TAP Vol 2 Issue 6

NCCN Guidelines updates 3 TM

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Ipilimumab in melanoma 30

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VOLUME 2, ISSUE 6

Pain management 36

APRIL 15, 2011 ASCOPost.com

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

Teamwork in Cancer Care: More Important Than Ever

2011 Genitourinary Cancers Symposium

Longer Screening Intervals Make Sense in Men with Initial PSA Levels < 2 ng/mL

By Alice Goodman

A

large cohort study suggests that an initial prostate-specific ‘Game-Changer’ in PSA Screening? antigen (PSA) level of 3 ng/mL should be the cutoff for biopsy of ■■ Men with initial PSA levels < 2 ng/mL do not require annual the prostate and that men with iniscreening, and the interval for men with initial PSA levels tial PSA values < 2 ng/mL should < 1 ng/mL could be adjusted upward to 8 years. be screened at substantially longer ■■ The cutoff threshold for biopsy should be PSA of 3 ng/mL or higher, intervals than is the current pracnot the current threshold of PSA equal to 4 ng/mL or higher. tice. Experts agreed that the study’s findings suggest a new cutoff for the European Randomized Study of Screening for prostate biopsy and longer screening intervals for Prostate Cancer (ERSPC) at the recent Genitourimen at very low risk of prostate cancer. nary Cancers Symposium held in Orlando, Florida.

Avoids Unnecessary Procedures “This means that we can possibly avoid unnecessary “These results justify use of a threshold of testing, diagnosis, and treatment of less aggressive ≥ 3 ng/mL for prostate biopsy,” stated Meelan disease, with the accompanying side effects, by foBul, MD, Erasmus University Medical Center of cusing biopsies and other follow-up on men with Rotterdam, The Netherlands, who presented the higher initial PSA levels above 3.0 ng/mL.” continued on page 13 findings of a Dutch cohort study that was part of Perspective

The Lessons of Japan and Radiation: Recognizing the Good and Ill of a Powerful Tool

By Nora Janjan, MD, MPSA, MBA, and John Goodman, PhD

The web of our life is of a mingled yarn, good and ill together.

—William Shakespeare

T

he massive devastation of Japan by an earthquake and tsunami is an overwhelming tragedy, and the world mourns for its victims. The brute destruction of the sophisticated infrastructure by natural forces and subsequent inclement weather continue 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

weapons is fateful. While the radiation that caused the wartime devastation could not be seen, the aftermath was viewed worldwide. Seeing the consequences of nuclear war struck fear into every world leader. This fear helped foster a mutual détente during 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 Incidents Even 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.

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

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 wanted 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 presence 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 profession has come and how important nurses are to the current health-care system.

Most Trusted Profession For years, Gallup poll results have shown that nurses are the most trusted profession continued on page 2

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

MORE IN THIS ISSUE Oncology Meetings Coverage NCCN 16th Annual Conference ������������������������������������������������ 3 2011 Genitourinary Cancers Symposium ����������1, 10, 17, 18 2011 Gastrointestinal Cancers Symposium ���������������������� 16, 31 A Conversation with James F. Holland ������� 4 Direct from ASCO ��������������������������������������� 16 FDA Update ���������������������������������� 30, 41, 53

continued on page 54

A Harborside Press® Publication

The ASCO Post | APRIL 15, 2011

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Opinion

Teamwork in Cancer Care continued from page 1

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

William T. McGivney, PhD National Comprehensive Cancer Network

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

James L. Mulshine, MD Rush University Medical Center

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology 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 Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

Derek Raghavan, MD, PhD Taussig Cancer Center at Cleveland Clinic Richard L. Schilsky, MD University of Chicago Comprehensive Cancer Center Andrew D. Seidman, MD Memorial Sloan-Kettering Cancer Center George W. Sledge, MD Indiana University Thomas J. Smith, MD Virginia Commonwealth University Jamie H. Von Roenn, MD Robert H. Lurie Comprehensive Cancer Center at Northwestern University Lynn D. Wilson, MD Yale University School of Medicine Stanley H. Winokur, MD Singer Island, Florida William C. Wood, MD Winship Cancer Institute, Emory University INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan 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

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in the United States. It is estimated that there are around 3 million nurses in our country, so nurses have power in numbers and are well respected. But from my vantage point as the 21st President of the Oncology Nursing Society (ONS), oncology nurses do not completely recognize the influence they have in the health-care arena, nor do they completely 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 Affordable 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 clinical trials, added research and education for pain management, and a more important future focus on prevention 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 affect patients with cancer. Surprisingly, 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 million Americans who currently do not have insurance will have access to coverage, and some of those millions will present with cancer diagnoses. 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 successful 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 successfully and safely.

Opportunities and Challenges So as I enter my final year as President 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. Nurses 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 funding to conduct research.

It will be a busy year, but an incredible 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!

■

Erratum:

In the March 15 print issue of The ASCO Post (2[5]:8, 2011), an article on the interim results of a trial comparing intermittent vs continuous androgen suppression in patients with PSA progression after radical therapy for prostate cancer (Klotz L, et al: 2011 Genitourinary Cancers Symposium, Abstract 3) misreported 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 version of the article reflects this correction and may be viewed via the SEE PAGE 51 2D barcode here.

ASCOPost.com | APRIL 15, 2011

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News Clinical Oncology

NCCN Clinical Practice Guidelines™:

Important Updates for 2011 T

he National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology™ are among the most widely used guidelines in oncology practice. The Guidelines cover 97% of all patients with cancer and are continually 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

Myeloid Growth Factors

“There is an increase in myelodysplastic syndrome and acute leukemia, but the allcause 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

“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 skeletal-related events in patients with bone metastases.

■■ Bevacizumab (Avastin), in combination with paclitaxel, was reaffirmed as an option for metastatic disease.

■■ Hormonal status and HER2 status should be determined in metastatic disease patients.

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

■■ Outcomes with pegfilgrastim (Neulasta) and filgrastim (Neupogen) 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 reduction in all-cause mortality in appropriate 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 melanoma.

■■ The presence of any mitosis (mitotic rate ≥ 1 mm2) in a thin melanoma (≤ 1 mm) upstages the patient to stage IB and has implications 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 immunotherapy strategies are yielding dramatic, and sometimes durable, responses and will change the treatment paradigm.

■■ Radiotherapy and genetic analysis 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 guidelines for the treatment of sarcoma pertains to the management of desmoid 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 shortterm 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 response; 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 catcontinued on page 9

The ASCO Post | APRIL 15, 2011

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Expert’s Corner Spotlight on Research

A Conversation with James F. Holland, MD

Reflections on cancer research, prevention, cure, and the common house mouse

By Ronald Piana

James F. Holland, MD

J

ames F. Holland, MD, Distinguished 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 accomplishments over the past several decades reinforce his concept that there are no incurable cancers, just precurable ones.

The Early Days Combining 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 learning 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 resistant 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 combination enhances the potential for eradication. Cells resistant to drug

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 Today What 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

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.

A might in fact not be resistant to simultaneously 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 became 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 cooperative group study in the United States,

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

How would you characterize clinical 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, often 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 Biology Over the past 2 decades, our understanding of tumor biology has increased at a breakneck pace. However, mortality rates from cancer remain high. Are you optimistic?

Absolutely. However, I personally think the phrases targeted or personalized therapies are slightly misleading. First off, the concept of specific targeting is not new. Targeting specific enzymes or receptors is simply more intelligent therapy.

