported no potential conflicts of interest.

Morton Kahlenberg, MD

SEE PAGE 51

Colorectal Cancer

■ Patients with advanced colorectal cancer expressing KRAS wild-type who stain for EGFR at greater than 10% derive a progression-free survival benefit from the addition of cetuximab to standard oxaliplatin-based therapy, according to an analysis of the MRC COIN trial.

■ On multivariate analysis, KRAS wild-type patients did not derive overall response or overall survival benefits from the addition of cetuximab.

■ EGFR-positive patients with KRAS mutant–expressing tumors did worse on cetuximab than those who received standard therapy alone, although this effect was not statistically significant.

■ EGFR immunohistochemistry may have prognostic value for patients with KRAS wild-type advanced colorectal cancer when considering the addition of cetuximab to therapy, but has no predictive value for these patients.

Predictive and Prognostic Value of EGFR

References: 1. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs. 2005;14:313-328. 2. Afinitor [prescribing information]. East Hanover, NJ: NovartisPharmaceuticals Corporation; 2010. 3. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82:381-388. 4. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell.2006;124:471-484. 5. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev.2004;18:1926-1945. 6. Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets,plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. In press.7. Creel PA. Management of mTOR inhibitor side effects. Clin J Oncol Nurs. 2009;13(suppl):19-23.

A different target from VEGFR-TKIs:

mTOR is an intracellular regulator downstream of VEGF1,2

mTOR regulates both angiogenic and proliferative tumor progression pathways1-4

Afinitor targets both tumor and blood vessel cells1,3,5

Adverse events are frequently class related and different from those seen with VEGFR-TKIs2,6,7

In advanced RCC:

Change to Afinitor after initial VEGFR-TKI*failure (sunitinib or sorafenib)†

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2010 Novartis Printed in U.S.A. 08/10 C-AFI-100068

2.5mg 5mg 10mg

For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.comFor reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648).

*VEGFR-TKI=vascular endothelial growth factor receptor tyrosine kinase inhibitor.†Inhibition of mTOR by Afinitor has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Important Safety InformationThere have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Please see Important Safety Information on right side of page.Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients withadvanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Important Safety InformationAfinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any ofthe excipients.

Non-infectious pneumonitis is a class effect of rapamycinderivatives, including Afinitor. Fatal outcomes have beenobserved. If symptoms are moderate or severe, patientsshould be managed with dose interruption until symptomsimprove or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances.

Afinitor has immunosuppressive properties and maypredispose patients to bacterial, fungal, viral or protozoaninfections, including infections with opportunistic pathogens. Localized and systemic infections, includingpneumonia, other bacterial infections, invasive fungalinfections, and viral infections including reactivation ofhepatitis B virus have occurred. Some of these infectionshave been severe (e.g. leading to respiratory or hepaticfailure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. Whiletaking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, instituteappropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasivesystemic fungal infection is made, discontinue Afinitor andtreat with appropriate antifungal therapy.

Oral ulcerations (i.e. mouth ulcers, stomatitis, and oralmucositis) have occurred in patients treated with Afinitor. Insuch cases, topical treatments are recommended, butalcohol- or peroxide-containing mouthwashes should beavoided. Antifungal agents should not be used unless fungalinfection has been diagnosed.

Elevations of serum creatinine, glucose, lipids, andtriglycerides and reductions of hemoglobin, lymphocytes,neutrophils, and platelets have been reported in clinical trials.Renal function, hematological parameters, blood glucose,and lipids should be evaluated prior to treatment andperiodically thereafter. When possible, optimal glucose andlipid control should be achieved before starting a patient on Afinitor.

Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose ofAfinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer.

Afinitor should not be used in patients with severe hepaticimpairment. Afinitor dose should be reduced to 5 mg dailyfor patients with moderate hepatic impairment.

The use of live vaccines and close contact with those whohave received live vaccines should be avoided duringtreatment with Afinitor.

Fetal harm can occur if Afinitor is administered to a pregnant woman.

The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The mostcommon grade 3/4 adverse reactions (incidence ≥3%) wereinfections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%),dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%),hypercholesterolemia (77%), hypertriglyceridemia (73%),hyperglycemia (57%), lymphopenia (51%), and increasedcreatinine (50%). The most common grade 3/4 laboratoryabnormalities (incidence ≥3%) were lymphopenia (18%),hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acuterespiratory failure (0.7%), infection (0.7%), and acute renalfailure (0.4%) were observed on the Afinitor arm.

mTOR Inhibition

Reduced cell growth

and proliferation

Reduced cell

metabolism

Reducedangiogenesis

BLOOD VESSEL CELL

mTOR mTOR

TUMOR CELL

Bleed: 21.25"

Ble

ed: 1

4.25

"

Trim: 21"

Trim

: 14"

Safety: 20.5"

Saf

ety:

13.

5"

References: 1. Dancey JE. Inhibitors of the mammalian target of rapamycin. Expert Opin Investig Drugs. 2005;14:313-328. 2. Afinitor [prescribing information]. East Hanover, NJ: NovartisPharmaceuticals Corporation; 2010. 3. Hartford CM, Ratain MJ. Rapamycin: something old, something new, sometimes borrowed and now renewed. Clin Pharmacol Ther. 2007;82:381-388. 4. Wullschleger S, Loewith R, Hall MN. TOR signaling in growth and metabolism. Cell.2006;124:471-484. 5. Hay N, Sonenberg N. Upstream and downstream of mTOR. Genes Dev.2004;18:1926-1945. 6. Schmidinger M, Bellmunt J. Plethora of agents, plethora of targets,plethora of side effects in metastatic renal cell carcinoma. Cancer Treat Rev. In press.7. Creel PA. Management of mTOR inhibitor side effects. Clin J Oncol Nurs. 2009;13(suppl):19-23.

A different target from VEGFR-TKIs:

mTOR is an intracellular regulator downstream of VEGF1,2

mTOR regulates both angiogenic and proliferative tumor progression pathways1-4

Afinitor targets both tumor and blood vessel cells1,3,5

Adverse events are frequently class related and different from those seen with VEGFR-TKIs2,6,7

In advanced RCC:

Change to Afinitor after initial VEGFR-TKI*failure (sunitinib or sorafenib)†

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936 ©2010 Novartis Printed in U.S.A. 08/10 C-AFI-100068

2.5mg 5mg 10mg

For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.comFor reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648).

*VEGFR-TKI=vascular endothelial growth factor receptor tyrosine kinase inhibitor.†Inhibition of mTOR by Afinitor has been shown to reduce cell proliferation, angiogenesis, and glucose uptake in in vitro and/or in vivo studies.

Important Safety InformationThere have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported.

Please see Important Safety Information on right side of page.Please see Brief Summary of full Prescribing Information on the following pages.

Afinitor is indicated for the treatment of patients withadvanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Important Safety InformationAfinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any ofthe excipients.

Non-infectious pneumonitis is a class effect of rapamycinderivatives, including Afinitor. Fatal outcomes have beenobserved. If symptoms are moderate or severe, patientsshould be managed with dose interruption until symptomsimprove or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances.

Afinitor has immunosuppressive properties and maypredispose patients to bacterial, fungal, viral or protozoaninfections, including infections with opportunistic pathogens. Localized and systemic infections, includingpneumonia, other bacterial infections, invasive fungalinfections, and viral infections including reactivation ofhepatitis B virus have occurred. Some of these infectionshave been severe (e.g. leading to respiratory or hepaticfailure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. Whiletaking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, instituteappropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasivesystemic fungal infection is made, discontinue Afinitor andtreat with appropriate antifungal therapy.

Oral ulcerations (i.e. mouth ulcers, stomatitis, and oralmucositis) have occurred in patients treated with Afinitor. Insuch cases, topical treatments are recommended, butalcohol- or peroxide-containing mouthwashes should beavoided. Antifungal agents should not be used unless fungalinfection has been diagnosed.

Elevations of serum creatinine, glucose, lipids, andtriglycerides and reductions of hemoglobin, lymphocytes,neutrophils, and platelets have been reported in clinical trials.Renal function, hematological parameters, blood glucose,and lipids should be evaluated prior to treatment andperiodically thereafter. When possible, optimal glucose andlipid control should be achieved before starting a patient on Afinitor.

Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose ofAfinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer.

Afinitor should not be used in patients with severe hepaticimpairment. Afinitor dose should be reduced to 5 mg dailyfor patients with moderate hepatic impairment.

The use of live vaccines and close contact with those whohave received live vaccines should be avoided duringtreatment with Afinitor.

Fetal harm can occur if Afinitor is administered to a pregnant woman.

The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The mostcommon grade 3/4 adverse reactions (incidence ≥3%) wereinfections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%),dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%),hypercholesterolemia (77%), hypertriglyceridemia (73%),hyperglycemia (57%), lymphopenia (51%), and increasedcreatinine (50%). The most common grade 3/4 laboratoryabnormalities (incidence ≥3%) were lymphopenia (18%),hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acuterespiratory failure (0.7%), infection (0.7%), and acute renalfailure (0.4%) were observed on the Afinitor arm.

mTOR Inhibition

Reduced cell growth

and proliferation

Reduced cell

metabolism

Reducedangiogenesis

BLOOD VESSEL CELL

mTOR mTOR

TUMOR CELL

Bleed: 21.25"

Ble

ed: 1

4.25

"

Trim: 21"

Trim

: 14"

Safety: 20.5"

Saf

ety:

13.

5"

AFINITOR (everolimus) tablets for oral administrationInitial U.S. Approval: 2009BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGEAFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure oftreatment with sunitinib or sorafenib.

4 CONTRAINDICATIONSHypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea,flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratoryimpairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS5.1 Non-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the ran-domized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. Theincidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%,respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, considerinterrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITORmay be reintroduced at 5 mg daily.For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy andthe use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR maybe re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.5.2 InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infec-tions, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virushave occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading torespiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk ofinfection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to startingtreatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if adiagnosis of an infection is made, institute appropriate treatment promptly and consider interruption ordiscontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinueAFINITOR and treat with appropriate antifungal therapy.5.3 Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the ran-domized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, ororal mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topi-cal treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoidedas they may exacerbate the condition. Antifungal agents should not be used unless fungal infection hasbeen diagnosed [see Drug Interactions (7.1)].5.4 Laboratory Tests and MonitoringRenal FunctionElevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions(6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum cre -atinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipidcontrol should be achieved before starting a patient on AFINITOR.Hematological ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of com plete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.5.5 Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong inhibitors ofCYP3A4 (e.g., ketoconazole, itraconazole, clarithro mycin, atazanavir, nefazodone, saquinavir, telithromycin,ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grape-fruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also beavoided during treatment [see Dosage and Administration (2.2) in the full prescribing information andDrug Interactions (7.1)].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) orPgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Inter -actions (7.1)].An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer(e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, car-bamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in thefull prescribing information and Drug Interactions (7.2)].5.6 Hepatic ImpairmentThe safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderatehepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure wasincreased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) andshould not be used in this population [see Dosage and Administration (2.2) in the full prescribing infor-mation and Use in Specific Populations (8.7)].5.7 VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps,rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.5.8 Use in PregnancyPregnancy Category DThere are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations(8.1)].

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].• Infections [see Warnings and Precautions (5.2)].6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observed inclinical practice.The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized,controlled trial in patients with meta static renal cell carcinoma who received prior treatment with sunitiniband/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78%were male. The median duration of blinded study treatment was 141 days (range 19-451) for patientsreceiving AFINITOR and 60 days (range 21-295) for those receiving placebo.The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue,cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections,dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most commonlaboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia,hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnor-malities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hyper -cholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure(0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergentadverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% forthe AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irre-spective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections,stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. Themost common medical interventions required during AFINITOR treatment were for infections, anemia, andstomatitis.Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organclass, the adverse reactions are presented in order of decreasing frequency.

Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate

in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day Placebo

N=274 N=137All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any Adverse Reaction 97 52 13 93 23 5Gastrointestinal Disorders

Stomatitisa 44 4 <1 8 0 0Diarrhea 30 1 0 7 0 0Nausea 26 1 0 19 0 0Vomiting 20 2 0 12 0 0

Infections and Infestationsb 37 7 3 18 1 0General Disorders and Administration Site Conditions

Asthenia 33 3 <1 23 4 0Fatigue 31 5 0 27 3 <1Edema peripheral 25 <1 0 8 <1 0Pyrexia 20 <1 0 9 0 0Mucosal inflammation 19 1 0 1 0 0

Respiratory, Thoracic and Mediastinal DisordersCough 30 <1 0 16 0 0Dyspnea 24 6 1 15 3 0Epistaxis 18 0 0 0 0 0Pneumonitisc 14 4 0 0 0 0

Skin and Subcutaneous Tissue DisordersRash 29 1 0 7 0 0Pruritus 14 <1 0 7 0 0Dry skin 13 <1 0 5 0 0

Metabolism and Nutrition DisordersAnorexia 25 1 0 14 <1 0

Nervous System DisordersHeadache 19 <1 <1 9 <1 0Dysgeusia 10 0 0 2 0 0

Musculoskeletal and Connective Tissue DisordersPain in extremity 10 1 0 7 0 0

Median Duration of Treatment (d) 141 60CTCAE Version 3.0aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.bIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most commonbeing nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis(3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).

cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonarytoxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with anincidence of <10% include:

Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills(4%), impaired wound healing (<1%)Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%),rhinorrhea (3%)Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythro -dysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion(4%), acneiform dermatitis (3%)Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset ofdiabetes mellitus (<1%)Psychiatric disorders: Insomnia (9%)Nervous system disorders: Dizziness (7%), paresthesia (5%)Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)Renal and urinary disorders: Renal failure (3%)Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)Musculoskeletal and connective tissue disorders: Jaw pain (3%)Hematologic disorders: Hemorrhage (3%)

Key treatment-emergent laboratory abnormalities are presented in Table 2.Table 2

Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Armthan the Placebo Arm

Laboratory Parameter AFINITOR 10 mg/day PlaceboN=274 N=137

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4% % % % % %

Hematologya

Hemoglobin decreased 92 12 1 79 5 <1Lymphocytes decreased 51 16 2 28 5 0Platelets decreased 23 1 0 2 0 <1Neutrophils decreased 14 0 <1 4 0 0

Clinical ChemistryCholesterol increased 77 4 0 35 0 0Triglycerides increased 73 <1 0 34 0 0Glucose increased 57 15 <1 25 1 0Creatinine increased 50 1 0 34 0 0Phosphate decreased 37 6 0 8 0 0Aspartate transaminase (AST)

increased 25 <1 <1 7 0 0Alanine transaminase (ALT)

increased 21 1 0 4 0 0Bilirubin increased 3 <1 <1 2 0 0

CTCAE Version 3.0aIncludes reports of anemia, leukopenia, lymphopenia, neutropenia, pancyto penia, thrombocytopenia.

Information from further clinical trialsIn clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, includingfatal outcomes.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.7.1 Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone therewere significant increases in everolimus exposure when AFINITOR was coadministered with:• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and

15.0-fold, respectively.• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and

4.4-fold, respectively.• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and

3.5-fold, respectively.Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions(5.5)].Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alterna-tive treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2)in the full prescribing information]7.2 Agents that may Decrease Everolimus Blood ConcentrationsCYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer ofCYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimustreatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers ofCYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP ifalternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpre-dictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].7.3 Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactionsbetween AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and prava -statin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)]There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraceptionwhile receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating andthrough organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantationand post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) andretarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetaltoxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommendeddose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oraldose approximately 1.6 times the recommended human dose on a body surface area basis. The effect inrabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lacta-tion. At approximately 10% of the recommended human dose based on body surface area, there were noadverse effects on delivery and lactation and there were no signs of maternal tox icity. However, therewas reduced body weight (up to 9% reduction from the control) and slight reduction in survival in off-spring (~5% died or missing). There were no drug-related effects on the developmental parameters(morphological development, motor activity, learning, or fertility assessment) in the offspring.Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).8.3 Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and effectiveness in pediatric patients have not been established.8.5 Geriatric UseIn the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percentwere 75 and over. No overall differences in safety or effectiveness were observed between these subjectsand younger subjects, and other reported clinical experience has not identified differences in responsesbetween the elderly and younger patients, but greater sensitivity of some older individuals cannot beruled out [see Clinical Pharmacology (12.3) in the full prescribing information].No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full pre-scribing information].8.6 Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renalimpairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recom -mended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].8.7 Hepatic ImpairmentFor patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mgdaily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions(5.6) and Clinical Pharmacology (12.3) in the full prescribing information].The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in thispatient population is not recommended [see Warnings and Precautions (5.6)].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved in either mice or rats given single oral doses of 2000 mg/kg (limit test).Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have beenadministered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGEStore AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).[See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture.Keep this and all drugs out of the reach of children.Procedures for proper handling and disposal of anticancer drugs should be considered. Several guide-lines on this subject have been published.AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

Revised: June 2010 T2010-56

Manufactured by:Novartis Pharma Stein AGStein, Switzerland

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936

©Novartis

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AFINITOR (everolimus) tablets for oral administrationInitial U.S. Approval: 2009BRIEF SUMMARY: Please see package insert for full prescribing information.