Over the past decades we’ve unearthed the complexity of cancer biology, and as we venture deeper into its molecular components it will undoubtedly become even more comcontinued on page 8

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The ASCO Post | APRIL 15, 2011

PAGE 8

Expert’s Corner

James F. Holland continued from page 4

plex. But for each bit of information we obtain about a particular gene, it clarifies a pathway that is either attackable today or that will be attackable 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

are showing signs of vulnerability to chemotherapy.

Cure vs Chronic Illness Another contemporary concept is that we need to reach a point at which we manage cancer as a long-term chronic disease. What’s your perspective on that approach?

The prime objective is prevention. 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 diseases this balance can be achieved. In metastatic cancer there are a few diseases, such as lymphoma, myeloma, and chronic myelogenous leukemia, where dramatic therapeutic advances have allowed patients to live without 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 decades. 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 number of cancers—choriocarcinoma, testis cancer, large-cell lymphomas, 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 living longer with metastatic disease is not as important or realistic as is the effort at cure.

In 1976, when Bonadonna, Veronesi, and colleagues published their report on adjuvant CMF [cyclophosphamide, methotrexate, fluorouracil] 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 portion of women who retrospectively must have had micrometastatic disease 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 chemotherapy after surgery (or perhaps radiation) for their primary tumor.

This paradigm offers opportunities for many other cancers. So I’m not an advocate of living with your cancer for a long period; I’m an advocate of getting rid of your cancer altogether. continued on page 17

ASCOPost.com | APRIL 15, 2011

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News

NCCN Guidelines continued from page 3

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egory 1 recommendation for adenocarcinoma, large cell disease, and NSCLC NOS but is not recommended for squamous cell carcinoma.

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

Platinum doublets, chemotherapy with bevacizumab, and newer targeted agents are improving outcomes 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 multimodality 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 guidelines is the addition of a new guideline for post-transplant lymphoproliferative disorder.

■■ Recommended treatment options for post-transplant lymphoproliferative disorder include reduction of immunosuppression, single-agent rituximab (Rituxan), and chemoimmunotherapy.

■■ Category 1 recommended treatments for follicular lymphoma now include bendamustine (Treanda)/ rituximab for first-line treatment, rituximab maintenance, and radioimmunotherapy for treatment after

first remission.

■■ Patients with mantle cell lymphoma who have a low proliferation fraction and are treated aggressively are potentially curable.

Head and Neck Cancer

Prostate Cancer

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

“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 incorporates the strictest Epstein criteria from all definitions for clinically insignificant prostate cancer.

■■ Active surveillance is recommended as the sole initial treatment for men meeting the criteria for very low-risk disease who have a life expectancy 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 considered 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 symptomatic castrate-resistant metastatic 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 alternative to zoledronic acid for the prevention of skeletal-related events.

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

■■ An algorithm for mucosal melanoma 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 better prognosis. Testing for the virus is now suggested for oropharynx cancers, as well as occult primary cancers with a squamous cell or undifferentiated histology.

■■ The therapeutic benefits associated with the integration of chemotherapy with radiation compared with radiation alone continues to be upheld in several disease settings.

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

Ovarian Cancer

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

■■ Stage II, III, or IV epithelial ovarian cancer should be considered for intraperitoneal 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 carboplatin/paclitaxel upfront; participation in clinical trials is encouraged.

■■ New language supports the discussion of the pros and cons of CA-125 monitoring, 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

“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.

■■ Bortezomib (Velcade)/cyclophosphamide/dexamethasone is now a category 2A option for induction therapy in the transplant setting, and lenalidomide (Revlimid)/bortezomib/dexamethasone is a promising category 2B alternative.

■■ Lenalidomide maintenance, which has nearly doubled progression-free survival, 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 nontransplant setting.

■■ Cyclophosphamide/bortezomib/ continued on page 10

The ASCO Post | APRIL 15, 2011

PAGE 10

2011 Genitourinary Cancers Symposium Kidney Cancer

Studies Address Schedule of Sunitinib, Novel Agent Added to Sorafenib in Metastatic Renal Cell Carcinoma

By Alice Goodman

T

wo studies presented at this year’s Genitourinary Cancers Symposium shed light on treatment of metastatic 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 angiogenesis did not provide additional efficacy when combined with the VEGF inhibitor sorafenib (Nexavar).

Dosing of Sunitinib The approved dosing schedule for sunitinib in metastatic renal cell carcinoma—4 weeks on treatment and 2 weeks off—should be followed to achieve optimal results, according to results of a randomized, phase II

NCCN Guidelines continued from page 9

dexamethasone and cyclophosphamide/lenalidomide/dexamethasone 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

ple, but the data impact the real-world use of sunitinib.

Physicians should have patients adhere to the standard dosing schedule. Some [community] physicians are inventing their own schedules, but they should be using the approved schedule.”

The standard schedule of Robert Motzer, MD Brian Rini, MD sunitinib (50 mg once daily, study.1 Time to progression was su4 weeks on/2 weeks off) was perior on the approved schedule vs a approved because studies suggested continuous schedule on lower-dose that this was the most effective way to sunitinib (see Fig. 1 on page 13). The give the drug. “The 2 weeks off gave study was supported by Pfizer. patients a break from the associated According to lead investigator Robtoxicities of fatigue, hand-foot synert Motzer, MD, Attending Physician drome, hypertension, and diarrhea,” at Memorial Sloan-Kettering Cancer Dr. Motzer explained.

Center, New York, “The message of “There has been interest in an alterthis study is straightforward and simnative dosing schedule to reduce side ■■ 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, although ASCO is not one of them.

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

Radiation Oncology

“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 SloanKettering Cancer Center, New York

“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

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

Study Data The phase II study randomly assigned 292 patients to the approved schedule (arm A) vs continuous sunitinib (arm B). Median age was 62 years, and 65% were male. Patients were treated with a median of four cycles 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; continued on page 12

indications for SBRT. ■■ Used to treat pediatric tumors, proton therapy can deliver an increased dose to the target volume while decreasing the dose to normal tissue, thereby reducing morbidity.

■■ Intensity-modulated radiation therapy 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 indicated serving on an advisory board, speakers bureau, as an expert witness, or consultant for Boehringer Ingelheim GmbH, Daiichi-Sankyo Co., Eli Lilly and Company, Genentech, Inc., Merck & Co., Inc., Novartis Pharmaceuticals Corporation, Biodesix, Inc., Poniard Pharmaceuticals, Inc., Prometheus, 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 Pharmaceuticals, 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 GeSEE PAGE 51 netics, Roche Laboratories, Inc., and sanofi-aventis U.S.

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

Proven CINV prevention in a single IV dose • Powerful CINV prevention in the first 24 hours and up to 5 days following moderately emetogenic chemotherapy 1,2 • Lasts long against nausea following moderately emetogenic chemotherapy 3 • Powerful acute CINV prevention following highly emetogenic chemotherapy 4 • Eisai offers a variety of support programs and resources

Indication ALOXI® (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 file. 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.

STARTS STRONG. LASTS LONG.

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

The ASCO Post | APRIL 15, 2011

PAGE 12

2011 Genitourinary Cancers Symposium Renal Cell Carcinoma continued from page 10

this difference was not statistically significant 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.

ALOXI® (palonosetron HCl) injection BRIEF SUMMARY OF PRESCRIBING INFORMATION INDICATIONS AND USAGE Chemotherapy-Induced Nausea and Vomiting ALOXI 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 courses DOSAGE AND ADMINISTRATION Recommended Dosing Chemotherapy-Induced Nausea and Vomiting Dosage 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. Administration ALOXI 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.

CONTRAINDICATIONS ALOXI 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 PRECAUTIONS Hypersensitivity Hypersensitivity reactions may occur in patients who have exhibited hypersensitivity to other 5-HT3 receptor antagonists.