1 INDICATIONS AND USAGEAFINITOR® is indicated for the treatment of patients with advanced renal cell carcinoma after failure oftreatment with sunitinib or sorafenib.

4 CONTRAINDICATIONSHypersensitivity to the active substance, to other rapamycin derivatives, or to any of the excipients.Hypersensitivity reactions manifested by symptoms including, but not limited to, anaphylaxis, dyspnea,flushing, chest pain, or angioedema (e.g., swelling of the airways or tongue, with or without respiratoryimpairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS5.1 Non-infectious PneumonitisNon-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the ran-domized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. Theincidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%,respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed.Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratorysigns and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neo-plastic, and other causes have been excluded by means of appropriate investigations. Advise patients toreport promptly any new or worsening respiratory symptoms.Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or nosymptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, considerinterrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITORmay be reintroduced at 5 mg daily.For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy andthe use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR maybe re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.5.2 InfectionsAFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, orprotozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infec-tions, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virushave occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading torespiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk ofinfection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to startingtreatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if adiagnosis of an infection is made, institute appropriate treatment promptly and consider interruption ordiscontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinueAFINITOR and treat with appropriate antifungal therapy.5.3 Oral UlcerationMouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the ran-domized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, ororal mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topi-cal treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoidedas they may exacerbate the condition. Antifungal agents should not be used unless fungal infection hasbeen diagnosed [see Drug Interactions (7.1)].5.4 Laboratory Tests and MonitoringRenal FunctionElevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions(6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum cre -atinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.Blood Glucose and LipidsHyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [seeAdverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipidcontrol should be achieved before starting a patient on AFINITOR.Hematological ParametersDecreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of com plete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.5.5 Drug-drug InteractionsDue to significant increases in exposure of everolimus, co-administration with strong inhibitors ofCYP3A4 (e.g., ketoconazole, itraconazole, clarithro mycin, atazanavir, nefazodone, saquinavir, telithromycin,ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grape-fruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also beavoided during treatment [see Dosage and Administration (2.2) in the full prescribing information andDrug Interactions (7.1)].A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) orPgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Inter -actions (7.1)].An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer(e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, car-bamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in thefull prescribing information and Drug Interactions (7.2)].5.6 Hepatic ImpairmentThe safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderatehepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure wasincreased in patients with moderate hepatic impairment, therefore a dose reduction is recommended.AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) andshould not be used in this population [see Dosage and Administration (2.2) in the full prescribing infor-mation and Use in Specific Populations (8.7)].5.7 VaccinationsThe use of live vaccines and close contact with those who have received live vaccines should be avoidedduring treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps,rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.5.8 Use in PregnancyPregnancy Category DThere are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraception

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations(8.1)].

6 ADVERSE REACTIONSThe following serious adverse reactions are discussed in greater detail in another section of the label:• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].• Infections [see Warnings and Precautions (5.2)].6.1 Clinical Studies ExperienceBecause clinical trials are conducted under widely varying conditions, the adverse reaction ratesobserved cannot be directly compared to rates in other trials and may not reflect the rates observed inclinical practice.The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized,controlled trial in patients with meta static renal cell carcinoma who received prior treatment with sunitiniband/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78%were male. The median duration of blinded study treatment was 141 days (range 19-451) for patientsreceiving AFINITOR and 60 days (range 21-295) for those receiving placebo.The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue,cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections,dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most commonlaboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia,hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnor-malities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hyper -cholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure(0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergentadverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% forthe AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irre-spective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections,stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. Themost common medical interventions required during AFINITOR treatment were for infections, anemia, andstomatitis.Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organclass, the adverse reactions are presented in order of decreasing frequency.

Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate

in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day Placebo

N=274 N=137All grades Grade 3 Grade 4 All grades Grade 3 Grade 4

% % % % % %Any Adverse Reaction 97 52 13 93 23 5Gastrointestinal Disorders

Stomatitisa 44 4 <1 8 0 0Diarrhea 30 1 0 7 0 0Nausea 26 1 0 19 0 0Vomiting 20 2 0 12 0 0

Infections and Infestationsb 37 7 3 18 1 0General Disorders and Administration Site Conditions

Asthenia 33 3 <1 23 4 0Fatigue 31 5 0 27 3 <1Edema peripheral 25 <1 0 8 <1 0Pyrexia 20 <1 0 9 0 0Mucosal inflammation 19 1 0 1 0 0

Respiratory, Thoracic and Mediastinal DisordersCough 30 <1 0 16 0 0Dyspnea 24 6 1 15 3 0Epistaxis 18 0 0 0 0 0Pneumonitisc 14 4 0 0 0 0

Skin and Subcutaneous Tissue DisordersRash 29 1 0 7 0 0Pruritus 14 <1 0 7 0 0Dry skin 13 <1 0 5 0 0

Metabolism and Nutrition DisordersAnorexia 25 1 0 14 <1 0

Nervous System DisordersHeadache 19 <1 <1 9 <1 0Dysgeusia 10 0 0 2 0 0

Musculoskeletal and Connective Tissue DisordersPain in extremity 10 1 0 7 0 0

Median Duration of Treatment (d) 141 60CTCAE Version 3.0aStomatitis (including aphthous stomatitis), and mouth and tongue ulceration.bIncludes all preferred terms within the ‘infections and infestations’ system organ class, the most commonbeing nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis(3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%).

cIncludes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonarytoxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with anincidence of <10% include:

Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%)General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills(4%), impaired wound healing (<1%)Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%),rhinorrhea (3%)Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythro -dysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion(4%), acneiform dermatitis (3%)Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset ofdiabetes mellitus (<1%)Psychiatric disorders: Insomnia (9%)Nervous system disorders: Dizziness (7%), paresthesia (5%)Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)Renal and urinary disorders: Renal failure (3%)Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%)Musculoskeletal and connective tissue disorders: Jaw pain (3%)Hematologic disorders: Hemorrhage (3%)

Key treatment-emergent laboratory abnormalities are presented in Table 2.Table 2

Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Armthan the Placebo Arm

Laboratory Parameter AFINITOR 10 mg/day PlaceboN=274 N=137

All grades Grade 3 Grade 4 All grades Grade 3 Grade 4% % % % % %

Hematologya

Hemoglobin decreased 92 12 1 79 5 <1Lymphocytes decreased 51 16 2 28 5 0Platelets decreased 23 1 0 2 0 <1Neutrophils decreased 14 0 <1 4 0 0

Clinical ChemistryCholesterol increased 77 4 0 35 0 0Triglycerides increased 73 <1 0 34 0 0Glucose increased 57 15 <1 25 1 0Creatinine increased 50 1 0 34 0 0Phosphate decreased 37 6 0 8 0 0Aspartate transaminase (AST)

increased 25 <1 <1 7 0 0Alanine transaminase (ALT)

increased 21 1 0 4 0 0Bilirubin increased 3 <1 <1 2 0 0

CTCAE Version 3.0aIncludes reports of anemia, leukopenia, lymphopenia, neutropenia, pancyto penia, thrombocytopenia.

Information from further clinical trialsIn clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, includingfatal outcomes.

7 DRUG INTERACTIONSEverolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug effluxpump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.7.1 Agents that may Increase Everolimus Blood ConcentrationsCYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone therewere significant increases in everolimus exposure when AFINITOR was coadministered with:• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and

15.0-fold, respectively.• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and

4.4-fold, respectively.• verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and

3.5-fold, respectively.Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions(5.5)].Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alterna-tive treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2)in the full prescribing information]7.2 Agents that may Decrease Everolimus Blood ConcentrationsCYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer ofCYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimustreatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers ofCYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP ifalternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpre-dictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].7.3 Agents whose Plasma Concentrations may be Altered by EverolimusStudies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactionsbetween AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and prava -statin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR.

8 USE IN SPECIFIC POPULATIONS8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)]There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based onmechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman.Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than humanexposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if thepatient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard tothe fetus. Women of childbearing potential should be advised to use an effective method of contraceptionwhile receiving AFINITOR and for up to 8 weeks after ending treatment.

In animal reproductive studies, oral administration of everolimus to female rats before mating andthrough organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantationand post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) andretarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetaltoxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommendeddose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oraldose approximately 1.6 times the recommended human dose on a body surface area basis. The effect inrabbits occurred in the presence of maternal toxicities. In a pre- and post-natal development study in rats, animals were dosed from implantation through lacta-tion. At approximately 10% of the recommended human dose based on body surface area, there were noadverse effects on delivery and lactation and there were no signs of maternal tox icity. However, therewas reduced body weight (up to 9% reduction from the control) and slight reduction in survival in off-spring (~5% died or missing). There were no drug-related effects on the developmental parameters(morphological development, motor activity, learning, or fertility assessment) in the offspring.Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2).8.3 Nursing MothersIt is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passedinto the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because manydrugs are excreted in human milk and because of the potential for serious adverse reactions in nursinginfants from everolimus, a decision should be made whether to discontinue nursing or to discontinue thedrug, taking into account the importance of the drug to the mother.8.4 Pediatric UseThe safety and effectiveness in pediatric patients have not been established.8.5 Geriatric UseIn the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percentwere 75 and over. No overall differences in safety or effectiveness were observed between these subjectsand younger subjects, and other reported clinical experience has not identified differences in responsesbetween the elderly and younger patients, but greater sensitivity of some older individuals cannot beruled out [see Clinical Pharmacology (12.3) in the full prescribing information].No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full pre-scribing information].8.6 Renal ImpairmentNo clinical studies were conducted with AFINITOR in patients with decreased renal function. Renalimpairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recom -mended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].8.7 Hepatic ImpairmentFor patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mgdaily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions(5.6) and Clinical Pharmacology (12.3) in the full prescribing information].The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in thispatient population is not recommended [see Warnings and Precautions (5.6)].

10 OVERDOSAGEIn animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity wereobserved in either mice or rats given single oral doses of 2000 mg/kg (limit test).Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have beenadministered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGEStore AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F).[See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture.Keep this and all drugs out of the reach of children.Procedures for proper handling and disposal of anticancer drugs should be considered. Several guide-lines on this subject have been published.AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

Revised: June 2010 T2010-56

Manufactured by:Novartis Pharma Stein AGStein, Switzerland

Distributed by:Novartis Pharmaceuticals CorporationEast Hanover, New Jersey 07936

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PAGE 36 The ASCO Post | APRIL 15, 2011

Perspective

Unrelieved cancer pain can render a patient bedbound, leading to

depression, fear, and suicidal ideation. Along with physical distress, severe pain is associated with existential suf-fering, a complex tormentor of patients with cancer and their families.

Studies show that most patients with advanced cancer in the United States suffer significant pain, and a majority of patients with any stage of disease report undertreated pain. Since we have the clinical tools to re-lieve cancer-related pain in most cases, it begs the question: Why does this problem persist on such a large scale?

Standardized ProceduresThe U.S. health-care system is vast

and highly fractionated, making uni-form adoption of pain guidelines a steep uphill battle. Diane E. Meier, MD, FACP, Director, Hertzberg Pal-liative Care Institute, Mount Sinai School of Medicine, New York, sug-gests that we implement standard op-erating procedures. “There are hospital discharge procedures, such as adminis-tration of pneumonia vaccine, that are done routinely for all patients,” said Dr. Meier. “Pain control procedures need to be standardized as well.”

Dr. Meier acknowledged that hos-pital and office practice doctors are stretched thin, but treating pain should be an established priority. “If a pa-tient has severe pain, there should be a mandatory protocol that assures that someone on the staff—a nurse prac-titioner or physician assistant—with pain expertise begin a pain regimen while simultaneously reaching out to the attending physician. Untreated pain should be a never-event,” stressed Dr. Meier.

Infrastructure Needed“We currently lack sufficient mo-

tivation to implement standards of operational pain control by empower-ing all health professionals to perform at their highest level of training,” said Dr. Meier. “We need an infrastructure to help hospitals apply their existing professional resources, such as well-trained nursing staff, to the relief of physical and other forms of suffering,” said Dr. Meier.

A step in that direction is the ac-creditation initiative by the American College of Surgeons Commission on

Cancer. Moving forward, to receive the Commission on Cancer’s accredi-tation, community cancer centers will need to demonstrate that they offer palliative care services to their patients.

“There are several ways for centers to approach this, but the important thing is that offering palliative care services to patients with cancer under active treatment will no longer be optional,” concluded Dr. Meier.

Redirection of PrioritiesRussell K. Portenoy, MD, Chair-

man, Department of Pain Medicine and Palliative Care, Beth Israel Medi-

cal Center, New York, told The ASCO Post that a recent survey he and his colleagues conducted, found that pain management education and training in medical schools and residency was rated as very poor.

A nationally regarded expert in pal-liative medicine, Dr. Portenoy opined, “We accept that good pain manage-ment is a best practice and that oncol-ogists are committed to it. So we have to ask the broader question: Why isn’t pain management given priority in ed-ucational programming?”

He offered a partial explanation: “Since the 1980s, the pace of advances in oncology has been extremely rapid, and the challenge of keeping up with advances in disease management has taken priority over pain and symptom control.”

There are a host of comorbid issues that complicate pain management. For instance, treating patients with cancer who have a history of substance abuse presents special challenges. Again, Dr.

Portenoy stressed education. “Basic knowledge of ‘Universal Precautions’ [in pain medicine], empowers on-cologists to treat patients who have substance abuse disorders. But most oncologists have never been taught the principles of risk management, and the result may be undertreated pain,” Dr. Portenoy said.

According to Dr. Portenoy, a simple national mandate would be the best

step forward in addressing undertreat-ed cancer pain. “In the United States, we need to refocus our attention on pain management as a best practice in oncology, which would be associated with skills-building in opioid-based pharmacotherapy directed at both op-

timizing analgesic outcomes and mini-mizing risk.”

Ethical BarriersIn some cases, pain is not relieved

because of ethical concerns. This may happen, for example, near the end of life, when opioid use is accompanied by the specter of unintentionally has-tened death. When pain is refractory to routine strategies, the ethically chal-lenging approach of palliative sedation may be considered. Palliative sedation is an accepted therapy, but mispercep-tions arise when clinicians do not un-derstand its ethical framework or stan-dards of care, and mistakenly perceive the approach as “slow euthanasia.”

Dr. Portenoy explained that on-cologists who offer sedation must ap-preciate both the medical and ethical implications of this intervention. “The key principle is the ‘double effect.’ Al-though sedation carries a risk of an ear-lier death, there is a clear line between sedation and physician-hastened death. The intent is to relieve suffering, and the doses of medication are appro-priate for achieving that outcome,” said Dr. Portenoy, adding that the impera-tive to relieve symptoms when other medical strategies fail justifies the ap-proach at the end of life.

The Patient Perception BarrierSpeaking with The ASCO Post, pal-

liative care expert Kathleen M. Foley, MD, Memorial Sloan-Kettering Can-cer Center, said that patient percep-tion about cancer pain creates its own barrier to care. “An ongoing obstacle we’re seeing more of is the belief by patients with cancer that pain is an unavoidable part of their disease. They’re tied into the treatment/cure paradigm and don’t seek out separate therapy for pain.”

Despite Awareness, Undertreated Cancer Pain PersistsBy Ronald Piana

Diane E. Meier, MD, FACP Russell K. Portenoy, MD Sloan Karver, MD

There are persistent negative myths about opioids that characterize the unexamined and sort of primal belief system within the medical community that greatly adds to unnecessary suffering among our patients.

—Diane E. Meier, MD, FACP

Pain Management

■ Neglect of cancer pain is a societal problem fueled by lack of knowledge and misperceptions.

■ Medical schools need to provide adequate pain management education.

■ Hospital pain management should follow a standardized protocol.

■ Better communication is needed with patients about pain treatment.

■ Community clinics need to implement pain assessment tools.

■ Untreated pain should be a never-event.

■ Palliative sedation is a “best practice” care option in refractory pain.