ADVERSE REACTIONS 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 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 ChemotherapyInduced Nausea and Vomiting Studies ≥ 2% in any Treatment Group ALOXI Ondansetron Dolasetron Event 0.25 mg 32 mg I.V. 100 mg I.V. (N=410) (N=194) (N=633) 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%) 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 flatulence.

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

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

General: 1%: weakness, < 1%: fatigue, fever, hot flash, flu-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 fluctuations, 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 Experience The following adverse reactions have been identified 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 INTERACTIONS Palonosetron 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 significant 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 significantly 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 significant 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 five chemotherapeutic agents tested (cisplatin, cyclophosphamide, cytarabine, doxorubicin and mitomycin C) in murine tumor models.

USE IN SPECIFIC POPULATIONS Pregnancy Teratogenic Effects: Category B Teratology 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 Delivery Palonosetron has not been administered to patients undergoing labor and delivery, so its effects on the mother or child are unknown.

Nursing Mothers It 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.

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

In general, quality of life was not significantly different in the two study arms.

It improved and then plateaued on continuous dosing, and as might be expect-

Pediatric Use Safety and effectiveness in patients below the age of 18 years have not been established.

Geriatric Use Population 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 efficacy were observed in geriatric patients for the CINV indication and none are expected for geriatric PONV patients. However, ALOXI efficacy in geriatric patients has not been adequately evaluated.

Renal Impairment Mild to moderate renal impairment does not significantly 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 Impairment Hepatic impairment does not significantly affect total body clearance of palonosetron compared to the healthy subjects. Dosage adjustment is not necessary in patients with any degree of hepatic impairment.

Race Intravenous 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.

OVERDOSAGE There 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 fixed 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 INFORMATION See FDA-Approved Patient Labeling (17.2) in full prescribing information Instructions 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 Only Mfd 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

ed, there was an “on/off” phenomenon with the 4/2 schedule. “We saw no benefit 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 continuous dosing,” he emphasized.

“We’ve been waiting for this information [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.

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.

Pazopanib vs Sunitinib Dr. 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 completed 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 certain patients. . . . The main point is to use whatever drug is best for the patient.”

Related Study Dr. Rini was lead author of a related phase II study designed to evaluate the combination of sorafenib—another

ASCOPost.com | APRIL 15, 2011

PAGE 13

2011 Genitourinary Cancers Symposium

PSA Screening Intervals continued from page 1

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 initial PSA values of less than 1 ng/mL support prolongation of the screening interval for these men for up to 8 years.”

Monique Roobol, PhD

Study Details The 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 cancer from 1997 on. Almost 20,000 men were randomly assigned to serial screening PSA tests, and the threshold for biopsy was PSA of 3 ng/mL or higher. The report at the Genito-

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

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

1.0 Probability of no tumor progression

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

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

The study randomly assigned 152 patients with metastatic renal cell carcinoma 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 endpoint of progression-free survival, all three arms of the study had a median progression-free survival of 9 months. The data showed a hint SEE PAGE 51 of a benefit for over-

0.8

■

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, Sanofiaventis, and Novartis.

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

0.6 0.4 0.2 0.0

HR = 0.77 (95% CI = 0.57–1.04) P = .090 (unstratified log-rank test) 0

10

Time (months)

30

20

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.

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 initiated, it was not clear that sunitinib would become the preferred first-line urinary Cancers Symposium focused on 15,758 (79%) men with PSA values < 3.0 ng/mL at the first screening test; men were screened every 4 years.

At baseline, men were stratified according 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 median follow-up of 11 years, 915 cancers were detected in the Dutch cohort, 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 occurred over the course of the study, for a mortality rate of 0.15%.

A fourfold increased risk of cancer was seen when men with initial PSA levels < 1 ng/mL were compared 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 during the study, 138 were deemed aggressive (ie, definite clinical stage T2c or higher, Gleason score ≥ 8, and PSA level of 20 ng/ mL or higher). A 2.7-fold increase was SEE PAGE 51 observed between

therapy for metastatic renal cell carcinoma. “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

References 1. Motzer RJ, Hutson TH, Olsen MR, et al: Randomized phase II multicenter study of the efficacy and safety of sunitinib on the 4/2 versus continuous dosing schedule as first-line therapy of metastatic renal cell carcinoma: Renal EFFECT Trial.

Genitourinary Cancers Symposium. Abstract 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 cancer: A randomized, double-blind, placebocontrolled, phase II study. Genitourinary Cancers Symposium. Abstract 309. February 19, 2011.

Expert Point of View

T

his study gives us confidence that annual PSA screening will become a thing of the past,” said Nicholas Vogelzang, MD, US Oncology, Las Vegas, who moderated the press telecast at the Genitourinary 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 Nicholas Vogelzang, MD the future is headed toward personalization of PSA screening. “The Dutch study is helpful, although it does not speak to the molecular 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.

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 observed 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.

Reference 1. Bul M, van Leeuwen PJ, Zhu X, et al: Prostate cancer incidence and diseasespecific 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.

EGFR EGFR

RAS

Searching for a target in metastatic melanoma?

Begin with BRAF MEK

ERK

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

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

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

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

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

The ASCO Post | APRIL 15, 2011

PAGE 16

2011 Gastrointestinal Cancers Symposium Pancreatic Cancer

Biomarkers Can Assess Recurrence Risk in Patients with Resected Pancreatic Cancer

By Caroline Helwick

T

he movement to relate gene profiles and protein expression to tumor aggressiveness is as active in pancreatic cancer as in other more common tumors, according to studies presented at the 2011 Gastrointestinal Cancers Symposium, held January 20–22 in San Francisco. Two investigations in particular correlated biomarkers with outcomes after surgery and/or chemoradiation.

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 survival better than nomograms derived from using clinicopathologic variables, which are only determined after examination of the resected speci-

S100A2 and A4 Related to Poor Prognosis

David Chang, MD

Dr. Chang and colleagues evaluated the expression of two biologically relevant proteins, S100A4 and S100A2,2 which are known to be related to metastatic potential, chemoresistance, and poor-prognosis cancer phenotypes. They associated the expression of these proteins with survival in a cohort of 372 patients who underwent surgical resection for pancreatic cancer and incorporated this information, along with clinicopatho-

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 polymorphism was associated with a significantly reduced overall survival in patients with resectable pancreatic cancer.3

1.0

Cummulative survival

Aberrant expression of two calcium-binding proteins stratifies pancreatic 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 potential 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 overall outcomes, but none have been defined for pancreatic cancer,” said David Chang, MD, of the Cancer Research Program at the Garvan Institute of Medical Research in Sydney, Australia, who is part of a team led by Professor Andrew Biankin.

RecQ1 A159C Polymorphism Associated with Survival

Median survival: 34.3 vs 15.6 vs 11.9 months n = 318 P < .0001

0.8 0.6

S100A2+

0.4

S100A2– / A4+ S100A2– / A4–

0.2 0 0

20

40

60

Patients at risk S100A2– / A4– 85 S100A2– / A4+ 185 S100A2+ 48

80

100

120

140

4 2

2 1

0 1

Months 54 62 7

28 24 2

11 9 0

5 6

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

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 after pancreatectomy, compared with 15.6 months for those who were S100A2-negative but S100A4-positive 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 consequence, overall outcomes for pancreatic cancer,” Dr. Chang concluded.

The investigators are now refining means of assessing biomarker status preoperatively, to put this information into clinical use.

The study included 154 patients with resected pancreatic cancer enrolled on the Radiation Therapy Oncology Group (RTOG) 9704 trial of fluorouracil (5‑FU)-based chemoradiation, preceded and followed by 5-FU or gemcitabine. Investigators evaluated the association between genotype (RecQ1 A159 AA, AC, and CC) and overall survival, and found the AA genotype to be protective.