Undertreatment of Cancer Pain

ASCOPost.com | APRIL 15, 2011 PAGE 37

Perspective

Dr. Foley said that reporting in the lay media about widespread abuse of opioids further exacerbates the patient perception barrier. “Patients with can-cer, many of whom are older, read sto-ries about overdose and addiction, and it scares them. It becomes one more reason for patients to shy away from proper pain control.”

Tools HelpDr. Foley said that a way to help

busy community doctors manage pain is by giving them tools such as patient-reported outcomes or enlist-ing physician extenders. She noted a study done in the 1990s, looking at how oncologists gauged their patients’ pain level. “The investigators found that if evaluation triggers and a nurse expert were put into the scenario, pain management scores improved mark-edly. That was because the oncologists were getting better quality information from their patients about their pain. It allowed them to personalize the pain management according to patient-spe-cific needs,” said Dr. Foley.

Barriers to proper cancer pain con-trol are multileveled, a phenomenon that is heavily influenced by the larger sociocultural perspective. “Over the past decade, we’ve embraced an idea that everyone is at risk for abuse, in some cases swinging the care pendu-lum in favor of caution over aggres-sive pain control. This is a big change in how we think about caring for pain in the cancer population,” stressed Dr. Foley.

Breakthrough Pain Breakthrough pain, a spike in oth-

erwise well-controlled persistent pain, presents a tricky clinical challenge for doctors treating patients with cancer living at home. Sloan Karver, MD, palliative care physician at the Mof-fitt Cancer Center, South Florida, said that many community oncologists are hesitant about prescribing the increas-ingly higher doses of potentially lethal drugs necessary to control pain in ad-

vanced disease, “whereas palliative care specialists are comfortable pre-scribing higher doses of opioids,” said Dr. Karver.

“The goal for patients is not to “chase” the pain but to keep ahead of the pain curve. Patients need to have a better understanding of their pain-control needs, not look at the clock and wait for a special time frame be-fore taking their pain meds,” said Dr. Karver.

As Dr. Karver pointed out, break-through pain remains undertreated due to a number of doctor/patient-driven factors. “By providing educa-tion to health-care providers, patients, and family caregivers, steps can be taken to ensure that persistent cancer pain and cancer breakthrough pain are properly treated,” said Dr. Karver.

ConclusionThe oncology community has iden-

tified undertreated cancer pain as an endemic problem. We have the phar-macotherapy tools to manage cancer pain; now we need consensus on how to best address this problem on a na-tional scale. ■

Financial Disclosures: Dr. Foley, Dr. Meier, Dr. Portenoy, and Dr. Karver reported no potential conflicts of interest.

Universal Precautions in Pain Medicine

Universal precautions in pain medicine include 10

steps developed to assist in man-aging patients with chronic pain. The goals are to improve

patient care, remove stigma, and contain risk. ■

Gourlay D, Heit HA, Almahrezi A. Universal precautions in pain medicine: A rational approach to the treatment of chronic pain. Pain Med 6:107-112, 2005.

SEE PAGE 51

Lessons Learned

Going through the dying process is, of course, difficult for the

patient, whose loss is total and per-manent. But watching that process is also hard on family members and friends—as well as on the treating oncologist. Engaging in simple acts of compassion can go a long way in facili-tating the grieving process, even in the dying patient.

Showing CompassionIn my experience, one of the kind-

est things an oncologist can say to a pa-tient faced with a terminal illness is, “I can’t imagine what this is like for you.” By showing that kind of compassion, we give the patient permission to be honest about what he is going through. Dying patients know that it’s difficult for loved ones—and even doctors—to hear the painful truth about their fears and anxieties, and that puts a lot of pressure on the patient. It can be very lonely for the patient if he doesn’t have the opportunity to express his true feelings, plus it takes more energy to have to sidestep the issue—energy the patient doesn’t have to spare.

Although each person will go through the grieving process different-ly, there are things we can do to make everyone, including the patient, feel safe about expressing his feelings. I’ve found it helpful to encourage patients and their family members to say what-ever it is they are feeling, including fear, anger, relief, rage, hopelessness, or guilt, and to provide a safe environ-ment that allows patients and loved

ones to freely express their truth with-out analysis, judgment, or criticism. It took me a long time to learn the im-portance of just listening to what my patients had to say, giving them a kind touch, leaning forward, and looking them in the eye when we spoke, so they could see that I understood and that whatever they were feeling, it was okay.

Encouraging Honest DialogueFor 4 years, a very close friend of

mine has had to endure heavy doses of chemotherapy. Every day is a strug-gle for him to pull himself together to get to work and keep his family life the same as it was before he was diagnosed with cancer. A fastidious dresser, he always makes sure his shirt is pressed, his pants neatly pleated, and his shoes shined.

To the outside world, he looks like a healthy man. He says he has no choice but “to make every day a yes.” The problem is, he can’t find the right words to express exactly how he’s feeling, and no one in his family has the skills to talk about his illness in an open way. As a result, my friend feels isolated, and his family is angry and hurt.

Encouraging honest dialogue between patients and their family members starts with our own open dialogue with our patients. Answering patients’ and family members’ ques-tions directly gives them permission to express their feelings, whatever they may be, and allows for emotional heal-ing, for both patient and family—and, hopefully, a more peaceful death for the patient. ■Dr. Winokur is a retired oncologist who lives with his family in Singer Island, Florida. He is the author of Grandfathered In: A Memoir, a book about finding balance between having a career in medicine and having a family.

Facilitating the Grieving ProcessBy Stanley Winokur, MD

The ASCO Post Wants to Hear from You

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

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.”

ASCOPost.com | APRIL 15, 2011 PAGE 39

Quality of Care

What are the most effective and humane ways to plan cancer

treatment, and how can caregivers and patients make these decisions together? These questions have been plaguing oncology since the begin-ning of modern care. Although sug-gested answers abound, implementa-tion has not always been successful.

This dilemma was the focus of a 2-day workshop, “Patient-centered Cancer Treatment Planning: Improv-ing the Quality of Oncology Care,” sponsored by the National Coalition of Cancer Survivorship (NCCS) and the Institute of Medicine (IOM) National Cancer Policy Forum. The workshop was held in Washington, DC, on February 28 and March 1.

Dramatic Changes NeededEllen Stovall, NCCS Senior

Health Policy Advisor, said in her in-troduction to the workshop that al-though comparative effectiveness re-search remains important, now more than ever, we need dramatic changes in the way health care is financed and provided.

Describing what it was like to be diagnosed with chronic myelog-enous leukemia at age 28, Richard Boyajian, RN, Clinical Director of the Adult Survivorship Program,

Dana-Farber Cancer Institute, said, “Cancer care is a two-way, poorly lit street. We need to teach both patients and caregivers how to navi-gate it.”

Mr. Boyajian spoke about his own allogeneic transplant and the many ways in which making decisions is difficult, not the least of which is the fact that patients often don’t hear much of what physicians tell them. “I remember nothing of the first few hours after diagnosis—and very lit-tle of the next few days,” he said.

“Evidence-based practice is criti-cal, of course, but we really need to talk to patients about what is impor-tant to them—and what’s not—as they decide what to do.”

Standardized SurveysCarolyn Clancy, Director of the

Agency for Healthcare Research and Quality (AHRQ), said, “Not only do we do a poor job of health-care commu-nication, but the rate of health illiteracy in this country is high. Both need to be improved.”

Every speaker at the workshop agreed and concurred with the need for long-term research about the consequences of health-care choices. “The only way to find out if care is patient-centered is to ask the patients themselves.”

To this end, AHRQ has embarked on a program called Consumer Assess-ment of Healthcare Providers and Sys-tems (CAHPS) to develop a set of stan-dardized surveys that ask patients to evaluate their experiences with health care. The surveys cover topics such as providers’ communication skills and service accessibility. They are designed to identify patients’ needs for informa-tion by means of scientific testing, data comparison, and other methods.

“CAHPS is one of our significant accomplishments, but by itself it can-not improve health literacy or the abil-ity of providers to communicate with patients and their families. That has to be a shared effort,” said Ms. Clancy.

Difficult Discussions Thomas J. Smith, MD, Professor of

Palliative Care Research, and Medical Director of the Thomas Palliative Care Unit at Virginia Commonwealth Uni-versity-Massey Cancer Center, said that only one-third of patients who

began cancer care with do-not-resus-citate preferences had also discussed hospice with their physician, which he said is a missed opportunity for health-care providers and patients alike. He noted that physicians often find these discussions difficult and time-con-suming. Dr. Smith pointed out that pa-tients who have these difficult discus-sions live just as long (or longer), have less depression, are much more likely to use hospice and be at home, are far less likely to die in the ICU, and their caregivers fare better.

J. Russell Hoverman, MD, PhD, Vice President of Quality Programs, Texas Oncology and Medical Director of Managed Care, US Oncology, had his own take on the obstacles to opti-mal cancer care, grouping them into 5 general categories: delivery (right treatment, safely, in a timely fashion); coverage (including direct costs); in-direct costs (lost work time, child care, travel, etc); personal issues (dignity,

Key Elements in Treatment Planning

A written treatment plan is critical to the success of cancer care. Key elements of such a plan include:

■ Tissue diagnosis and stage ■ Initial treatment and duration ■ Expected toxicities and long-term effects ■ Responsibility for specific aspects of care ■ Management of psychosocial, vocational, and financial concerns ■ Advance directives ■

Barriers to Patient Centricity

W hen people get cancer, they are then called patients, which is perhaps one of the prob-

lems. It is as if they cease being “regular” people who happen to have a dread disease and turn into subjects of the oncology endeavor who are expect-ed to demonstrate patience, forbearance, and grati-tude. Patients, of course, are the entire reason for care, but are they really at its center?

According to Patricia A. Ganz, MD, the lack of focus on patients is a result of cancer care being complex, multimodal, multidisciplinary, toxic, ex-

pensive, and often poorly coordinated. What’s more, 80% of it is delivered in the community, not in comprehensive cancer centers, and much of it occurs in isolation from patients’ primary caregivers.

Barriers to patient centricity enumerated by Dr. Ganz and other speakers include: ■ Challenges surrounding communication: complexity of the information in-

volved, limitations of heath literacy, patient distress that diminishes com-prehension, and the pressure to make a treatment decision

■ Structural limitations: decentralization and fragmentation of the care system, financial problems of oncology practices (which average three physicians with limited space and treatment facilities), surgical care provided by gen-eralists rather than cancer specialists, lack of integrated electronic health re-cords, few patient navigators, and almost no consultation planning

■ Costs and challenges to patient and family: the time that cancer care takes, time and income lost from work, unreimbursed financial expenses, and lack of knowledge about treatment goals, toxicities, and likely outcomes ■

Patient-centered Treatment Planning Urged to Improve Quality of Cancer CareIOM/NCCS workshop examines the need for patient perspective in decision-making processBy Margot Fromer

continued on page 40

Communication

Carolyn Clancy Thomas J. Smith, MD J. Russell Hoverman, MD, PhD

Patricia A. Ganz, MD

PAGE 40 The ASCO Post | APRIL 15, 2011

Quality of Care

control, family burden, denial); and access. Of these, physician efforts to improve quality will mostly impact this first category.

Even just considering this first cat-egory, physicians have their own chal-lenges, Dr. Hoverman said. “The aver-age medical oncology practice is 3 to 4 physicians. Most practices are single specialty. From 2007 to 2008 alone, oncology practices suffered a 25% drop in practice income. At the same time, medical oncologists are seeing more new patients (350+) per year, and it’s difficult to communicate elec-tronically with other specialists, labo-ratories, radiologists, and pathologists. Even within practices, software pro-grams often don’t talk to each other.”

Best PracticesSpeaking at the IOM/NCCS

workshop, Patricia A. Ganz, MD, Director of the Division of Cancer Prevention and Control Research, UCLA Jonsson Comprehensive Can-cer Center, said there is an ideal way to provide cancer care: in a multi-disciplinary team whose members work in close proximity to each other, whose members review the relevant radiology and pathology from the patient, discuss findings and options with patients and family, and create a verbal and written treatment plan that is communicated to the patient and all the caregivers.

A written treatment plan was one of the central ideas of the workshop and was unanimously believed to be critical to the success of cancer care. Alas, it is usually not in evidence.

Key elements of such a plan include tissue diagnosis and stage; initial treat-ment and duration; expected toxicities and long-term effects; responsibility for specific aspects of care; management of psychosocial, vocational, and financial concerns; and advance directives.

Such plans are not mandated, but they should be, said Dr. Ganz. “Some-one has to be ultimately accountable.”

Limited ResearchAnthony Back, MD, Director,

Program in Cancer Communication, Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, said that research on treatment plan-ning is limited because of inadequate outcome measures such as satisfac-tion with care, regrets about deci-sions, and inadequate understanding

of what goes into a decision.“Breaking bad news is part of oncol-

ogy practice, but it stresses disclosure as an end rather than the beginning of a dialogue. Recent studies demon-strate the value of devising a plan, and patients want guidance, so we have to teach physicians how to do it,” he said.

“This may be a new role for them—

discussing values, assumptions, qual-ity of life—and there is little research that tells us how,” Dr. Back continued. “But we must improve communica-tion, and we have to invite patients’ participation.” ■

Financial Disclosure: The speakers at the NCCS/IOM workshop reported no potential conflicts of interest.

Patient-centered Treatmentcontinued from page 39

Coverage of the NCCS/IOM work-shop continues in the next issue of The ASCO Post, highlighting ses-sions that addressed theory and re-search in patient-centered care, dif-ficulties underlying patient-informed decisions, and the challenge of discus-sions about death.

729US10AB13506_TrimSize: 7.625”x10.5” 729US10AB13506_TrimSize: 7.625”x10.5”

Start With SPRYCEL (dasatinib) for Superior Response

Tablet not actual size.

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

vs Imatinib in 1st Line

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

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 confi rmed complete cytogenetic response (CCyR)† by 12 months

• 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 signifi cantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confi rmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1

• Among responders, median time to confi rmed 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; fl uid 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, fl uid retention events (pleural effusion, superfi cial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash

• Please see detailed Important Safety Information on adjacent pages

IndicationSPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome-positive 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.

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Major Molecular Response (MMR)‡ at Any Time1

P<0.0001§

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

Start With Convenient Once-Daily Dosing

1 pill100 mg1 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

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

SPRYCEL Can Be Taken Either With or Without Food1

SPRYCEL—the only treatment for adults with newly diagnosed Ph+ CML in chronic phase with:

• No fasting requirements

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FASTING

*Stratifi ed by Hasford risk score.2

†Confi rmed CCyR is defi ned as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1

‡ MMR (at any time) was defi ned 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 signifi cance at a pre-defi ned nominal level of signifi cance.1

729US10AB13506_1stLineCore_7.625x10.5.indd 1-2 2/11/11 4:18 PM

ASCOPost.com | APRIL 15, 2011 PAGE 41

FDA Update

Novocure announced that the FDA Neurological Devices Advisory

Panel of the Medical Devices Advisory Committee voted (7 yes; 3 no; 2 ab-stain) that for patients with supraten-

torial glioblastoma multiforme tumors that recur after maximal surgical and radiation treatments, there is reasonable assurance that the benefits of the Novo-TTF-100A system—a portable, inves-

tigational device for cancer treatment using very low-intensity, alternating electric fields to the tumor site through the scalp—outweigh its risks when ad-ministered as a monotherapy in place of

standard medical therapy.The committee’s recommenda-

tion followed a review of data from the EF-11 trial, a randomized phase III

FDA Advisory Committee Finds Data Support Safety, Effectiveness of NovoTTF-100A System

continued on page 42

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Start With SPRYCEL (dasatinib) for Superior Response

Tablet not actual size.

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

vs Imatinib in 1st Line

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

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 confi rmed complete cytogenetic response (CCyR)† by 12 months

• 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 signifi cantly higher rate of patients on SPRYCEL (77%) (95% CI, 71-82) achieved confi rmed CCyR by 12 months vs 66% (95% CI, 60-72) of patients on imatinib (P=0.007§)1

• Among responders, median time to confi rmed 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; fl uid 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, fl uid retention events (pleural effusion, superfi cial localized edema, generalized edema), diarrhea, headache, musculoskeletal pain, and rash

• Please see detailed Important Safety Information on adjacent pages

IndicationSPRYCEL® (dasatinib) is indicated for the treatment of adults with newly diagnosed Philadelphia chromosome-positive 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.