The RecQ1 variant AC/CC genotype 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

Donghui Li, PhD

Cancer Center, Houston. The RecQ1 effect (AA vs AC/CC) is more definitive 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 prognostic or predictive factor for patients with resectable pancreatic cancer who are treated with adjuvant 5-FU before and after 5-FU-based chemoradiation,” Dr. Li commented.

“The value of the current study is that it confirmed our previous finding that the RecQ1 A159C variSEE PAGE 51 ant was associated with significantly reduced overall survival in patients with resectable pancreatic cancer,” Dr. Li told The ASCO Post. “The current study was conducted 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. Gastrointestinal Cancers Symposium. Abstract 154. Presented January 21, 2011.

2. Biankin AV, Kench JG, Colvin EK, et al: Expression of S100A2 calciumbinding 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 polymorphism with overall survival of patients with resected pancreatic cancer: A replication study in RTOG 9704. Gastrointestinal Cancers Symposium. Abstract 156.

Presented January 21, 2011.

ASCOPost.com | APRIL 15, 2011

PAGE 17

2011 Genitourinary Cancers Symposium Most Patients with Muscle-invasive Bladder Cancer Did Not Receive Optimal Multimodality Care at 15 Academic Centers

By Alice Goodman

A

lthough guidelines for the management of muscle-invasive bladder cancer recommend cisplatinbased neoadjuvant chemotherapy based on level 1 evidence showing a survival advantage, only a small percentage of patients undergoing radical cystectomy who were eligible for this treatment received it in a recent study, which was presented at the 2011 Genitourinary Cancers Symposium.1 Surprisingly, these findings emerged from a survey of academic centers, where one would expect state-of-the-art treatment to be implemented.

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

Among all patients treated with perioperative chemotherapy, only 9% received neoadjuvant cisplatinSEE PAGE 51 based chemotherapy; 31% of those treated with neoadjuvant chemotherapy did not receive cisplatin,” stated Andrew Feifer, MD, Memorial Sloan-Kettering Cancer

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

Study Details The survey was conducted among 15 academic centers and included 4,972 patients who underwent radical cystectomy for nonmetastatic muscle-invasive bladder cancer from 2003 to 2008. The retrospective study sought to determine current baseline practice patterns regarding four quality care indicators at academic centers. A second part of the study will explore the reasons for practice variations found during the first phase, Dr. Feifer explained.

The four quality indicators were: referral to medical oncology for multimodality therapy; if neoadjuvant therapy was recommended, use of cisplatin for at least three cycles; if adjuvant therapy was recommended, use of adjuvant cisplatin for at least three cycles; and bilateral pelvic lymphadenectomy of at least the iliac, hypogastric, and obturator lymph nodes.

Results showed that 33.6% of pa-

Practice Patterns in Bladder Cancer ■■ 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.

James F. Holland continued from page 8

Preventive Approaches What are your thoughts on the advances we’ve seen in preventive vaccines such as that for human papillomavirus (HPV)?

The rate of cervical carcinoma in the United States has been decreasing 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 development of cervical cancer might be 20 years. So we’ll have to wait for the data before we come to conclusions about immunization against cancer. Until then, increased awareness about known risk factors for developing cancer such as tobacco products, various pollutants, and dietary habits must still command medical attention.

Expert Point of View

T

hese 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 standard of care,” said Maha A. Hussain, MD, Program Chair of the 2011 Genitourinary Cancers Symposium and Professor and Associate Director for Clinical 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 contributors, 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 chemotherapy 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.

tients received any perioperative chemotherapy: 12.4% received any neoadjuvant therapy and 21.7% received any adjuvant chemotherapy. An analysis of time trends during 2003 to 2008 showed that the use of neoadjuvant therapy increased while the use of adjuvant therapy was slightly reduced. In a subset of 3,298 patients, among those who received any neoadjuvant chemotherapy, 69.4% received cisplatin; among those who received any perioperative chemotherapy, 63.5% received cisplatin.

Overall, 80% of patients treated with perioperative chemotherapy received

Ongoing Research What 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 research. My research partner, Dr. Beatriz Pogo, our colleagues, and I have identified a human mammary tumor virus (HMTV) in breast cancer that is 95% homologous to the mouse mammary tumor virus (MMTV) known to cause breast cancer in mice. The viral sequences are not in adjacent normal tissues, and thus are not genetically

three cycles. Almost 95% of patients underwent bilateral lymph node dissection. The reasons for which patients were treated with or without systemic therapy are speculative.

■

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

Reference 1. Feifer A, Taylor JM, Shouery M, et al: Multi-institutional quality-of-care initiative for nonmetastatic, muscle invasive, transitional cell carcinoma of the bladder: Phase I. Genitourinary Cancers Symposium. Abstract 240. Presented February 18, 2011.

inherited, but rather, acquired. The virus 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 indigenous, only 1% to 12% of breast cancers 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.

■

The ASCO Post | APRIL 15, 2011

PAGE 18

2011 Genitourinary Cancers Symposium GU Cancer Roundup

Salvage Therapies Show Mixed Results for Metastatic Urothelial Cancer in Preliminary Studies

By Alice Goodman

D

espite research efforts, an effective salvage treatment for metastatic urothelial cancer that has relapsed following first-line chemotherapy for metastatic disease remains an unmet need. Three different abstracts presented at the recent Genitourinary Cancers Symposium evaluated therapies in this setting. A randomized phase II study was negative for the addition of vandetanib to docetaxel in patients with advanced urothelial cancer. Two separate phase II studies had reported favorable results for singleagent nab-paclitaxel (Abraxane) and cetuximab (Erbitux) plus paclitaxel, respectively, in this setting, although both studies were small and not definitive. At best, “cautious optimism” is the watchword regarding these two strategies. Both require further study.

Vandetanib plus Docetaxel In a multi-institutional, doubleblind, randomized phase II trial in 142 patients with previously treated, platinum-resistant advanced urothelial cancer, the addition of the investigational agent vandetanib to docetaxel failed to improve progression-free survival, overall response rate, or overall survival and incurred greater toxicity compared with docetaxel alone.1 A total of 37 patients whose disease progressed on the docetaxel arm crossed over to vandetanib. Vandetanib had no benefit in these patients.

“There is no standard of care for metastatic urothelial cancer that progresses after platinum-containing chemotherapy. The study sought to evalu-

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.

ate whether the addition of vandetanib, a dual antiangiogenesis inhibitor which blocks VEGF and EGFR simultaneously, 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.

INDICATIONS XELODA 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 defined 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.

Single-agent Nab-paclitaxel A phase II trial evaluated singleagent nab-paclitaxel, the albuminbound nanoparticle formulation of

y Assista nc e Co-payC o-pa Card RxBIN:

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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 hyperbilirubinemia. Other adverse reactions, including serious fluoropyrimidine therapy alone is preferred. XELODA was nonadverse reactions, have been reported. inferior to 5-fluorouracil and leucovorin (5-FU/LV) for diseaseGENEXL-1043_Card_FM.indd 1 11/30/10 Important Safety Information – Monotherapy in MBC free survival (DFS). Although neither XELODA nor combination In a single arm study of XELODA monotherapy in metastatic chemotherapy prolongs overall survival (OS), combination breast cancer, serious adverse events (grade 3/4) occurring in therapy has been demonstrated to improve disease-free ≥5% of patients receiving XELODA (%) were lymphopenia (59), survival compared to 5-FU/LV. Physicians should consider diarrhea (15), hand-foot syndrome (11), hyperbilirubinemia these results when prescribing single-agent XELODA in the (11), fatigue (8), stomatitis (7), and dehydration (5). The most adjuvant treatment of Dukes’ C colon cancer. common adverse events for all grades occurring in ≥30% of Boxed WARNING and Additional Important Safety Information patients receiving XELODA were lymphopenia (94), anemia (72), diarrhea (57), hand-foot syndrome (57), nausea (53), Boxed WARNING fatigue (41), dermatitis (37), and vomiting (37).