MM

R at

Any

Tim

e

34%

52%

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

SPRYCEL (95% CI, 46-58)

Imatinib (95% CI, 28-40)

0 10 20 30 40 50 60 70 80 90 100 MMR (%)

Major Molecular Response (MMR)‡ at Any Time1

P<0.0001§

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

Start With Convenient Once-Daily Dosing

1 pill100 mg1 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

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

SPRYCEL Can Be Taken Either With or Without Food1

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

FASTING

*Stratifi ed by Hasford risk score.2

†Confi rmed CCyR is defi ned as a CCyR (0% Ph+ metaphases) noted on 2 consecutive assessments at least 28 days apart.1

‡ MMR (at any time) was defi ned 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 signifi cance at a pre-defi ned nominal level of signifi cance.1

729US10AB13506_1stLineCore_7.625x10.5.indd 1-2 2/11/11 4:18 PM

PAGE 42 The ASCO Post | APRIL 15, 2011

FDA Update

study in 237 patients with glioblastoma tumors that had recurred or progressed despite previous treatments. The trial demonstrated that patients treated with the NovoTTF device alone achieved a comparable overall survival time to patients treated with the physician’s

choice of the best chemotherapy. Pa-tients treated with the device also had higher rates of progression-free survival at 6 months (21% vs 15%) and higher tumor response rates (14% vs 10%) compared to chemotherapy-treated patients in the trial. NovoTTF-treated patients reported better quality-of-life scores and fewer side effects. The No-

voTTF’s most commonly reported side effect was a mild-to-moderate rash be-neath the electrodes.

Indian Company Receives U.S. Orphan Drug Designation

The Hyderabad, India–based NAT-CO Pharma’s novel anticancer drug (NRC-AN-019) has received Orphan

Drug designation from the FDA for three indications: glioma, pancreatic cancer, and chronic myelogenous leu-kemia. It is the first time that an Indian company’s drug has been designated an Orphan Drug by the U.S. FDA for three indications.

NATCO is close to completing the phase I clinical trial of NRC-AN-019 in

NovoTTF-100A Systemcontinued from page 41

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Important Safety Information

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.

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.

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

© 2011 Bristol-Myers Squibb 729US10AB13506 1/11

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ASCOPost.com | APRIL 15, 2011 PAGE 43

FDA Update

India. The company has plans for fur-ther clinical trials in the United States and other countries, in addition to In-dia.

FDA, EMA Announce Parallel Assessment of New Drugs

The FDA and the European Medi-cines Agency (EMA) have launched

a pilot program that will allow paral-lel evaluation of relevant development and manufacturing data components, known as quality by design (QbD), of new drug marketing applications that are submitted to both agencies.

The parallel evaluation within this voluntary pilot program means that reviewers from both agencies will sep-

arately assess the quality/chemistry, manufacturing, and control section of new drug applications (NDAs) submit-ted to the FDA and marketing authori-zation applications (MAAs) submitted to the EMA. However, there will be regular communication and consulta-tion between European regulators and their U.S. colleagues throughout the

review process relevant to QbD aspects of the applications. QbD in pharmaceu-ticals involves developing formulations and processes to help ensure product manufacturing quality. This pilot pro-gram began out of concern that certain international guidelines were being in-terpreted differently in Europe and the United States. ■

729US10AB13506_TrimSize: 7.625”x10.5” 729US10AB13506_TrimSize: 7.625”x10.5”

Important Safety Information

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.

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.

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

© 2011 Bristol-Myers Squibb 729US10AB13506 1/11

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PAGE 44 The ASCO Post | APRIL 15, 2011

Appointments

The Society of Surgi-cal Oncology (SSO)

has elected James S. Economou, MD, as 2011–2012 President of the Soci-ety, succeeding Mitchell C.

Posner, MD. Dr. Econo-mou is Vice Chancellor for Research, the Beau-mont Professor of Sur-gery and Chief, Division of Surgical Oncology at

the University of California, Los Angeles. The Society has also elected Monica

Morrow, MD, as its President-Elect, and V. Suzanne Klimberg, MD, as Vice President. Dr. Morrow is Chief, Breast Service, Department of Surgery, and the

Anne Burnett Windfohr Chair of Clini-cal Oncology at Memorial Sloan-Ketter-ing Cancer Center, New York. Dr. Klim-berg is the Muriel Balsam Kohn Chair in Breast Surgical Oncology at the Univer-sity of Arkansas for Medical Sciences. ■

Society of Surgical Oncology Elects President and Officers for 2011–2012 TermSurgical Oncology

James S. Economou, MD

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SPRYCEL® (dasatinib) Tablet for Oral Use

Brief Summary of Prescribing Information. For complete prescribing information consult officialpackage insert. INDICATIONS AND USAGESPRYCEL® (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 responserates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further datawill be required to determine long-term outcome.

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

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

CONTRAINDICATIONS: None.WARNINGS AND PRECAUTIONSMyelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombo-cytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CMLor Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intoleranceto prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequentlyin 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 clinicallyindicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCELtemporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and AdverseReactions]. Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib causedplatelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, includingfatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, includingfatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Othercases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severethrombocytopenia. Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibitplatelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidalanti-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 plateletfunction or anticoagulants. Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention wasreported 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 ofpleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion mayrequire thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive caremeasures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention eventswere 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 ventricularrepolarization (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 maximummean 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 includepatients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients takinganti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-doseanthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adversereactions 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. Monitorpatients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Use in PregnancyPregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. Innonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses ofdasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. Thereare no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in SpecificPopulations]. ADVERSE REACTIONSThe 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 theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newlydiagnosed 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 medianaverage daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 yearsfollow-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 medianduration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The medianduration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) foraccelerated 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 diagnosedchronic 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 adversereaction 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 resistanceor intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reactionwas 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 chronicphase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema,generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31patients (see Table 1). The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance toprior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skinrash, 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 mostfrequently 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/cardiacdysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reportedin at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML andTable 2 for CML patients with resistance or intolerance to prior imatinib therapy.

Laboratory AbnormalitiesMyelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronicphase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratoryvalues as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption orreduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phaseCML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions].

Preferred Term

All Grades Grade 3/4SPRYCEL (dasatinib)

(n=258)Imatinib(n=258)

SPRYCEL(n=258)

Imatinib(n=258)

Percent (%) of PatientsFluid retention 23 43 1 1

Pleural effusion 12 0 <1 0Superficial localized edema 10 36 0 <1Generalized edema 3 7 0 0Congestive heart failure/

cardiac dysfunctiona2 1 <1 <1

Pericardial effusion 2 <1 <1 0Pulmonary hypertension 1 0 0 0Pulmonary edema <1 0 0 0

Diarrhea 18 19 <1 1Headache 12 10 0 0Musculoskeletal pain 12 16 0 <1Rashb 11 17 0 1Nausea 9 21 0 0Fatigue 8 11 <1 0Myalgia 6 12 0 0Hemorrhagec 6 5 1 1

Gastrointestinal bleeding 2 <1 1 0Other bleedingd 5 5 0 1CNS bleeding 0 <1 0 <1

Vomiting 5 10 0 0Muscle inflammation 4 19 0 <1a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejectionfraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rashgeneralized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reactionof 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 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed ChronicPhase CML

Table 2: Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy

Preferred Term

100 mg Once Daily 140 mg Once Daily

Chronic(n=165)

Accelerated(n=157)

MyeloidBlast

(n=74)

LymphoidBlast

(n=33) All

GradesGrade

3/4All

GradesGrade

3/4All

GradesGrade

3/4All

GradesGrade

3/4Percent (%) of Patients

Fluid Retention 34 4 35 8 34 7 21 6Superficial

localized edema18 0 18 1 14 0 3 0

Pleural effusion 18 2 21 7 20 7 21 6Generalized edema 3 0 1 0 3 0 0 0Pericardial effusion 2 1 3 1 0 0 0 0Congestive heart failure/

cardiac dysfunctiona0 0 0 0 4 0 0 0

Pulmonary edema 0 0 1 0 4 3 0 0Headache 33 1 27 1 18 1 15 3Diarrhea 27 2 31 3 20 5 18 0Fatigue 24 2 19 2 20 1 9 3Dyspnea 20 2 20 3 15 3 3 3Musculoskeletal pain 19 2 11 0 8 1 0 0Nausea 18 1 19 1 23 1 21 3Skin rashb 17 2 15 0 16 1 21 0Myalgia 13 0 7 1 7 1 3 0Arthralgia 12 1 10 0 5 1 0 0Infection (including

bacterial, viral, fungal, and non-specified)

12 1 10 6 14 7 9 0

Abdominal pain 12 1 6 0 8 3 3 0Hemorrhage 11 1 26 8 19 9 24 9

Gastrointestinal bleeding 2 1 8 6 9 7 9 3CNS bleeding 0 0 1 1 0 0 3 3

Vomiting 7 1 11 1 12 0 15 0Pyrexia 5 1 11 2 18 3 6 0Febrile neutropenia 1 1 4 4 12 12 12 12a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythemamultiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rashfollicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skinirritation, urticaria vesiculosa, and rash vesicular.

Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, andhypophosphatemia were reported in patients with all phases of CML but were reported with an increasedfrequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin wereusually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia duringthe 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 laboratoryparameters.

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

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 oftreatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar tothose with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retentionevents such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such asdiarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), anddyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions includedpleural 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 of1%–<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 SubcutaneousTissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (includingeczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acutefebrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory,Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonaryhypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. NervousSystem 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% – muscularweakness; 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 respiratorytract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fataloutcomes). 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 (includingventricular 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 Systemand Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and ProceduralComplications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% –vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and UrinaryDisorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, andUnspecified: 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 (includingpulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitiallung disease. DRUG INTERACTIONSDrugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mgSPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax andAUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 mayincrease exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, closemonitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of apotent 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 continuousevening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinibwere decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential shouldbe considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL shouldbe 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 healthysubjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mgdose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjectsconcomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmaxwere observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy isneeded, 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 antagonistsor proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reducedthe AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administrationof a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reducedthe AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or protonpump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hoursafter the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors inpatients 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 AUCof simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin wasadministered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known tohave a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl,pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should beadministered 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 noadequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should beadvised 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 tothe fetus. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic dosesof dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In bothrats 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-foldthe human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations atmultiple 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 areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromSPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount 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 beenestablished. Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age andover and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL withresistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75years of age and over. No differences in efficacy were observed between older and younger patients. Comparedto 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 evaluatedin 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, thedose 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) inFull Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepaticimpairment. Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renalfunction. Less than 4% of dasatinib and its metabolites are excreted via the kidney. OVERDOSAGEExperience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mgper 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 AdverseReactions], patients who ingested more than the recommended dosage should be closely monitored formyelosuppression and given appropriate supportive treatment.Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricularnecrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. Therewas 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

1284903 DS-B0001A-10-10 Rev October 2010

Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed ChronicPhase CML

SPRYCEL(n=258)

Imatinib(n=258)

Percent (%) of PatientsHematology Parameters

Neutropenia 22 20Thrombocytopenia 19 10Anemia 11 7

Biochemistry Parameters Hypophosphatemia 5 24Hypokalemia 0 2Hypocalcemia 3 2Elevated SGPT (ALT) <1 1Elevated SGOT (AST) <1 1Elevated Bilirubin 1 0Elevated Creatinine <1 1

CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/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).

Table 4: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance orIntolerance to Prior Imatinib Therapy

Chronic Phase CML Advanced Phase CML

100 mgOnce Daily

(n=165)

140 mg Once DailyAccelerated

Phase(n=157)

MyeloidBlast Phase

(n=74)

LymphoidBlast Phase

(n=33)Percent (%) of Patients

Hematology ParametersNeutropenia 36 58 77 79Thrombocytopenia 23 63 78 85Anemia 13 47 74 52

Biochemistry ParametersHypophosphatemia 10 13 12 18Hypokalemia 2 7 11 15Hypocalcemia <1 4 9 12Elevated SGPT (ALT) 0 2 5 3Elevated SGOT (AST) <1 0 4 3Elevated Bilirubin <1 1 3 6Elevated 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 ×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, Grade4 <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).

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ASCOPost.com | APRIL 15, 2011 PAGE 45

News

The members of the American As-sociation for Cancer Research have

elected Frank McCormick, PhD, DSc (hon), as their President-elect. McCor-mick is the Director of the University of California, San Francisco (UCSF) Helen Diller Family Comprehensive

Cancer Center. He holds the E. Dixon Heise Distinguished Professorship in Oncology and the David A. Wood Dis-tinguished Professorship of Tumor Bi-ology and Cancer Research at UCSF. Additionally, he is the Associate Dean of the UCSF School of Medicine and a

Distinguished Professor in Residence in the Department of Microbiology and Immunology as well as in the Depart-ment of Biochemistry and Biophysics.

“I am thrilled and honored to serve as President-Elect,” said Dr. McCormick. “The AACR is a remarkable organiza-

tion that continues to grow as the field evolves. We are poised to make incred-ible breakthroughs in the coming years. I have greatly enjoyed working with the AACR in the past, and look forward to the opportunity of working with the membership and staff to help lead the AACR as it moves from strength to strength.”

Dr. McCormick officially became President-elect at the AACR 102nd An-nual Meeting.

At that meeting, Judy E. Garber, MD, MPH, was sworn in as President of the AACR. Dr. Garber is Director of the Center for Cancer Genetics and Pre-vention at the Dana-Farber Cancer Insti-tute, Associate Professor of Medicine at Harvard Medical School, and Associate Physician of Medicine and Attending Physician of Medical Service at Brigham and Women’s Hospital.

Dr. Garber succeeded Elizabeth H. Blackburn, PhD, Nobel Laureate and the Morris Herzstein Professor of Biol-ogy and Physiology in the Department of Biochemistry and Biophysics at Uni-versity of California, San Francisco. Dr. Blackburn served with distinction as AACR President for the 2010 to 2011 term and has assumed the role of Past-President. ■

AACR Officers Assume New Roles at Annual MeetingLeadership

Judy E. Garber, MD, MPH

Frank McCormick, PhD, DSc (hon)

729US10AB13506_TrimSize: 7.5”x10” Spread: 15”x10” 729US10AB13506_TrimSize: 7.5”x10” Spread: 15”x10”

SPRYCEL® (dasatinib) Tablet for Oral Use

Brief Summary of Prescribing Information. For complete prescribing information consult officialpackage insert. INDICATIONS AND USAGESPRYCEL® (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 responserates [see Clinical Studies (14.1) in Full Prescribing Information]. The trial is ongoing and further datawill be required to determine long-term outcome.

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

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

CONTRAINDICATIONS: None.WARNINGS AND PRECAUTIONSMyelosuppression: Treatment with SPRYCEL is associated with severe (NCI CTC Grade 3 or 4) thrombo-cytopenia, neutropenia, and anemia. Their occurrence is more frequent in patients with advanced phase CMLor Ph+ ALL than in chronic phase CML. In a dose-optimization study in patients with resistance or intoleranceto prior imatinib therapy and chronic phase CML, Grade 3 or 4 myelosuppression was reported less frequentlyin 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 clinicallyindicated. Myelosuppression was generally reversible and usually managed by withholding SPRYCELtemporarily or dose reduction [see Dosage and Administration (2.3) in Full Prescribing Information and AdverseReactions]. Bleeding Related Events: In addition to causing thrombocytopenia in human subjects, dasatinib causedplatelet dysfunction in vitro. In all clinical studies, severe central nervous system (CNS) hemorrhages, includingfatalities, occurred in 1% of patients receiving SPRYCEL. Severe gastrointestinal hemorrhage, includingfatalities, occurred in 4% of patients and generally required treatment interruptions and transfusions. Othercases of severe hemorrhage occurred in 2% of patients. Most bleeding events were associated with severethrombocytopenia. Patients were excluded from participation in initial SPRYCEL clinical studies if they took medications that inhibitplatelet function or anticoagulants. In subsequent trials, the use of anticoagulants, aspirin, and non-steroidalanti-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 plateletfunction or anticoagulants. Fluid Retention: SPRYCEL is associated with fluid retention. In clinical trials, severe fluid retention wasreported 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 ofpleural effusion such as dyspnea or dry cough should be evaluated by chest X-ray. Severe pleural effusion mayrequire thoracentesis and oxygen therapy. Fluid retention events were typically managed by supportive caremeasures that include diuretics or short courses of steroids. In dose-optimization studies, fluid retention eventswere 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 ventricularrepolarization (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 maximummean 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 includepatients with hypokalemia or hypomagnesemia, patients with congenital long QT syndrome, patients takinganti-arrhythmic medicines or other medicinal products that lead to QT prolongation, and cumulative high-doseanthracycline therapy. Correct hypokalemia or hypomagnesemia prior to SPRYCEL administration. Congestive Heart Failure, Left Ventricular Dysfunction, and Myocardial Infarction: Cardiac adversereactions 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. Monitorpatients for signs or symptoms consistent with cardiac dysfunction and treat appropriately. Use in PregnancyPregnancy Category D: SPRYCEL may cause fetal harm when administered to a pregnant woman. Innonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic doses ofdasatinib, embryo-fetal toxicities, including skeletal malformations, were observed in rats and rabbits. Thereare no adequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potentialshould be advised to avoid becoming pregnant while receiving treatment with SPRYCEL [see Use in SpecificPopulations]. ADVERSE REACTIONSThe 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 theclinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may notreflect the rates observed in practice. The data described below reflect exposure to SPRYCEL in clinical studies including 258 patients with newlydiagnosed 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 medianaverage daily dose was 99 mg. In the imatinib resistant or intolerant CML or Ph+ ALL clinical trials, patients had a minimum of 2 yearsfollow-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 medianduration of treatment with SPRYCEL 100 mg once daily was 24 months (range 1–33 months). The medianduration of treatment with SPRYCEL 140 mg once daily was 15 months (range 0.03–36 months) foraccelerated 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 diagnosedchronic 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 adversereaction 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 resistanceor intolerance to prior imatinib therapy and chronic phase CML, the rate of discontinuation for adverse reactionwas 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 chronicphase CML included myelosuppression, fluid retention events (pleural effusion, superficial localized edema,generalized edema), diarrhea, headache, musculoskeletal pain, and rash. Pleural effusions were reported in 31patients (see Table 1). The most frequently reported adverse reactions reported in ≥20% of patients with resistance or intolerance toprior imatinib therapy included myelosuppression, fluid retention events, diarrhea, headache, dyspnea, skinrash, 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 mostfrequently 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/cardiacdysfunction (2%), pericardial effusion (1%), and CNS hemorrhage (1%). Chronic Myeloid Leukemia (CML): Adverse reactions (excluding laboratory abnormalities) that were reportedin at least 10% of patients are shown in Table 1 for newly diagnosed patients with chronic phase CML andTable 2 for CML patients with resistance or intolerance to prior imatinib therapy.