Warfarin Interaction—Coagulopathy Important Safety Information – Combination Therapy with >> Patients receiving concomitant capecitabine and oral Docetaxel in MBC coumarin-derivative anticoagulant therapy should have In a phase 3 study of XELODA combination therapy (XELODA their anticoagulant response (INR or prothrombin time) plus docetaxel) in metastatic breast cancer, serious adverse monitored frequently in order to adjust the anticoagulant events (grade 3/4) occurring at a ≥2% higher incidence in patients dose accordingly. receiving XELODA plus docetaxel vs docetaxel alone (%;%) were >> A clinically important XELODA-Warfarin drug interaction lymphocytopenia (89;84), hand-foot syndrome (24;1), stomatitis was demonstrated in a clinical pharmacology trial. (<18;5), diarrhea (<15;<6), anemia (10;<6), hyperbilirubinemia (9;4), nausea (7;2), vomiting (5;2), constipation (2;0), and nail >> Altered coagulation parameters and/or bleeding, disorder (2;0). The most common adverse events for all grades including death, have been reported in patients taking occurring at a ≥5% higher incidence in patients receiving XELODA concomitantly with coumarin-derivative XELODA plus docetaxel vs docetaxel alone were diarrhea (67;48), anticoagulants such as warfarin and phenprocoumon. stomatitis (67;43), hand-foot syndrome (63;8), nausea (45;36), >> Clinically significant increases in prothrombin time (PT) thrombocytopenia (41;23), vomiting (35;24), abdominal pain and INR have been observed in patients who were (30;24), hyperbilirubinemia (20;6), weakness (16;11), dyspepsia stabilized on anticoagulants at the time XELODA was (14;8), lacrimation increase (12;7), and appetite decrease (10;5). introduced. These events occurred within several days Important Safety Information – Monotherapy in Adjuvant and up to several months after initiating XELODA Colon Cancer therapy, and infrequently within 1 month after stopping XELODA. These events occurred in patients with and In a phase 3 study of XELODA monotherapy in colon cancer without liver metastases. in the adjuvant setting, serious adverse events (grade 3/4) occurring in ≥5% of patients receiving either XELODA or 5-FU/ >> Age greater than 60 and a diagnosis of cancer LV (%;%) were increase in bilirubin (20;7), hand-foot syndrome independently predispose patients to an increased risk (17;<1), decrease in lymphocytes (13;13), diarrhea (12;14), of coagulopathy. decrease in neutrophils/granulocytes (3;27), decrease in neutrophils (3;27), stomatitis (2;14), and neutropenia (<1;5).

Contraindications The most common adverse events for all grades occurring in XELODA is contraindicated in patients with known ≥30% of patients receiving either XELODA or 5 FU/LV were hypersensitivity to capecitabine or to any of its components or hand-foot syndrome (60;9), diarrhea (47;65), nausea (34;47), to 5-fluorouracil. XELODA is also contraindicated in patients and stomatitis (22;60). A total of 18 deaths due to all causes with known dihydropyrimadine dehydrogenase (DPD) occurred either on study or within 28 days of receiving study deficiency, or severe renal impairment. drug: 8 (0.8%) patients randomized to XELODA and 10 (1.0%) randomized to 5-FU/LV Most Common Adverse Reactions The most common adverse reactions (≥30%) reported with Please see following brief summary of full Prescribing XELODA were diarrhea, hand-and-foot syndrome, nausea, Information, including Boxed WARNING, for additional vomiting, abdominal pain, fatigue/weakness, and Important Safety Information.

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

2:11 P

ASCOPost.com | APRIL 15, 2011

PAGE 19

2011 Genitourinary Cancers Symposium paclitaxel, in 48 patients with urothelial cancer that progressed on or after platinum-based first-line chemotherapy.2 Among 47 patients evaluable for response, partial responses were achieved in 15 patients (32%) and stable disSEE PAGE 51 ease in 10 (21%); 22

patients (47%) had progressive disease.

Thus, the clinical benefit rate (response or stable disease) was 53%, reported 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 Paclitaxel

Srikala S. Sridhar, MD

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

Pays up to 80% of XELODA co-pay toward each prescription and refill.

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 benefits per calendar year. (Proof of income is required.)

Eligibility

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

PM

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.

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

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. Terms and conditions No 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.

A 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 furcontinued on page 20

The ASCO Post | APRIL 15, 2011

PAGE 20

2011 Genitourinary Cancers Symposium Urothelial Cancer continued from page 10

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 noncomparative. The goal was to study the effect of cetuximab with or with-

Yu-Ning Wong, MD

out paclitaxel in this setting. The investigators decided to close the cetuximab-alone arm after 9 of the first 11 patients showed disease progression by 8 weeks. A total of 28 patients completed accrual to the cetuximab/paclitaxel 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 combination 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

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 BristolMyers Squibb. She has also served as a paid and unpaid consultant to Bristol-Myers Squibb.

References 1. Choueiri TK, Vaishampayan UN, Yu EY, et al: A double-blind, randomized

trial of docetaxel plus vandetanib versus docetaxel plus placebo in platinum-pretreated advanced urothelial cancer. Genitourinary 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 platinumrefractory 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 cetuximab on the efficacy of paclitaxel in previously treated metastatic urothelial cancer.

Genitourinary Cancers Symposium. Abstract 243. Presented February 18, 2011.

Expert Point of View

Maha A. Hussain, MD

I

n an interview with The ASCO Post, Maha A. Hussain, MD, Professor of Medicine and Urology and Associate Director for Clinical Research at the University of Michigan, Ann Arbor, and Program Chair of the 2011 Genitourinary Cancers Symposium, discussed these three presentations on metastatic urothelial cancer.

She said metastatic urothelial cancer is a terminal disease and despite relatively high response rates to chemotherapy (about 50%), the vast majority of patients, including responders, will relapse and die.

“We have no standard secondline 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 research have been pursued: chemotherapy, targeted therapy, and the combination of the two. Dr. Sridhar’s abstract focused on chemotherapy, and the other two abstracts evaluated targeted therapy plus chemotherapy with drugs that have a biologic rationale in urothelial cancer, she continued.

“The vandetanib trial was negative, but the other two trials suggest that both nab-paclitaxel and the combination of cetuximab/ paclitaxel are potentially promising. Ultimately, however, larger trials will be needed to better assess the magnitude of the observed effects,” 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.

The ASCO Post | APRIL 15, 2011

PAGE 22

Direct from ASCO

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

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 educational 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 coverage 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

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

This Education Session will cover advances 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: •H ow do we distinguish aberrant genes that are “drivers” from those that are “passengers?”

• S hould we measure gene mutations and copy number, gene regulation, transcription of genes, or the protein products of genes, or are all of these parameters required?

•H ow do we balance patient risks and benefits in dealing with necessarily imprecise 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 It’s likely direct-to-consumer tests consumers is one of the most rapidly will become part of the frontline advancing areas of personalized gearmamentarium for personalized nomics. This Education Session will medicine in the future. address the evolution and current state of technology, analysis, and reporting — Sancy Leachman, MD, PhD, of test results to patients. Presenters Huntsman Cancer Institute 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 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

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 become 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.

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 Synergistic possibilities arise because these genes are important in both tuto normal cells.