Laboratory AbnormalitiesMyelosuppression was commonly reported in all patient populations. The frequency of Grade 3 or 4neutropenia, thrombocytopenia, and anemia was higher in patients with advanced phase CML than in chronicphase CML (Tables 3 and 4). Myelosuppression was reported in patients with normal baseline laboratoryvalues as well as in patients with pre-existing laboratory abnormalities. In patients who experienced severe myelosuppression, recovery generally occurred following dose interruption orreduction; permanent discontinuation of treatment occurred in 2% of patients with newly diagnosed chronic phaseCML and 5% of patients with resistance or intolerance to prior imatinib therapy [see Warnings and Precautions].

Preferred Term

All Grades Grade 3/4SPRYCEL (dasatinib)

(n=258)Imatinib(n=258)

SPRYCEL(n=258)

Imatinib(n=258)

Percent (%) of PatientsFluid retention 23 43 1 1

Pleural effusion 12 0 <1 0Superficial localized edema 10 36 0 <1Generalized edema 3 7 0 0Congestive heart failure/

cardiac dysfunctiona2 1 <1 <1

Pericardial effusion 2 <1 <1 0Pulmonary hypertension 1 0 0 0Pulmonary edema <1 0 0 0

Diarrhea 18 19 <1 1Headache 12 10 0 0Musculoskeletal pain 12 16 0 <1Rashb 11 17 0 1Nausea 9 21 0 0Fatigue 8 11 <1 0Myalgia 6 12 0 0Hemorrhagec 6 5 1 1

Gastrointestinal bleeding 2 <1 1 0Other bleedingd 5 5 0 1CNS bleeding 0 <1 0 <1

Vomiting 5 10 0 0Muscle inflammation 4 19 0 <1a Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejectionfraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rashgeneralized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reactionof 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 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed ChronicPhase CML

Table 2: Adverse Reactions Reported in ≥10% of Patients with CML Resistant or Intolerant to Prior Imatinib Therapy

Preferred Term

100 mg Once Daily 140 mg Once Daily

Chronic(n=165)

Accelerated(n=157)

MyeloidBlast

(n=74)

LymphoidBlast

(n=33) All

GradesGrade

3/4All

GradesGrade

3/4All

GradesGrade

3/4All

GradesGrade

3/4Percent (%) of Patients

Fluid Retention 34 4 35 8 34 7 21 6Superficial

localized edema18 0 18 1 14 0 3 0

Pleural effusion 18 2 21 7 20 7 21 6Generalized edema 3 0 1 0 3 0 0 0Pericardial effusion 2 1 3 1 0 0 0 0Congestive heart failure/

cardiac dysfunctiona0 0 0 0 4 0 0 0

Pulmonary edema 0 0 1 0 4 3 0 0Headache 33 1 27 1 18 1 15 3Diarrhea 27 2 31 3 20 5 18 0Fatigue 24 2 19 2 20 1 9 3Dyspnea 20 2 20 3 15 3 3 3Musculoskeletal pain 19 2 11 0 8 1 0 0Nausea 18 1 19 1 23 1 21 3Skin rashb 17 2 15 0 16 1 21 0Myalgia 13 0 7 1 7 1 3 0Arthralgia 12 1 10 0 5 1 0 0Infection (including

bacterial, viral, fungal, and non-specified)

12 1 10 6 14 7 9 0

Abdominal pain 12 1 6 0 8 3 3 0Hemorrhage 11 1 26 8 19 9 24 9

Gastrointestinal bleeding 2 1 8 6 9 7 9 3CNS bleeding 0 0 1 1 0 0 3 3

Vomiting 7 1 11 1 12 0 15 0Pyrexia 5 1 11 2 18 3 6 0Febrile neutropenia 1 1 4 4 12 12 12 12a Includes ventricular dysfunction, cardiac failure, cardiac failure congestive, cardiomyopathy, congestive cardiomyopathy,diastolic dysfunction, ejection fraction decreased, and ventricular failure. b Includes drug eruption, erythema, erythemamultiforme, erythrosis, exfoliative rash, generalized erythema, genital rash, heat rash, milia, rash, rash erythematous, rashfollicular, rash generalized, rash macular, rash maculopapular, rash papular, rash pruritic, rash pustular, skin exfoliation, skinirritation, urticaria vesiculosa, and rash vesicular.

Grade 3 or 4 elevations of transaminase or bilirubin and Grade 3 or 4 hypocalcemia, hypokalemia, andhypophosphatemia were reported in patients with all phases of CML but were reported with an increasedfrequency in patients with myeloid or lymphoid blast phase CML. Elevations in transaminase or bilirubin wereusually managed with dose reduction or interruption. Patients developing Grade 3 or 4 hypocalcemia duringthe 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 laboratoryparameters.

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

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 oftreatment was 3 months (range 0.03–31 months). The safety profile of patients with Ph+ ALL was similar tothose with lymphoid blast phase CML. The most frequently reported adverse reactions included fluid retentionevents such as pleural effusion (24%) and superficial edema (19%), and gastrointestinal disorders such asdiarrhea (31%), nausea (24%), and vomiting (16%). Hemorrhage (19%), pyrexia (17%), rash (16%), anddyspnea (16%) were also frequently reported. The most frequently reported serious adverse reactions includedpleural 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 of1%–<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 SubcutaneousTissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (includingeczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acutefebrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory,Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonaryhypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. NervousSystem 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% – muscularweakness; 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 respiratorytract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fataloutcomes). 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 (includingventricular 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 Systemand Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and ProceduralComplications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% –vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and UrinaryDisorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, andUnspecified: 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 (includingpulmonary embolism, deep vein thrombosis). Respiratory, thoracic, and mediastinal disorders: interstitiallung disease. DRUG INTERACTIONSDrugs That May Increase Dasatinib Plasma Concentrations CYP3A4 Inhibitors: Dasatinib is a CYP3A4 substrate. In a study of 18 patients with solid tumors, 20-mgSPRYCEL once daily coadministered with 200 mg of ketoconazole twice daily increased the dasatinib Cmax andAUC by four- and five-fold, respectively. Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 mayincrease exposure to dasatinib and should be avoided. In patients receiving treatment with SPRYCEL, closemonitoring for toxicity and a SPRYCEL dose reduction should be considered if systemic administration of apotent 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 continuousevening administration of 600 mg of rifampin, a potent CYP3A4 inducer, the mean Cmax and AUC of dasatinibwere decreased by 81% and 82%, respectively. Alternative agents with less enzyme induction potential shouldbe considered. If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL shouldbe 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 healthysubjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mgdose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjectsconcomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmaxwere observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy isneeded, 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 antagonistsor proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reducedthe AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administrationof a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reducedthe AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or protonpump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hoursafter the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors inpatients 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 AUCof simvastatin, a CYP3A4 substrate, were increased by 37% and 20%, respectively, when simvastatin wasadministered in combination with a single 100-mg dose of SPRYCEL. Therefore, CYP3A4 substrates known tohave a narrow therapeutic index such as alfentanil, astemizole, terfenadine, cisapride, cyclosporine, fentanyl,pimozide, quinidine, sirolimus, tacrolimus, or ergot alkaloids (ergotamine, dihydroergotamine) should beadministered 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 noadequate and well-controlled studies of SPRYCEL in pregnant women. Women of childbearing potential should beadvised 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 tothe fetus. In nonclinical studies, at plasma concentrations below those observed in humans receiving therapeutic dosesof dasatinib, embryo-fetal toxicities were observed in rats and rabbits. Fetal death was observed in rats. In bothrats 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-foldthe human AUC) in rats and rabbits, respectively. Embryo-fetal toxicities included skeletal malformations atmultiple 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 areexcreted in human milk and because of the potential for serious adverse reactions in nursing infants fromSPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking intoaccount 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 beenestablished. Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age andover and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL withresistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75years of age and over. No differences in efficacy were observed between older and younger patients. Comparedto 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 evaluatedin 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, thedose 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) inFull Prescribing Information]. Caution is recommended when administering SPRYCEL to patients with hepaticimpairment. Renal Impairment: There are currently no clinical studies with SPRYCEL in patients with impaired renalfunction. Less than 4% of dasatinib and its metabolites are excreted via the kidney. OVERDOSAGEExperience with overdose of SPRYCEL in clinical studies is limited to isolated cases. Overdosage of 280 mgper 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 AdverseReactions], patients who ingested more than the recommended dosage should be closely monitored formyelosuppression and given appropriate supportive treatment.Acute overdose in animals was associated with cardiotoxicity. Evidence of cardiotoxicity included ventricularnecrosis and valvular/ventricular/atrial hemorrhage at single doses ≥100 mg/kg (600 mg/m2) in rodents. Therewas 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

1284903 DS-B0001A-10-10 Rev October 2010

Table 3: CTC Grade 3/4 Laboratory Abnormalities in Patients with Newly Diagnosed ChronicPhase CML

SPRYCEL(n=258)

Imatinib(n=258)

Percent (%) of PatientsHematology Parameters

Neutropenia 22 20Thrombocytopenia 19 10Anemia 11 7

Biochemistry Parameters Hypophosphatemia 5 24Hypokalemia 0 2Hypocalcemia 3 2Elevated SGPT (ALT) <1 1Elevated SGOT (AST) <1 1Elevated Bilirubin 1 0Elevated Creatinine <1 1

CTC grades: neutropenia (Grade 3 ≥0.5–<1.0 × 109/L, Grade 4 <0.5 × 109/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).

Table 4: CTC Grade 3/4 Laboratory Abnormalities in Clinical Studies of CML: Resistance orIntolerance to Prior Imatinib Therapy

Chronic Phase CML Advanced Phase CML

100 mgOnce Daily

(n=165)

140 mg Once DailyAccelerated

Phase(n=157)

MyeloidBlast Phase

(n=74)

LymphoidBlast Phase

(n=33)Percent (%) of Patients

Hematology ParametersNeutropenia 36 58 77 79Thrombocytopenia 23 63 78 85Anemia 13 47 74 52

Biochemistry ParametersHypophosphatemia 10 13 12 18Hypokalemia 2 7 11 15Hypocalcemia <1 4 9 12Elevated SGPT (ALT) 0 2 5 3Elevated SGOT (AST) <1 0 4 3Elevated Bilirubin <1 1 3 6Elevated 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 ×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, Grade4 <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).

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PAGE 46 The ASCO Post | APRIL 15, 2011

Awards

A physician-scientist credited with dis-covering the first human oncogene

and isolating the first known tumor-sup-pressor gene is among the notable award-ees to be honored by ASCO at its 2011 Annual Meeting.

Each year through its Special Awards, ASCO recognizes quality researchers, pa-tient advocates, and leaders of the global oncology community who, through their work, have made significant contributions to enhancing cancer care.

“The recipients of this year’s awards have made outstanding contributions to the oncology field,” said Douglas Blayney, MD, Immediate Past President of ASCO and Chair of the Special Awards Selection Committee. “For their commit-ment to improving the prevention, treat-ment, and care of people with cancer, it is our honor to bestow upon them ASCO’s highest achievement awards.”

David A. Karnofsky Memorial Award and Lecture

Kenneth C. Anderson, MD, is the recipient of the 2011 David A. Karnofsky Memorial Award and Lecture for his out-standing achievements in cancer research and for his influence on the treatment of patients with cancer. Dr. Anderson cur-rently serves as the Director of the LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple My-eloma at Dana-Farber Cancer Institute and the Kraft Family Professor of Medi-cine at Harvard Medical School. Over the past 3 decades, Dr. Anderson has focused his laboratory and clinical research studies on novel biologically based therapies for multiple myeloma.

Science of Oncology Award and Lecture

Robert A. Weinberg, PhD, Found-ing Member of the Whitehead Institute for Biomedical Research and Professor of Biology at the Massachusetts Institute of Technology, is the recipient of the 2011 Science of Oncology Award and Lecture. Dr. Weinberg is most widely known for his discovery of the first human oncogene, the ras oncogene, which causes normal cells to form tumors, and the isolation of the first known tumor suppressor gene, the Rb gene.

ASCO–American Cancer Society Award and Lecture

Jamie H. Von Roenn, MD, is the recipient of the 2011 ASCO–American

Cancer Society Award and Lecture for her pioneering work in palliative medi-cine and for her substantial contribu-tions to oncology care and cancer pain management. As a Professor of Medicine at Northwestern University Feinberg School of Medicine and Co-Director of the Cancer Control Program at Robert H. Lurie Comprehensive Cancer Center, Dr. Von Roenn has focused her career on the integration of palliative medicine skills

and principles into oncology care, and breast oncology. She also has been a lead-ing proponent for developing palliative care training for oncologists.

Gianni Bonadonna Breast Cancer Award and Lecture

Luca Gianni, MD, Director of the De-partment of Medical Oncology and Head of the Project of Development of New Drugs and Innovative Therapies in Solid Tumors at the San Raffaele Cancer Center in Milan, Italy, is the recipient of the 2011 Gianni Bonadonna Breast Cancer Award and Lecture. His research has led to the definition of a successful new regimen for breast cancer, as well as the clarification of relevant aspects of the pharmacology of paclitaxel and the mechanisms of drug–drug enhancement with doxorubicin. Dr. Gianni also made a major contribution to the development of HER2-directed ther-apies in women with breast cancer by de-signing and conducting the collaborative neoadjuvant trials NOAH with trastu-zumab (Herceptin) and NEOSPHERE with trastuzumab and pertuzumab, and by acting as a member of the Executive Committee of the HERA trial.

B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology

John M. Bennett, MD, Professor Emeritus of Medicine, Pathology, and Laboratory Medicine at the University of Rochester Medical Center in New York,

is the recipient of the 2011 B.J. Kennedy Award and Lecture for Scientific Excel-lence in Geriatric Oncology. His interest in cancer in the aging population derived from studies of older patients with hema-tologic malignancies. Dr. Bennett was a founding member of the International So-ciety for Geriatric Oncology and the first chair of the Myelodysplastic Syndromes Foundation, has contributed over 500 publications to medical literature.

Pediatric Oncology Award and Lecture

Lee J. Helman, MD, is the recipient of the 2011 Pediatric Oncology Award and Lecture for his scientific achievements in the field of pediatric oncology. As Scien-tific Director for Clinical Research at the National Cancer Institute’s Center for Cancer Research, Dr. Helman’s laboratory currently focuses on the biology and treat-ment of pediatric sarcomas, specifically Ewing’s sarcoma, rhabdomyosarcoma, and osteosarcoma.

Partners in Progress AwardBenjamin O. Anderson, MD, is the

recipient of the 2011 Partners in Progress Award for his commitment to women throughout the world and his dedicated efforts to improve their quality of care. As Professor of Surgery and Global Health Medicine at the University of Washington in Seattle, he has devoted his clinical prac-tice to the care of patients with breast can-cer and breast health issues. For the past decade, Dr. Anderson has been a leading voice in the international breast cancer clinical improvement and best practices movement through establishment of the Breast Health Global Initiative.

Distinguished Achievement Award

David Khayat, MD, PhD, serves as Head of the Department of Medical On-cology at the Pitié-Salpêtrière Hospital in Paris, and is the recipient of the 2011 Distinguished Achievement Award for

his extraordinary leadership in the field of oncology. Dr. Khayat formerly served as President of the French National Can-cer Institute. His research and clinical in-terests focus on the development of new agents for breast cancer, colorectal cancer, lung cancer, and melanoma.

Special Recognition AwardDaniel G. Haller, MD, is the recipient

of the 2011 Special Recognition Award for his outstanding contributions to clini-cal oncology and cancer research and for his dedicated service to the oncology community. Dr. Haller serves as Professor of Medicine and Attending Physician at the Hospital of the University of Pennsyl-vania. His chief areas of clinical research are in the management of gastrointestinal malignancies. In May 2001, Dr. Haller assumed the role of Editor-in-Chief of the Journal of Clinical Oncology, the of-ficial journal of the American Society of Clinical Oncology. He is the author or coauthor of more than 125 peer-reviewed publications.

Public Service AwardThe Honorable Sherrod Brown, se-

nior U.S. Senator from Ohio, is the 2011 recipient of the Public Service Award. As part of the new health-care law, Sen. Brown led the efforts to ensure the law included important consumer protec-tions that require insurance plans to cover routine patient care for patients undergo-ing cancer clinical trials, working closely with ASCO and others in the cancer com-munity to achieve this goal. ASCO will honor Sen. Brown for his commitment to advancing legislation in support of cancer research, treatment, and care. ■

Researchers and Scientists Honored by ASCO for Improving Prevention, Treatment, and Care of People Living with Cancer

Douglas Blayney, MD Jamie H. Von Roenn, MD Luca Gianni, MD

Annual Meeting

All of the above awards will be presented at the Society’s 47th An-nual Meeting taking place in Chi-cago, June 3–7 at McCormick Place, with the exception of the Public Ser-vice Award, which will be presented at a private event, and the Gianni Bonadonna Breast Cancer Award and Lecture, which will be presented at the 2011 Breast Cancer Sympo-sium, taking place September 8–10 in San Francisco.

For a list of the specific dates and room locations of the awards presen-tations, contact Danielle Potuto at danielle.potuto@asco.org. ■

ASCOPost.com | APRIL 15, 2011 PAGE 47

JCO Spotlight

The phase III Cancer and Leukemia Group B (CALGB) 49907 trial

was conducted to determine whether older patients with early-stage breast cancer receiving adjuvant capecitabine (Xeloda) would have equivalent re-lapse-free and overall survival com-pared with patients receving standard adjuvant chemotherapy with either CMF (cyclophosphamide/methotrex-ate/fluorouracil) or AC (doxorubicin/cyclophosphamide). The trial showed that standard adjuvant chemotherapy was associated with significantly greater relapse-free survival (84.7% vs 67.7% at 3 years, P  < .001) and overall survival (90.6% vs 86.4% at 3 years, P  ≤ .02) compared with capecitabine.1 Toxicity varied among the three regimens, with capecitabine being less toxic than either CMF or AC.

Quality MeasuresA preplanned substudy compared

quality-of-life (QOL) measures during and after treatment between 182 pa-tients receiving standard chemotherapy and 168 receiving capecitabine.2 The average age of the patients was 72 years. QOL was measured by the European Organisation for Research and Treat-ment of Cancer Quality of Life Ques-tionnaire C30 (EORTC QLQ-C30, the systemic adverse effects subscale of the EORTC breast module (EORTC BR23), and the Hospital Anxiety and Depression Scale (HADS).

Patients were assessed at baseline (before treatment), at midtreatment (approximately day 77 for those re-ceiving CMF, day 29 for those receiv-ing AC, and day 63 for those receiv-ing capecitabine), within 1 month post-treatment (end of treatment, approximately 6–7 months for CMF, 4–5 months for AC, and 4–5 months for capecitabine) and at 12, 18, and 24 months after the baseline mea-surement. The treatment schedules were: oral cyclophosphamide daily on days 1 to 14 and IV methotrexate and fluorouracil on days 1 and 8 ev-ery 28 days for six cycles for CMF; IV doxorubicin and cyclophospha-

mide on day 1 ev-ery 21 days for four cycles for AC; and capecitabine orally on days 1 to 14 every 21 days for six cycles.

Substudy FindingsCompared with patients receiving

standard chemotherapy, patients treat-ed with capecitabine had significantly better global QOL scores, significantly fewer systemic treatment-related ad-verse events, and significantly better HADS scores at midtreatment and end of treatment (Fig. 1). With regard to individual QOL domains, patients

receiving capecitabine had signifi-cantly better EORTC role functioning (P ≤ .002) and social functioning (P < .001). There were no significant dif-ferences between groups over time in physical functioning, neurobehavioral functioning, or pain.

Among systemic adverse effects, capecitabine patients had significantly less fatigue (P < .001), nausea and

vomiting (P < .001), and constipation (P ≤ .004), and significantly better appetite (P  = .005), but significantly worse hand-foot syndrome symptoms (P < .001) and diarrhea (P = .005) at midtreatment and/or end of treatment. At midtreatment, 18.8% of patients receiving standard chemotherapy and 6.5% of patients receiving capecitabine (P = .002) had HADS scores ≥ 15, in-dicating clinically important anxiety/depression. Psychosocial services were used by less than 10% of patients in ei-ther group over 24 months.

Although capecitabine was associ-ated with better QOL and reduced sys-temic adverse effects during treatment, differences between the two groups in global QOL, systemic adverse effects, and HADS outcome were no longer ap-parent at 12 months after starting treat-ment or thereafter (Fig. 1). Given the superiority of standard adjuvant che-motherapy in relapse-free survival and overall survival for older patients with early-stage breast cancer, the transient QOL benefits seen with capecitabine are not sufficient to warrant substitu-tion of capecitabine for standard che-motherapy in this patient population.

‘Modest Price to Pay’“The results of the parent trial and

the QOL study should be reassuring to older women who are given stan-dard adjuvant therapy,” noted Alice B. Kornblith, PhD, of Dana-Farber Can-cer Institute, Boston, and lead author of the QOL study. “Although even brief worsening of quality of life is undesir-able, the goal of adjuvant therapy is to increase the chance for cure—and the brief change in quality of life with stan-dard therapy is a modest price to pay for increased survival.” ■

Financial Disclosures: Dr. Kornblith reported no potential conflicts of interest.

References 1. Muss HB, Berry DA, Cirrincione

CT, et al: Adjuvant chemotherapy in older women with early-stage breast cancer. N Engl J Med 360:2055-2065, 2009.

2. Kornblith AB, Lan L, Archer L, et al: Quality of life of older patients with early-stage breast cancer receiving adju-vant chemotherapy: A companion study to Cancer and Leukemia Group B 49907. J Clin Oncol February 22, 2011 (early re-lease online).

QOL Benefits of Capecitabine Fail to Outweigh Improved Survival with Standard Adjuvant Therapy in Older Women with Early Breast Cancer By Matthew Stenger

80

70

60

50

90

100

Baseline

Better

Time (months)

*P < .01

Mid-treatment

Endtreatment

12 18 24

EOR

TC G

loba

l Qua

lity

of L

ife

CapecitabineCMF or AC

A

30

20

10

0

40

50

Baseline

Worse

Time (months)

CapecitabineCMF or AC

*P < .01

Mid-treatment

Endtreatment

12 18 24

EOR

TC S

yste

mic

Adv

erse

Effe

cts

B

24

18

12

0

36

42

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Worse

Time (months)

*P < .01

Mid-treatment

Endtreatment

12 18 24

HA

DS

Ove

rall

Scor

e

6

30

CapecitabineCMF or AC

C

Fig. 1: EORTC global QOL (A), EORTC systemic adverse effects (B), and HADS overall score (C) among older patients with early-stage breast cancer receiving standard adjuvant chemotherapy (CMF or AC, n = 182) or capecitabine (n = 168) in CALGB-49907. Data are predicted mean scores. Reproduced with permission from Kornblith AB, et al.1 Copyright © 2011 by the American Society of Clinical Oncology. All rights reserved.

Breast Cancer

SEE PAGE 51

CODE: CRI00102/280033-01 PUB/POST: Oncology Times, ASCO Post, PRODUCTION: N/A LIVE: None

DESCRIPTION: Cancer ribbon spread WORKORDER #: 002098 TRIM: 21” x 14”

Delivery Support: 212.237.7000 FILE: 05A-002098-05A-PFZONC.11006.CZR007_Ad.indd SAP #: PFZ.PFZONC.11006.K.011 BLEED: 21.25” x 14.25”

Art: CZR007_AD_A.tif (CMYK; 300 ppi; Up to Date), Pfizer_Oncology_KO.eps (Up to Date), CANCER_its_personal_Tag_4C.eps (Up to Date)

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.

CODE: CRI00102/280033-01 PUB/POST: Oncology Times, ASCO Post, PRODUCTION: N/A LIVE: None

DESCRIPTION: Cancer ribbon spread WORKORDER #: 002098 TRIM: 21” x 14”

Delivery Support: 212.237.7000 FILE: 05A-002098-05A-PFZONC.11006.CZR007_Ad.indd SAP #: PFZ.PFZONC.11006.K.011 BLEED: 21.25” x 14.25”

Art: CZR007_AD_A.tif (CMYK; 300 ppi; Up to Date), Pfizer_Oncology_KO.eps (Up to Date), CANCER_its_personal_Tag_4C.eps (Up to Date)

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.

PAGE 50 The ASCO Post | APRIL 15, 2011

In the Literature

© J.C. Duffy/The New Yorker Collection/www.cartoonbank.com

PANCREATIC CANCER

Two Studies Offer Optimism for Treatment of Malignant Pancreatic Endocrine Tumors

Two studies published in The New England Journal of Medicine “provide optimism regarding the treatment of malignant pancreatic neuroendo-crine tumors,” suggested an edito-rial accompanying the articles. Both studies were phase III, double-blind, randomized, placebo-controlled tri-als involving sufficient numbers of patients with progressive malignant disease “to yield clear statistical re-sults,” according to the editorial.

One study randomly assigned 171 patients to best supportive care with either continuous daily admin-istration of the tyrosine kinase in-hibitor sunitinib (Sutent) at a dose of 37.5  mg or placebo. Compared to those receiving placebo, patients receiving sunitinib had an improved objective response rate (9.3% vs 0%) and median progression-free survival (11.4 vs 5.5 months).

“The trial was terminated early because of the risk of serious ad-verse events, disease progression, and death among patients receiving placebo,” the investigators reported. In the sunitinib group, the most frequently reported adverse events were diarrhea, nausea, vomiting, as-thenia, and fatigue.

Sunitinib is manufactured by Pfizer, which funded the study, col-lected the data, performed the sta-tistical analyses, and, in conjunction with the investigators, designed the study. The conduct of the trial was overseen by an independent data and safety monitoring committee.

RADIANT-3In the other study, RAD001 in

Advanced Neuroendocrine Tumors, third trial (RADIANT-3), 410 pa-tients were randomly assigned to best supportive care plus everoli-mus (Afinitor), an oral inhibitor of mammalian target of rapamycin (mTOR), or placebo. Patients re-ceiving everolimus had significantly prolonged median progression-free survival compared to those in the placebo group (11.0 vs 4.6 months), “representing a 65% reduction in the estimated risk of progression or death,” the investigators noted. The proportions of patients alive and progression-free at 18 months were estimated at 34% for the everolimus group compared to 9% for the place-bo group. “It is not yet clear whether sunitinib and everolimus can be combined and, if so, whether anti-tumor activity would be further in-creased with combined treatment,” the authors of the everolimus study wrote.

“The adverse events seen with everolimus were mainly grade 1 and

2 events, thus allowing for long-term daily administration,” the authors concluded. These events included stomatitis, rash, diarrhea, fatigue, and infections, primarily of the upper respiratory tract. Grade 3 or 4 events that were more frequent with everoli-mus than with placebo included ane-mia and hyperglycemia.

The study was funded by Novar-tis, the manufacturer of everolimus.

Adverse Events and Other Considerations

The editorial writers pointed out that the adverse events “resulted in an increase by a factor of 2 in the case of everolimus and 3 in the case of sunitinib, as compared with placebo, in the number of patients requiring dose reductions or temporary treat-ment interruptions.” They added that it is “unclear how the side-effect pro-files will affect long-term adherence to treatment.”

Other unknown factors that could determine the usefulness of sunitinib and everolimus in the treatment of malignant pancreatic neuroendo-crine include whether patients would “have to continue taking these drugs for years, since both drugs primarily stabilize, rather than cure, the dis-ease” and whether patients who no longer have a response to one drug can then be effectively treated with the other drug.

Jensen RT, Delle Fave G: N Engl J Med 364:564-565, 2011.

Raymond E, et al: N Engl J Med 364:501-513, 2011.

Yao JC, et al: N Engl J Med 364:514-523, 2011.

BLADDER CANCER

Bladder-sparing Approach to Metastatic Disease Features Gemcitabine and Radiotherapy

A bladder-sparing approach using concurrent gemcitabine and hypo-fractionated radiotherapy in 50 pa-tients with muscle-invasive bladder cancer showed a complete response rate of 88% among the 47 partici-pants who had cystoscopy 3 months after treatment. The overall survival rate at 3 years was 75%, and disease-specific survival, 82%. In addition, 89% of all survivors had an intact bladder and no significant changes

in sexual, bladder, or bowel function at 2 years after treatment. The results of the phase  II study in the United Kingdom were reported in the Jour-nal of Clinical Oncology.

All participating patients complet-ed radiotherapy, and 46 tolerated all four cycles of gemcitabine given in-travenously at 100 mg/m2 on days 1, 8, 15, and 22 of a 28-day radiotherapy schedule that delivered 52.5  Gy in 20 fractions. The four patients who stopped gemcitabine did so due to bowel toxicity.

Among the 14 deaths, 7 resulted from metastatic muscle-invasive bladder cancer, 5 from intercurrent disease, and 2 from treatment-associ-ated deaths. Four patients underwent cystectomy—three because of recur-rent disease and one because of tox-icity. One patient required a bowel resection for late toxicity.

Patient Selection“It is accepted implicitly that there

is a group of patients who are most appropriately managed by cystecto-my (eg, those with poor bladder func-tion or extensive carcinoma in situ),” the authors noted. “Nonetheless, with good patient selection, a pro-portion of patients can be offered the opportunity of cure while they retain a well-functioning bladder and sexual function. It is, therefore, vital to con-tinue to strive to identify the clinical and biologic features that will predict a favorable outcome with bladder preservation to counsel patients and to enable them to choose the most effective treatment for their disease.” The authors added that “encouraging results warrant consideration of ad-ditional study in a phase III setting.”

Choudhury A, et al: J Clin Oncol 29:733-738: 2011.

BREAST CANCER

Timing of Hormonal Therapy Influences Breast Cancer Risk

The Million Women Study (MWS) found that starting hormone therapy around the time of meno-pause is associated with a greater risk of breast cancer than starting it later. This “pattern of risk was seen across different types of hormonal therapy, among women who used hormonal therapy for either short or long durations, and also in lean and

Emerging Clinical Data on Cancer Management

ASCOPost.com | APRIL 15, 2011 PAGE 51

In the Literature

in overweight and obese women,” the authors reported in the Journal of the National Cancer Institute. The study analyzed data from 1,129,025 post-menopausal women in the United Kingdom “who provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk,” the authors ex-plained.

Comparisons to WHI FindingsIn an accompanying editorial,

Rowan T. Chlebowski, MD, PhD, of Los Angeles Biomedical Research Institute at Harbor-UCLA Medical Center, and Garnet L. Anderson, PhD, from the Fred Hutchinson Cancer Research Center in Seattle, stated that the study provides sub-stantial support for similar findings from the Women’s Health Initiative (WHI) in the United States, as well as the French E3N cohort. “Given the considerable methodologic dif-ferences between” the MWS and the WHI, “the similarity of results is re-markable and increases confidence in the validity of the conclusions,” they wrote.

The editorialists also pointed to discrepancies between the MWS and the WHI findings. While the MWS found statistically significant increas-es in breast cancer risk among wom-en, except those overweight or obese, receiving estrogen-only therapy, the WHI study did not. And while both studies found that women who used estrogen/progestin therapy within 5 years of menopause had greater breast cancer risk than those who used it 5 or more years after meno-pause, the magnitude of the effects was greater in the MWS trial.