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

mor development and tumor therapy—many tumors are defective in one or more DNA repair genes because continued on page 24

ASCOPost.com | APRIL 15, 2011

PAGE 23

Direct from ASCO

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

I

n recent years, ASCO and Cancer.

Net have joined television-driven, sports-related cancer campaigns under the Society’s Champions Against Cancer initiative. Millions 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 resources from Cancer.Net.

ASCO member William Blackstock, MD, (center), Professor and Chairman of the Department of Radiation Oncology at the Wake Forest 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 during the ACC basketball tournament in Greensboro on March 11. This effort is the latest addition to ASCO’s Champions Against Cancer initiative, which uses sports-oriented collaborations and platforms to educate and empower people about cancer and their health. At left is sportscaster Mike Hogwood.

Following in the same vein, Champions 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-

ASCO Prostate Cancer Advisory Panel son’s ACC Men’s Basketball Tournament, which took place last month in Greensboro, North Carolina. ASCO member William Blackstock, MD, of North Carolina’s Wake Forest University was at the tournament along with ACC Commissioner John Swofford to announce the launch of the new collaboration. Information was provided to ACC fans through a booth at FanFest, online at Cancer.Net and the official 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 cancer. Through primary media vehicle ESPN, athletes, commentators, celebrities, and legendary sports coaches are encouraging a dialogue between men and their families, friends, and physicians about risk factors and treatment options for prostate cancer. ON THE LINE draws on the expertise of ASCO; a panel of ASCO prostate cancer 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

Bruce J. Roth, MD, Panel Chair Washington University School of Medicine

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

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

Howard M. Sandler, MD Cedars-Sinai Medical Center

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

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.

■■ 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.

■

The ASCO Post | APRIL 15, 2011

PAGE 24

Direct from ASCO

ASCO Global Express Launches as New Resource for International Members

T

he 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-

signed to serve and inform these clinicians, who practice outside the United States and deliver cancer care in more than 100 countries worldwide.

PHA

SE I

II TR

IAL

Published every other month, the ASCO Global Express provides commentary from ASCO’s leadership on topics of international priority, information about ASCO’s

CUR

REN

TLY

REC

RUIT

ING

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

Created in response to member requests for a communications channel devoted to the concerns of the international cancer community, in part for the recognition and appreciation of international members, 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 international members. Increasingly, international volunteers are playing an important role in ASCO, from making up over half of the attendees at the Annual Meeting in recent years to serving on the ASCO Board of Directors and numerous committees, including the vibrant International Affairs Committee.

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

Questions or comments about the newsletter should be sent to international@asco.org.

■

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

Annual Meeting continued from page 22

the 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 pathway, 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.

ASCOPost.com | APRIL 15, 2011

PAGE 25

Direct from ASCO

Can’t Go to the 2011 ASCO Annual Meeting? Attend a Best of ASCO® Meeting.

I

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

Vol 28, No 34

December 1, 2010

J OURNAL OF C LINICAL O NCOLOGY Impact of Androgen-Deprivation Therapy on Cognitive Function in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Impact of Androgen-Deprivation Therapy on Physical Function and QOL in Men With Nonmetastatic Prostate Cancer. S.M.H. Alibhai et al Optimizing Collection of Adverse Event Data in Cancer Clinical Trials Supporting Supplemental Indications. L.D. Kaiser et al Editorial: D.J. Sargent et al Availability of Experimental Therapy Outside of Randomized Clinical Trials in Oncology. E.P. Hamilton et al Survival Patterns in Patients With Hodgkin’s Lymphoma With a Pre-Existing Autoimmune Disease. O. Landgren et al Prospective Analysis of Hepatitis B Virus Reactivation in Patients With Diffuse Large B-Cell Lymphoma After Rituximab Combination Chemotherapy N. Niitsu et al Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Continuous Treatment With Bortezomib-Thalidomide Compared With BortezomibMelphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial. A. Palumbo et al Phase I Study of Everolimus Plus Weekly Paclitaxel and Trastuzumab in Patients With Metastatic Breast Cancer Pretreated With Trastuzumab F. Andre et al Review Article: Strategies for Prolonged Therapy in Patients With Advanced Non–Small-Cell Lung Cancer. P. Fidias et al Art of Oncology: Stand and Wait. G.F. Blackall Official Journal of the American Society of Clinical Oncology

www.jco.org

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 leadership, the science presented at Best of ASCO will highlight the most timely research on a wide array of oncology disciplines including breast cancer, developmental therapeutics,

What’s Hot in

JCO

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

JCO.org 1.

2.

3.

4.

Randomized Trial of Carboplatin Versus Radiotherapy for Stage I Seminoma: Mature Results on Relapse and Contralateral Testis Cancer Rates in MRC TE19/EORTC 30982 Study (ISRCTN27163214) R. Timothy D. Oliver, et al 29(8): 957 Carboplatin in Clinical Stage I Seminoma: Too Much and Too Little at the Same Time George J. Bosl, et al 29(8): 949 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 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 Decisions With Real-Time Patient-

Reported Outcomes Ethan Basch JCO March 10, 2011 vol. 29 no. 8 954-956 7.

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

8.

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

9.

Treatment of Low-Risk Gestational 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

lung cancer, gastrointestinal cancers, genitourinary cancers, gynecologic cancers, head and neck cancer, malignant hematology, and more.

Housing and Registration for Best of ASCO Miami and Best of ASCO Seattle will open in early April 2011. Please check boa2011.asco.org for additional information and a complete program agenda.

■

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

Journal of Oncology Practice

What’s Hot in

American Society of Clinical Oncology

THE AUTHORITATIVE RESOURCE

VOLUME 6

ISSUE 1

FOR

ONCOLOGY PRACTICES

JANUARY 2010

Filling the Gap: Development of the Oncology Nurse Practitioner Workforce “Developing new strategies for oncology care delivery by increasing the numbers and expanding the roles of nonphysician practitioners, such as nurse practitioners (NPs) and physician assistants (PAs), is critically important to meet the current and potential cancer care needs of the US population.”

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

Ensuring Quality Cancer Care Through the Oncology Workforce

“There is a crisis in the oncology workforce. Health professionals . . . are experiencing significant workforce shortages . . . because of the rapidly growing population of Americans requiring cancer care, an aging oncology workforce, and inadequate numbers of newly trained workers. This mismatch between supply and demand for cancer care could threaten patient care, safety, and quality.”

By Laura Levit, JD, et al

http://jop.ascopubs.org

Role of Advanced Nurse Practitioners and Physician Assistants in Washington State

By Jonathan C. Britell, MD

Practical Model for Psychosocial Care

By Susan S. Hendrick, PhD, et al

Physician Assistant Perspective on the ASCO Workforce Study Regarding the Use of Physician Assistants and Nurse Practitioners

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

Georgia Society of Clinical Oncology Forms a Patient Navigator Affiliate Basic Steps to Building a Research Program

By Allison Baer, RN, BSN, et al

JOP

jop.ascopubs.org

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

New Video Series Helps Patients Understand Cancer Clinical Trials

D

irect 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 trials, and the other explains the process of

informed consent. They can check back in May and June for the final two installments in the series, which address how clinical trials are reviewed to ensure safety and why patients should consider 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.

The ASCO Post | APRIL 15, 2011

PAGE 26

Direct from ASCO

JCO Launches Podcast Program

O

n February 22, 2011, the Journal of Clinical Oncology released its first podcast online, making it possible for busy readers to now access important JCO content on the go at JCO.org.