“Although the similarities be-tween the patterns of breast cancer risk observed in these two method-ologically diverse studies increase the likely validity of the results,” the editorialists wrote, “the difference in the magnitude of effects remains of interest, particularly for estrogen-on-ly users, for which the interpretation is still unclear.” They add that con-flicting data may be due to methodo-logic differences between the studies and that additional postintervention follow-up of the WHI estrogen-only trial should lead to further clarifica-tion.

Beral V, et al: J Natl Cancer Inst 103:296-305, 2011.

Chlebowski RT, Anderson G: J Natl Cancer Inst 103:284-285, 2011. ■

What’s this?

Simply text the word “scan” to 43588.

Go to www.getscanlife.com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

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

1 2 3

Using 2D BarcodesThe 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Getting the ApplicationThere are three ways to download the ScanLife application:

Breast Cancer Symposium 2011

September 8-10, 2011

San FranciSco marriott marquiS

San FranciSco, caLiFornia

To submit an abstract or to view guidelines, visit breastcasym.org.This live activity has been approved for AMA PRA Category 1 Credit.™

S u b m i t a n a b S t r a c t

Topic caTegories• Detection/Screening/imaging• Systemic therapy• prevention, Survivorship & Health policy• Local/regional therapy

This year’s Symposium will focus on the theme of “The continuum of breast care: Science to

Survivorship,” and will foster dialogue between investigators and clinicians to translate research

directly into practice. make your contribution to this multidisciplinary scientific forum by

submitting your original research abstract.

may 10, 2011 at 11:59 pm (eDt): abstract Submission Deadline

august 3, 2011 at 11:59 pm (eDt): Housing and early registration Deadline

T A R G E T I N G C A N C E R C A R E

The ConTinuum of BreasT Care: sCienCe To survivorship

Primary Supporter

PAGE 52 The ASCO Post | APRIL 15, 2011

In the News

Practice-changing is how many me-dia reports describe the results of

a study finding that complete axillary lymph node dissection did not offer survival benefits over sentinel lymph node dissection for women with early-stage breast cancer treated with breast conservation and systemic therapy. The results were published in The Journal of the American Medical Association.1 “The discovery turns standard medical prac-tice on its head,” according to the ac-count in the New York Times.2

In commenting on the study to The ASCO Post, William C. Wood, MD, of Winship Cancer Institute, Emory Uni-versity, emphasized that only patients who had whole breast irradiation were eligible to participate in the study. He cautioned that the results therefore cannot be generalized to patients who have undergone mastectomy or others who will not receive irradiation cover-ing the whole breast, and consequently, much of the axilla.

“Some institutions are already changing,” lead investigator Armando E. Giuliano, MD, told The ASCO Post, citing Memorial Sloan-Kettering Can-cer Center in New York, M.D.  Ander-son Cancer Center in Houston, and John Wayne Cancer Institute in Santa Monica, California, where Dr. Giuliano served as Chief of Surgical Oncology at the time the findings were published. (He was recently named to a new posi-tion as Executive Vice Chair of Surgery for Surgical Oncology at Cedars-Sinai Medical Center in Los Angeles.) The Washington Post reported that Gary Lyman, MD, Co-chair of the Ameri-can Society of Clinical Oncology ex-pert panel on the breast cancer lymph node dissection issue, said, “I think this will be practice-changing.” He added that the study findings will likely lead to changes in the ASCO guidelines.4

2 to 17 Nodes RemovedThe American College of Surgeons

Oncology Group Z0011 trial was a phase  III noninferiority trial involv-ing 891 women at 115 sites. Targeted enrollment was 1,900 women, but the trial was closed early because the mor-tality rate was lower than expected. Eli-gible patients were women with clini-cal T1 or T2 invasive breast cancer of 5  cm or less, no palpable adenopathy, and one to two sentinel lymph nodes containing metastases identified by

frozen section, touch preparation, or hematoxylin and eosin staining on per-manent section.

All patients underwent lumpectomy and tangential whole-breast irradiation. Those identified by sentinel lymph node dissection (SLND) as having sen-tinel lymph node metastases were ran-domly assigned to undergo no further axillary treatment or axillary lymph node dissection (ALND) of 10 or more nodes. “Disease characteristics at base-line were well-balanced between the two groups,” the study report noted. The median number of nodes removed was 17 with ALND and 2 with SLND alone. Systemic therapy was left to the discretion of the treating physician. At a median follow-up of 6.3 years, 5-year overall survival was 91.8% with ALND and 92.5% with SLND alone. “This was substantially greater than the 80% an-ticipated at protocol design,” the inves-tigators reported. The 5-year disease-free survival was 82.2% with ALND and 83.9% with SLND alone.

Patients Dread LymphedemaIt might be difficult for surgical,

medical, and radiation oncologists (and some patients) to accept that it is not necessary to remove more than a couple of nodes, Dr. Giuliano said. “It is counterintuitive to think that if you leave involved nodes in, it is okay.”

A strong inducement to remove few-er nodes is the reduced rate of compli-cations with sentinel lymph node dis-section. In this study, the rate of wound infections, axillary seromas, and pares-thesias was 70% for the ALND group vs 25% for the SLND-alone group. “Lymphedema in the ALND group was significantly more common by subjec-tive report (P < .001) and also tended to be higher by objective assessment of arm circumference,” the investigators reported. “These findings,” they added, “are in accordance with other random-ized comparisons of SLND with vs without ALND.”

When it comes to the benefits of avoiding complications, particularly lymphedema, “you don’t have to con-vince patients,” Dr. Giuliano said. “Pa-tients dread lymphedema.” And physi-cians will do what they can to prevent or minimize lymphedema from occur-ring in their patients with breast cancer.

The complications and the lack of

proof that axillary dissection improved survival were what inspired Dr. Giulia-no to undertake the comparison study of ALND and SLND alone. “He has a lot of credibility on this issue,” said NPR reporter Richard Knox on Morn-ing Edition the day after the report was published.5 “Back in the mid-1990s,” he commented, “Dr. Giuliano was in-strumental in establishing the current practice of sampling one or two senti-nel lymph nodes and then using those results to determine whether other lymph nodes in the area should be ex-cised.”

Revisiting NSABP B04In the current era, with breast cancer

being diagnosed earlier, “fewer women have positive nodes, and women who do have positive nodes have fewer posi-tive nodes,” Dr. Giuliano said. “So it seemed like a good idea to reexamine

NSABP B04.” The National Surgical Adjuvant Breast and Bowel Project B04 study randomly assigned women with clinically negative nodes to treat-ment with radical mastectomy, total mastectomy plus nodal irradiation, or total mastectomy with delayed ALND if nodal recurrence was observed. “Ini-tially and at each interim analysis for up to 25 years of follow-up, no statistically significant survival differences were ob-served between any of the groups,” the investigators wrote.

“For patients treated in the mod-ern era, the relevance of the B04 study, which included patients with larger tumors undergoing mastectomy with-out adjuvant systemic therapy, is uncertain, because an axillary re-currence after SLND in patients with a low-er risk of death from

Results of Breast Cancer Lymph Node Dissection Study Are Already Changing Standard Medical PracticeBy Charlotte Bath

In the News focuses on media re-ports that your patients may have questions about at their next visit. This continuing column will pro-vide summaries of articles in the popular press that may prompt such questions, as well as com-ments from colleagues in the field.

Expect Questions from Your Patients

With such widespread media coverage, it would be natural for patients with breast

cancer to have read or heard about the Z0011 study and to ask questions. “That is really the advantage of the press interest,” Dr. Giuliano said. “It encour-ages patients to speak to their physicians and get what’s best for them.”

The most common question from patients, Dr. Giuliano said, is “Would this be right for me?” At this point, he added, people need to understand what group of patients the study applies to—wom-

en with limited sentinel lymph node metastatic breast cancer treated with breast-conserving surgery, whole-breast irradiation, and adjuvant systemic therapy.

“I think it would be wrong to generalize and say this approach applies to all positive nodes,” he cautioned. “That may be the case, but we will need more research. I think oncologists—surgical oncologists, medical oncologists, ra-diation oncologists—have to be careful that we apply these findings only to the types of patients who were included in the study.” ■

Armando E. Giuliano, MD

SEE PAGE 51

Oncologists have to be careful

to apply these findings only to the

types of patients who were included

in the study.

ASCOPost.com | APRIL 15, 2011 PAGE 53

In the News

distant disease might negatively affect survival. The findings from Z0011 document the high rate of locore-gional control achieved with modern multimodality therapy, even without ALND,” they added.

“The excellent local and distant out-comes in this study highlight the effects of multiple changes in breast cancer management during the interval be-tween the two studies,” the investigators continued. “These changes, which in-clude improved imaging, more detailed pathologic evaluation, improved plan-ning of surgical and radiation approach-es, and more effective systemic therapy, emphasize the need for ongoing reeval-uation of ‘standard’ local therapy.”

The Next StepSeveral media reports of the study

pointed out that the results of Z0011 were originally presented at last year’s ASCO Annual Meeting. While some physicians and institutions started changing practice back then, others were waiting for the full report.

“I think the next step would be long-term follow-up on this study and to determine whether the findings are ap-propriate for other patients,” Dr. Giulia-no said. He added that he is working to design studies for high-risk patients with T1 or T2 breast cancer and those who have been treated with neoadju-

vant chemotherapy, but these studies have yet to be formalized. ■

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

References1. Giuliano AE, Hunt KK, Ballman KV,

et al: Axillary dissection vs no axillary dis-

section in women with invasive breast can-cer and sentinel node metastasis. JAMA 305:569-575, 2011.

2. Grady D: Lymph node study shakes pillar of breast cancer care. The New York Times. February 8, 2011. Available at www.nytimes.com.

3. Carlson GW, Wood WC: Manage-ment of axillary lymph node metastasis

in breast cancer: Making progress. JAMA 305(6):606-607, 2011.

4. Stein R: Breast-cancer study ques-tions lymph node removal. Washington Post. February 9, 2011. Available at www.washingtonpost.com.

5. Knox R: Certain breast cancer pa-tients may nix node surgery. NPR. Febru-ary 9, 2011. Available at www.npr.org.

Peginterferon alfa-2b Approved for Postsurgical Melanoma with Nodal Involvement

On March 29, the FDA approved peginterferon alfa-2b (Sylatron),

for the treatment of patients with mela-noma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

The approval was based on an open-label, multicenter trial (EORTC 18991) enrolling 1,256 patients. Patients who had been adequately surgically resected for their primary cutaneous melanoma and affected regional lymph nodes were randomly assigned to receive peginter-feron alfa-2b or observation for 5 years. An improvement in relapse-free sur-vival for peginterferon-treated patients was observed (median of 34.8 and 25.5 months in the peginterferon and obser-vation arms, respectively). Following 525 deaths, there was no difference in overall survival between the two arms. ■

FDA Update

PAGE 54 The ASCO Post | APRIL 15, 2011

Perspective

In contrast, just 7 years later in 1986, the Chernobyl incident in the former Union of Soviet Socialist Re-publics released massive amounts of radioactive material into the environ-ment.2 Boron and sand, poured from the air, was not effective in contain-ing the radiation. Later, a temporary concrete sarcophagus entombed the damaged unit. Access to a 30-km area was closed, and nearly half a million people were evacuated. Among the 600 workers on-site at the time of the accident, 2 died within hours and 134 received high radiation doses and de-veloped acute radiation sickness. More than 600,000 workers were in-volved in the Chernobyl cleanup, and 200,000 recovery workers continue to be monitored for late radiation ef-fects. About 4,000 cases of thyroid cancer were diagnosed among chil-dren who drank contaminated milk; 99% of these children have been suc-cessfully treated. The U.S. Nuclear Regulatory Agency emphasizes that U.S. reactors have different plant designs, broader shutdown margins, and protective operational controls.

The potential for devastation caused by an unseen and insidious danger significantly stifled the de-velopment of nuclear power in the United States for more than 40 years; 12 proposed reactors were cancelled, and the construction of 8 that were already underway was suspended. Since 1990, only 5 new nuclear re-actors have been built, and only 1 is under construction. Despite this, in 2009 the United States produced more than 30% of the worldwide nu-clear generation of electricity, with 104 nuclear reactors in 31 states pro-ducing 799  billion kWh, represent-ing over 20% of the country’s total electrical output.3 Approximately 5 new units are planned to come online by 2018, the first of 24 new nuclear reactors approved in mid-2007. It is now unclear whether the plans for construction of these reactors will

also be suspended in reaction to the tragedy in Japan.

Advances in Radiation Oncology

In the context of these events, the use of nuclear power continues to be debated, but meanwhile, the diag-nosis and treatment of cancer with radiation has made tremendous tech-nologic progress. The radiographic early detection of cancer, particularly with mammography, has significantly improved cancer survival rates. Tech-nologic improvements in computed tomography (CT) and the develop-ment of magnetic resonance imaging (MRI) and positron-emission to-mography (PET) have transformed oncologic practice.

For radiation oncology, there have been three major advances. First, the use of radiation therapy has ex-panded, in conjunction with more conservative surgical approaches to accomplish organ preservation. Second, multidisciplinary care has expanded to include multimodality cancer therapy, particularly the ad-ministration of chemotherapy during

the course of radiation. Third, radia-tion to the tumor has become more precisely targeted, allowing the safe administration of higher total doses of radiation. All of these advances depended on the development of more sophisticated linear accelera-tors, radiation treatment planning, and verification of the delivered ra-diation dose, which ushered in in-tensity-modulated radiation therapy (IMRT) and proton therapy.

Debates and Recommendations

Despite these advances in onco-logic care, disagreements about the risks of radiation used in medicine are ongoing. In particular, the risks of radiation administered during mam-mography continue to be debated, al-though mammography has been rou-tinely and safely used to detect breast cancer for more than 30 years. This debate, however, transformed into a recommendation from a recently convened government task force to

restrict mammography for women under the age of 50 years. In Febru-ary 2010, the FDA published a policy paper entitled, “Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging,” which in-cluded three recommendations.4 In order to promote safe use of medical imaging devices, the FDA will:

1. Establish requirements for manufacturers of CT and fluoroscop-ic devices to incorporate additional safeguards into equipment design, labeling, and user training.

2. Partner with the Centers for Medicare and Medicaid Services (CMS) to incorporate key quality as-surance practices into accreditation and participation criteria for imaging facilities and hospitals.

3. Recommend that the health-care professional community, in collaboration with FDA, continue efforts to develop diagnostic refer-ence levels for CT, fluoroscopy, and nuclear medicine procedures locally and also through a national radiation dose registry.

The FDA emphasized the “appro-priate justification for ordering and

performing each procedure” and the “careful optimization of the radia-tion dose during each procedure” in December 2010. The aim is to re-cord the radiation dose from each CT, fluoroscopy, and nuclear medi-cine procedure (including PET). These records of radiation dose will then be sent to a radiation dose reg-istry for the collection, initially, of de-identified patient radiation dose data. Pooling dose data across imag-ing facilities nationwide, a national radiation dose registry will initially be used “to support the development of diagnostic reference levels where they do not yet exist,” and “allow for broad validation of those levels that have been developed to date.”

Included in the December 2010 document is an initiative to increase patient awareness regarding the risks of radiation with the develop-ment of a “patient medical imaging record card,” which will compile the patient’s total radiation exposure from every radiologic procedure

performed. This radiation exposure summary document ultimately will be incorporated into the patient’s medical record. Significant potential drawbacks of the card include ques-tions about how the patient and non-radiologist physicians will interpret the data (particularly in differentiat-ing localized vs whole-body radiation exposure) and whether the data will be used to limit future radiation pro-cedures (which could be especially problematic for cancer diagnosis, treatment, and follow-up).

ConclusionsThe good or ill of radiation, in

providing power or in medical care, must be grounded in data, and not based on emotion and fear. Risks associated with nuclear energy, like those with radiology in medicine, are well controlled, and these ap-plications of radiation improve and save lives. Nevertheless, policymak-ing must always consider unintended consequences. With potential signifi-cant restrictions looming in nuclear energy and the medical application of radiation, we hope that we will not also see risks resulting from signifi-cant energy shortages, like frail in-dividuals dying in their homes from excessive heat without air condition-ing, and a reversal of the improve-ments achieved in cancer survival. ■References

1. U.S. Nuclear Regulatory Commis-sion: Backgrounder on the Three Mile Island accident. August 2009. Available at www.nrc.gov. Accessed March 21, 2011.