JCO Editor-in-Chief designate

Stephen A. Cannistra, MD, expects the podcast program to enhance readers’ experiences by providing both a summary of and further insights into high-profile JCO articles in short, convenient 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 increasingly clear that many readers do not have time to delve into the details Stephen A. Cannistra, MD

Mark Your Calendar

A program licensed by the American Society of Clinical Oncology

Bringing the Latest Science from the World’s premier Oncology Event Close to You Best of ASCO® Germany

Best of ASCO® China

Best of ASCO® Singapore

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

July 15 – 16 Chinese Society of Clinical Oncology – Hangzhou

September 2 – 4 Singapore Society of Oncology – Singapore

Best of ASCO® India

Best of ASCO® Czech Republic

July 16 – 17 Indian Society of Medical and Paediatric Oncology (ISMPO) – Pune

September 10 Czech Oncology Society – Prague

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® 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® 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

of an article and yet still wish to understand how the results will impact their practice or clinical research.” JCO podcasts, 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 Deaconess 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 (Excluding Breast and Prostate Cancer) or Multiple Myeloma,” by David H. Henry, 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 cancer, breast cancer, and colorectal cancer. 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 opportunity to play JCO podcasts directly 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 recent 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.

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

ASCOPost.com | APRIL 15, 2011

PAGE 27

XXXX

SARCOMA: THE ONLY THING PROGRESSING IS THE DISEASE THE 5-Y EAR SURV IVAL RATE IS 17 % FOR PATIEN TS W ITH ME TASTAT IC SOF T TISSUE SA RC O MA , YE T SIGNIF ICAN T THERAPEU TIC ADVANCEM ENTS ARE LAG GING. 1

NEW TREATMENTS ARE URGENTLY NEEDED.

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

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

The ASCO Post | APRIL 15, 2011

PAGE 28

Appointments

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

H

oward C. Bauchner, MD, from Boston University School of Medicine, will become the next Editorin-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 Executive Officer of the American Medical Association. Dr. Bauchner will be the 16th editor in the journal’s 127-year history.

Current Credentials Dr. Bauchner is currently the Editorin-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 Community Health Sciences at Boston University Schools of Medicine (BUSM) and Public Health. He is also the Vice Chairman of the Department of Pediatrics and Assistant Dean, Alumni Affairs and Continuing Medical Education at BUSM. He has served on many editorial boards, including currently for the British 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 prosper under his leadership. The future of JAMA—one of the AMA’s most treasured assets—is in great hands.”

Departing Editor Dr. Bauchner is following Catherine D. DeAngelis, MD, MPH, who is leaving 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 opportunity to be its new editor.”

Dr. Bauchner graduated from Boston University School of Medicine in 1979.

He completed his internship and junioryear 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 training in epidemiology and statistics as a

Robert Wood Johnson General Pediatrics 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 Packard Foundation and then as a Scholar in Residence at the Agency for Healthcare Research and Quality.

TREANDA® is his chemo.

■

This is his therapy.

B:17

T:15

S:14

5.5”

4.5”

PAGE 29

News

CMS Issues Proposed Decision Memo for Sipuleucel-T

I

n a decision memo released March 30, the Centers for Medicare and Medicaid Services (CMS) proposed that “the evidence is adequate to conclude that the use of autologous cellular immunotherapy treatment sipuleucel-T [Provenge] improves health outcomes

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

public comments on the proposed determination, 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 patients, 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 median 4.1-month survival benefit. The unusual decision by CMS to formally study the drug prior to granting coverage stirred further debate.

■

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

Survival distribution function

7.25”

ASCOPost.com | APRIL 15, 2011

TREANDA (n=153)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3 0.2 0.1

Chlorambucil (n=148)

18 months median PFS

6 months median PFS

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

0

5

10

15

20

25

30

35

40

45

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

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

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

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

S:10”

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

T:10.5”

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.

B:11.125”

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

The ASCO Post | APRIL 15, 2011

PAGE 30

FDA Update Skin Cancer

Ipilimumab Receives Approval for Late-stage Melanoma

O

n March 25, the FDA approved Bristol-Myers Squibb’s ipilimumab (Yervoy) for the treatment of unresectable or metastatic melanoma.

The last agent to be approved for melanoma, interleukin-2 (Proleukin), only

benefits 10% to 15% of those with advanced melanoma.

“Late-stage melanoma is devastating, with very few treatment options for patients, none of which previT:7.75” ously prolonged a patient’s life,” said

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

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

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

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

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

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

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

50

static melanoma live longer by taking this treatment.”

Ipilimumab is a monoclonal antibody that blocks cytotoxic T-lymphocyte 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 Trial Ipilimumab’s effectiveness was established 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, participants had disease that had spread or that could not be surgically removed.

The randomly assigned patients received ipilimumab plus an experimental tumor vaccine called gp100, ipilimumab alone, or the vaccine alone. Median overall survival for those who received the combination of ipilimumab plus the vaccine or ipilimumab alone was about 10 months, compared with 6.4 months for those who received only the experimental vaccine.

T:10.5” S:10”

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

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

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

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

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

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

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

ADVERSE REACTIONS: The data described below reflect exposure to TREANDA in 153 patients who participated in an actively-controlled trial for the treatment of CLL. Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The following serious adverse reactions have been associated with TREANDA in clinical trials and are discussed in greater detail in other sections [See Warnings and Precautions] of the label: Myelosuppression; Infections; Infusion Reactions and Anaphylaxis; Tumor Lysis Syndrome; Skin Reactions; Other Malignancies. Clinical Trials Experience in CLL. The data described below reflect exposure to TREANDA in 153 patients. TREANDA was studied in an active-controlled trial. The population was 45-77 years of age, 63% male, 100% white, and had treatment naïve CLL. All patients started the study at a dose of 100 mg/m2 intravenously over 30 minutes on days 1 and 2 every 28 days. Adverse reactions were reported according to NCI CTC v.2.0. In the randomized CLL clinical study, non-hematologic adverse reactions (any grade) in the TREANDA group that occurred with a frequency greater than 15% were pyrexia (24%), nausea (20%), and vomiting (16%). Other adverse reactions seen frequently in one or more studies included asthenia, fatigue, malaise, and weakness; dry mouth; somnolence; cough; constipation; headache; mucosal inflammation; and stomatitis. Worsening hypertension was reported in 4 patients treated with TREANDA in the randomized CLL clinical study and none treated with chlorambucil. Three of these 4 adverse reactions were described as a hypertensive crisis and were managed with oral medications and resolved. The most frequent adverse reactions leading to study withdrawal for patients receiving TREANDA were hypersensitivity (2%) and pyrexia (1%). Table 1 contains the treatment emergent adverse reactions, regardless of attribution, that were reported in ≥ 5% of patients in either treatment group in the randomized CLL clinical study.

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

S:7”

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 therapy approved by the FDA to clearly demonstrate that patients with meta-

Potential Side Effects Common side effects that can result from autoimmune reactions associated with ipilimumab use include fatigue, diarrhea, skin rash, endocrine deficiencies, and colitis. Severe to fatal autoimmune reactions were seen in 12.9% of patients treated with ipilimumab.

Due to the unusual and severe side effects associated with ipilimumab, the therapy is being approved with a Risk Evaluation and Mitigation Strategy to inform health-care professionals about these serious risks.

■

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

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

March 2010 All rights reserved.

According 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.”