2. U.S. Nuclear Regulatory Com-mission: Backgrounder on Chernobyl nuclear power plant accident. April 2009. Available at www.nrc.gov. Accessed March 21, 2011.

3. World Nuclear Association: Nu-clear power in the USA. Updated March 2011. Available at www.world-nuclear.org. Accessed March 21, 2011.

4. U.S. Food and Drug Administra-tion: White paper: Initiative to reduce unnecessary radiation exposure from medical imaging. Updated December 14, 2010. Available at www.fda.gov. Accessed March 21, 2011.

Dr. Janjan is Senior Fellow in Healthcare Policy and Dr. Goodman is President and CEO, National Center for Policy Analysis. The National Center for Policy Analysis is a nonprofit conservative think tank es-tablished in 1983 and headquartered in Dallas.

Japan and Radiationcontinued from page 1

The good or ill of radiation, in providing power or in medical care, must be grounded in data,

and not based on emotion and fear.

Nora Janjan, MD, MPSA, MBA

Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe 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 ComplicationsThe 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).]HemorrhageSevere 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).]

1 INDICATIONS AND USAGE1.1 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 GlioblastomaAvastin 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 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious 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 ComplicationsAvastin 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 HemorrhageAvastin 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 FormationSerious 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 EventsSerious, 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 HypertensionThe 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%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of 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 encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

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 ReactionsInfusion 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 REACTIONSThe 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 ExperienceBecause 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 ComplicationsThe 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).]HemorrhageThe 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 EventsThe 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 InfectionThe 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%.ProteinuriaGrade 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 FailureThe 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.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL + Placebo IFL + Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central 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.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring 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 (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%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Body as a Whole Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition Weight loss 4% 9%Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin‑related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

Table 4 NCI‑CTC Grades 1−5 Adverse Events in Study 9

(Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); 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) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. 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.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8  patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for 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 (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.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 Precautions (5.8).]In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any 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 cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with 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 (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

02/11 AVA000030660010127309

Initial U.S.Approval: February 2004Code Revision Date: February 2011

Avastin® is a registered trademark of Genentech, Inc.

©2011 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

71819ge_c 1 3/8/11 11:24 PM

Solution for intravenous infusion Initial U.S. Approval: 2004

WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGEGastrointestinal PerforationsThe 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 ComplicationsThe 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).]HemorrhageSevere 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).]

1 INDICATIONS AND USAGE1.1 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 GlioblastomaAvastin 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 CONTRAINDICATIONSNone.5 WARNINGS AND PRECAUTIONS5.1 Gastrointestinal PerforationsSerious 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 ComplicationsAvastin 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 HemorrhageAvastin 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 FormationSerious 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 EventsSerious, 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 HypertensionThe 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%.Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated hypertension after discontinuation of 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 encephalopathy. [See Dosage and Administration (2.4).]5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS)RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder which can present with headache, seizure, lethargy, confusion, blindness and other visual and neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS.Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Dosage and Administration (2.4).]5.8 ProteinuriaThe incidence and severity of proteinuria is increased in patients receiving Avastin as compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a published case series, kidney biopsy of six patients with proteinuria showed findings consistent with thrombotic microangiopathy.Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine dipstick reading should undergo further assessment with a 24‑hour urine collection.

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 ReactionsInfusion 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 REACTIONSThe 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 ExperienceBecause 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 ComplicationsThe 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).]HemorrhageThe 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 EventsThe 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 InfectionThe 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%.ProteinuriaGrade 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 FailureThe 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.

Table 1 NCI‑CTC Grade 3−4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 2%] Avastin vs. Control)

Arm 1 Arm 2 IFL + Placebo IFL + Avastin (n = 396) (n = 392)

NCI‑CTC Grade 3‑4 Events 74% 87%Body as a Whole Asthenia 7% 10% Abdominal Pain 5% 8% Pain 5% 8%Cardiovascular Hypertension 2% 12% Deep Vein Thrombosis 5% 9% Intra‑Abdominal Thrombosis 1% 3% Syncope 1% 3%Digestive Diarrhea 25% 34% Constipation 2% 4%Hemic/Lymphatic Leukopenia 31% 37% Neutropeniaa 14% 21%

a Central 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.

Grade 1–4 adverse events which occurred at a higher incidence (≥ 5%) in patients receiving bolus‑IFL plus Avastin as compared to the bolus‑IFL plus placebo arm are presented in Table 2. Grade 1–4 adverse events were collected for the first approximately 100 patients in each of the three treatment arms who were enrolled until enrollment in Arm 3 (5‑FU/LV + Avastin) was discontinued.

Table 2 NCI‑CTC Grade 1‑4 Adverse Events in Study 1

(Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL)

Arm 1 Arm 2 Arm 3 IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin (n = 98) (n = 102) (n = 109)

Body as a Whole Pain 55% 61% 62% Abdominal Pain 55% 61% 50% Headache 19% 26% 26%Cardiovascular Hypertension 14% 23% 34% Hypotension 7% 15% 7% Deep Vein Thrombosis 3% 9% 6%Digestive Vomiting 47% 52% 47% Anorexia 30% 43% 35% Constipation 29% 40% 29% Stomatitis 18% 32% 30% Dyspepsia 15% 24% 17%

GI Hemorrhage 6% 24% 19% Weight Loss 10% 15% 16% Dry Mouth 2% 7% 4% Colitis 1% 6% 1%

Hemic/Lymphatic Thrombocytopenia 0% 5% 5%Nervous Dizziness 20% 26% 19%Respiratory Upper Respiratory Infection 39% 47% 40% Epistaxis 10% 35% 32% Dyspnea 15% 26% 25% Voice Alteration 2% 9% 6%Skin/Appendages Alopecia 26% 32% 6% Skin Ulcer 1% 6% 6%Special Senses Taste Disorder 9% 14% 21%Urogenital Proteinuria 24% 36% 36%

Avastin in Combination with FOLFOX4 in Second‑line mCRCOnly Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely to under‑estimate the true adverse event rates due to the reporting mechanisms used in Study 2.Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC)Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring 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 (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%).Metastatic Breast Cancer (MBC)Only Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events were collected in Study 5. Grade 3–4 adverse events occurring at a higher incidence (≥2%) in 363 patients receiving paclitaxel plus Avastin compared with 348 patients receiving paclitaxel alone were sensory neuropathy (24% vs. 18%), hypertension (16% vs. 1%), fatigue (11% vs. 5%), infection without neutropenia (9% vs. 5%), neutrophils (6% vs. 3%), vomiting (6% vs. 2%), diarrhea (5% vs. 1%), bone pain (4% vs. 2%), headache (4% vs. 1%), nausea (4% vs. 1%), cerebrovascular ischemia (3% vs. 0%), dehydration (3% vs. 1%), infection with unknown ANC (3% vs. 0.3%), rash/desquamation (3% vs. 0.3%) and proteinuria (3% vs. 0%).Sensory neuropathy, hypertension, and fatigue were reported at a ≥ 5% higher absolute incidence in the paclitaxel plus Avastin arm compared with the paclitaxel alone arm.Fatal adverse reactions occurred in 6/363 (1.7%) of patients who received paclitaxel plus Avastin. Causes of death were gastrointestinal perforation (2), myocardial infarction (2), diarrhea/abdominal, and pain/weakness/hypotension (2).Avastin is not approved for use in combination with capecitabine or for use in second or third line treatment of MBC. The data below are presented to provide information on the overall safety profile of Avastin in women with breast cancer since Study 6 is the only randomized, controlled study in which all adverse events were collected for all patients. All patients in Study 6 received prior anthracycline and taxane therapy in the adjuvant setting or for metastatic disease. Grade 1– 4 events which occurred at a higher incidence (≥5%) in patients receiving capecitabine plus Avastin compared to the capecitabine alone arm are presented in Table 3.

Table 3 NCI‑CTC Grade 1−4 Adverse Events in Study 6 (Occurring at Higher Incidence [≥5%] in Capecitabine + Avastin vs. Capecitabine Alone)

Capecitabine Capecitabine + Avastin (n = 215) (n = 229)

Body as a Whole Asthenia 47% 57% Headache 13% 33% Pain 25% 31%Cardiovascular Hypertension 2% 24%Digestive Stomatitis 19% 25%Metabolic/Nutrition Weight loss 4% 9%Musculoskeletal Myalgia 8% 14%Respiratory Dyspnea 18% 27% Epistaxis 1% 16%Skin/Appendages Exfoliative dermatitis 75% 84%Urogenital Albuminuria 7% 22%

GlioblastomaAll adverse events were collected in 163 patients enrolled in Study 7 who either received Avastin alone or Avastin plus irinotecan. All patients received prior radiotherapy and temozolomide. Avastin was administered at 10 mg/kg every 2 weeks alone or in combination with irinotecan. Avastin was discontinued due to adverse events in 4.8% of patients treated with Avastin alone. In patients receiving Avastin alone (N=84), the most frequently reported adverse events of any grade were infection (55%), fatigue (45%), headache (37%), hypertension (30%), epistaxis (19%) and diarrhea (21%). Of these, the incidence of Grade ≥3 adverse events was infection (10%), fatigue (4%), headache (4%), hypertension (8%) and diarrhea (1%). Two deaths on study were possibly related to Avastin: one retroperitoneal hemorrhage and one neutropenic infection.In patients receiving Avastin alone or Avastin plus irinotecan (N=163), the incidence of Avastin‑related adverse events (Grade 1– 4) were bleeding/hemorrhage (40%), epistaxis (26%), CNS hemorrhage (5%), hypertension (32%), venous thromboembolic event (8%), arterial thromboembolic event (6%), wound‑healing complications (6%), proteinuria (4%), gastrointestinal perforation (2%), and RPLS (1%). The incidence of Grade 3–5 events in these 163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).Metastatic Renal Cell Carcinoma (mRCC)All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract hemorrhage, and traumatic hematoma).Grade 1–5 adverse events occurring at a higher incidence (≥ 5%) in patients receiving IFN‑α plus Avastin compared to the IFN‑α plus placebo arm are presented in Table 4.

Table 4 NCI‑CTC Grades 1−5 Adverse Events in Study 9

(Occuring at Higher Incidence [≥ 5%] in IFN‑α + Avastin vs. IFN‑α + Placebo)

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin Preferred terma (n = 304) (n = 337)Gastrointestinal disorders Diarrhea 16% 21%General disorders and administration site conditions Fatigue 27% 33%Investigations Weight decreased 15% 20%Metabolism and nutrition disorders Anorexia 31% 36%Musculoskeletal and connective tissue disorders Myalgia 14% 19% Back pain 6% 12%Nervous system disorders Headache 16% 24%Renal and urinary disorders Proteinuria 3% 20%Respiratory, thoracic and mediastinal disorders Epistaxis 4% 27% Dysphonia 0% 5%Vascular disorders Hypertension 9% 28%

aAdverse events were encoded using MedDRA, Version 10.1.

The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); 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) and pulmonary embolism (5 vs. 1).6.2 ImmunogenicityAs with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody development in patients receiving Avastin has not been adequately determined because the assay sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.Immunogenicity data are highly dependent on the sensitivity and specificity of the assay. Additionally, the observed incidence of antibody positivity in an assay may be influenced by several factors, including sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin with the incidence of antibodies to other products may be misleading.6.3 Postmarketing ExperienceThe following adverse reactions have been identified during post‑approval use of Avastin. 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.Body as a Whole: PolyserositisCardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusionEye disorders (reported from unapproved use for treatment of various ocular disorders): Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual disturbances; Ocular hyperemia; Ocular pain and/or discomfortGastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulcerationHemic and lymphatic: PancytopeniaRenal: Renal thrombotic microangiopathy (manifested as severe proteinuria)Respiratory: Nasal septum perforation, dysphonia7 DRUG INTERACTIONSA drug interaction study was performed in which irinotecan was administered as part of the FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.In a randomized study in 99 patients with NSCLC, based on limited data, there did not appear to be a difference in the mean exposure of either carboplatin or paclitaxel when each was administered alone or in combination with Avastin. However, 3 of the 8  patients receiving Avastin plus paclitaxel/carboplatin had substantially lower paclitaxel exposure after four cycles of treatment (at Day 63) than those at Day 0, while patients receiving paclitaxel/carboplatin without Avastin had a greater paclitaxel exposure at Day 63 than at Day 0.In Study 9, there was no difference in the mean exposure of interferon alfa administered in combination with Avastin when compared to interferon alfa alone.8 USE IN SPECIFIC POPULATIONS8.1 PregnancyPregnancy Category CThere are no studies of bevacizumab in pregnant women. Reproduction studies in rabbits treated with approximately 1 to 12 times the recommended human dose of bevacizumab resulted in teratogenicity, including an increased incidence of specific gross and skeletal fetal alterations. Adverse fetal outcomes were observed at all doses tested. Other observed effects included decreases in maternal and fetal body weights and an increased number of fetal resorptions. [See Nonclinical Toxicology (13.3).]Human IgG is known to cross the placental barrier; therefore, bevacizumab may be transmitted from the mother to the developing fetus, and has the potential to cause fetal harm when administered to pregnant women. Because of the observed teratogenic effects of known inhibitors of angiogenesis in humans, bevacizumab should be used during pregnancy only if the potential benefit to the pregnant woman justifies the potential risk to the fetus.8.3 Nursing MothersIt is not known whether Avastin is secreted in human milk, but human IgG is excreted in human milk. Published data suggest that breast milk antibodies do not enter the neonatal and infant circulation in substantial amounts. Because many drugs are secreted in human milk and because of the potential for 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 (approximately 20 days [range 11–50 days]) and the importance of the drug to the mother. [See Clinical Pharmacology (12.3).]8.4 Pediatric UseThe safety, effectiveness and pharmacokinetic profile of Avastin in pediatric patients have not been established.Antitumor activity was not observed among eight children with relapsed glioblastoma treated with bevacizumab and irinotecan. There is insufficient information to determine the safety and efficacy of Avastin in children with glioblastoma.Juvenile cynomolgus monkeys with open growth plates exhibited physeal dysplasia following 4 to 26 weeks exposure at 0.4 to 20 times the recommended human dose (based on mg/kg and exposure). The incidence and severity of physeal dysplasia were dose‑related and were partially reversible upon cessation of treatment.8.5 Geriatric UseIn Study 1, severe adverse events that occurred at a higher incidence (≥ 2%) in patients aged ≥65 years as compared to younger patients were asthenia, sepsis, deep thrombophlebitis, hypertension, hypotension, myocardial infarction, congestive heart failure, diarrhea, constipation, anorexia, leukopenia, anemia, dehydration, hypokalemia, and hyponatremia. The effect of Avastin on overall survival was similar in elderly patients as compared to younger patients.In Study 2, patients aged ≥ 65 years receiving Avastin plus FOLFOX4 had a greater relative risk as compared to younger patients for the following adverse events: nausea, emesis, ileus, and fatigue.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 Precautions (5.8).]In Study 5, there were insufficient numbers of patients ≥ 65 years old to determine whether the overall adverse events profile was different in the elderly as compared with younger patients.Of the 742 patients enrolled in Genentech‑sponsored clinical studies in which all adverse events were captured, 212 (29%) were age 65 or older and 43 (6%) were age 75 or older. Adverse events of any 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 cough, and voice alteration.In an exploratory, pooled analysis of 1745 patients treated in five randomized, controlled studies, there were 618 (35%) patients aged ≥65 years and 1127 patients <65 years of age. The overall incidence of arterial thromboembolic events was increased in all patients receiving Avastin with 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 (8.5% vs. 2.9%) as compared to those < 65 years (2.1% vs. 1.4%). [See Warnings and Precautions (5.5).]10 OVERDOSAGEThe highest dose tested in humans (20 mg/kg IV) was associated with headache in nine of 16 patients and with severe headache in three of 16 patients.

AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab) AVASTIN® (bevacizumab)

02/11 AVA000030660010127309

Initial U.S.Approval: February 2004Code Revision Date: February 2011

Avastin® is a registered trademark of Genentech, Inc.

©2011 Genentech, Inc.

Avastin® (bevacizumab) Manufactured by:Genentech, Inc.A Member of the Roche Group1 DNA WaySouth San Francisco, CA94080‑4990

71819ge_c 1 3/8/11 11:24 PM

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…To reach beyond convention…

IndicationsAvastin 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 informationGastrointestinal (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 beendetermined. 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 vaginalbleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events amongpatients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp ofred 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 fistulaformation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverseevents for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posteriorleukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurredin 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 reactionsIn NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treatedpatients 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-abdominalthrombosis (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% vs5%), 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.

©2010 Genentech USA, Inc. All rights reserved. 9146401 (01/10) Printed in USA. www.avastin.com

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