ASCOPost.com | APRIL 15, 2011

PAGE 31

2011 Gastrointestinal Cancers Symposium Colorectal Cancer

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

By Barbara Boughton

A

n analysis of epidermal growth factor receptor (EGFR) immunohistochemistry 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-positive immunohistochemistry was not prognostic for either progression-free survival, overall survival, or overall response among patients with KRAS

wild-type tumors. EGFR-positive patients with KRAS mutations also did worse on cetuximab than those who received just standard therapy. The results of the EGFR analysis of the MRC COIN trial were presented in January at the Gastrointestinal Cancers Symposium in San Francisco.1 “Although this effect in patients with KRAS mutant disease was not statistically significant, it was a strong trend in keeping with other studies, said Richard Adams, MD, a Senior Lecturer at Cardiff University School of Medi-

Expert Point of View

T

he findings from the EGFR analysis of the MRC COIN trial are significant because they underline the importance of KRAS status in deciding whether or not to add cetuximab to standard therapy in advanced colorectal cancer, said Morton Kahlenberg, 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 metaMorton Kahlenberg, MD 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 status does not predict response to therapy. Yet with more EGFR staining in KRAS wild-type patients, progression-free survival was enhanced,” he said.

Provocative Question Although EGFR testing might add an additional layer of information to oncologists 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.

Visit The ASCO Post website at:

Predictive and Prognostic Value of EGFR ■■ 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 oxaliplatinbased 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.

cine in the United Kingdom. The addition of cetuximab to standard therapy had little effect on the outcomes of patients 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 tumors do provide some prognostic value with progression-free survival and overall survival in univariate analysis, but this statistical significance is lost in the multivariate analysis when assessing overall survival,” he added.

Additional Insight into Prognosis In the MRC COIN trial, 2,445 patients were randomly assigned to three arms that included treatment with oxaliplatin plus a fluoropyrimidine with or without cetuximab. EGFR immunohistochemistry 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. Although the study on cetuximab was negative, analyzing results in terms of EGFR biomarker status can provide additional insight into prognosis, Dr. Adams noted.

ASCOPost.com

Although EGFR was not prognostic for progression-free survival within KRAS wild-type patients at the standardized cutoff point, it was prognostic 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 immunochemistry as a prognostic variable in patients with KRAS wild-type advanced colorectal cancer. Yet SEE PAGE 51 the extensive assessment 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. Abstract 359. Presented January 22, 2011.

In advanced RCC:

Change to Afinitor after initial VEGFR-TKI* failure (sunitinib or sorafenib)â&#x20AC; mTOR Inhibition

OD VESSEL CEL L BLO

TUMOR CELL

mTOR

Reduced cell growth and proliferation

mTOR

Reduced cell metabolism

Reduced angiogenesis

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 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *VEGFR-TKI=vascular endothelial growth factor receptor tyrosine kinase inhibitor. â&#x20AC; 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 Information There 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 with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib.

Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients.

Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve 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 may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy.

Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed.

Elevations of serum creatinine, glucose, lipids, and triglycerides 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 and periodically thereafter. When possible, optimal glucose and lipid 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 of Afinitor 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 hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment.

The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment 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 most common grade 3/4 adverse reactions (incidence ≥3%) were infections (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 increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

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: Novartis Pharmaceuticals 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.

2.5mg 5mg 10mg

Novartis Pharmaceuticals Corporation East Hanover, NJ 07936

©2010 Novartis

Printed in U.S.A.

08/10

C-AFI-100068

AFINITOR (everolimus) tablets for oral administration

Initial U.S. Approval: 2009 BRIEF SUMMARY: Please see package insert for full prescribing information.

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

4 CONTRAINDICATIONS Hypersensitivity 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 respiratory impairment) have been observed with everolimus and other rapamycin derivatives.

5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence 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 respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms.

Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily.

For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances.

5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)].

Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy.

5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)].

5.4 Laboratory Tests and Monitoring Renal Function Elevations 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 creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter.

Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse 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 lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter.

5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)].

A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (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, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)].

5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased 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) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)].

5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during 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 Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism 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 human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the 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 REACTIONS The 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 Experience Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates in other trials and may not reflect the rates observed in clinical practice.

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/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 patients receiving 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 common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. 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-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective 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. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis.

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 organ class, 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 N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

97

52

13

93

23

5

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

0 0 0 0

Infections and Infestationsb

37

7

3

18

1

0

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

Respiratory, Thoracic and Mediastinal Disorders Cough 30 <1 Dyspnea 24 6 Epistaxis 18 0 14 4 Pneumonitisc

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

Skin and Subcutaneous Tissue Disorders Rash 29 Pruritus 14 Dry skin 13

1 <1 <1

0 0 0

7 7 5

0 0 0

0 0 0

1

0

14

<1

0

<1 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

0

7

0

0

General Disorders and Administration Site Conditions Asthenia 33 3 Fatigue 31 5 Edema peripheral 25 <1 Pyrexia 20 <1 Mucosal inflammation 19 1

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

60

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis.

Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence 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 erythrodysesthesia 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 of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

Vascular disorders: Hypertension (4%)

In animal reproductive studies, oral administration of everolimus to female rats before mating and through organogenesis induced embryo-fetal toxicities, including increased resorption, pre-implantation and post-implantation loss, decreased numbers of live fetuses, malformation (e.g., sternal cleft) and retarded skeletal development. These effects occurred in the absence of maternal toxicities. Embryo-fetal toxicities occurred at approximately 4% the exposure (AUC0-24h) in patients receiving the recommended dose of 10 mg daily. In rabbits, embryotoxicity evident as an increase in resorptions occurred at an oral dose approximately 1.6 times the recommended human dose on a body surface area basis. The effect in rabbits occurred in the presence of maternal toxicities.

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 Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

25

<1

<1

7

0

0

21 3

1 <1

0 <1

4 2

0 0

0 0

Hematologya Hemoglobin decreased Lymphocytes decreased Platelets decreased Neutrophils decreased Clinical Chemistry Cholesterol increased Triglycerides increased Glucose increased Creatinine increased Phosphate decreased Aspartate transaminase (AST) increased Alanine transaminase (ALT) increased Bilirubin increased

Grade 3 %

Grade 4 %

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia.

Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes.

7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~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 Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, 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.

8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established.

8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled 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 prescribing information].

8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

7.1 Agents that may Increase Everolimus Blood Concentrations CYP3A4 Inhibitors and PgP Inhibitors: In healthy subjects, compared to AFINITOR treatment alone there were significant increases in everolimus exposure when AFINITOR was coadministered with:

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [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].

• ketoconazole (a strong CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 3.9- and 15.0-fold, respectively.

The impact of severe hepatic impairment (Child-Pugh class C) has not been assessed and use in this patient population is not recommended [see Warnings and Precautions (5.6)].

• 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 alternative 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 Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed 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 been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose.

16 STORAGE Store 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 guidelines on this subject have been published.

AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (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 POPULATIONS 8.1 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 on mechanism 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 human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

Revised: June 2010 Manufactured by: Novartis Pharma Stein AG Stein, Switzerland Distributed by: Novartis Pharmaceuticals Corporation East Hanover, New Jersey 07936 ©Novartis

T2010-56

The ASCO Post | APRIL 15, 2011

PAGE 36

Perspective Pain Management

Despite Awareness, Undertreated Cancer Pain Persists

By Ronald Piana

U

nrelieved cancer pain can render a patient bedbound, leading to depression, fear, and suicidal ideation.

Along with physical distress, severe pain is associated with existential suffering, 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 relieve cancer-related pain in most cases, it begs the question: Why does this problem persist on such a large scale?

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

Standardized Procedures

“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.

The U.S. health-care system is vast and highly fractionated, making uniform adoption of pain guidelines a steep uphill battle. Diane E. Meier, MD, FACP, Director, Hertzberg Palliative Care Institute, Mount Sinai School of Medicine, New York, suggests that we implement standard operating procedures. “There are hospital discharge procedures, such as administration 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 hospital and office practice doctors are stretched thin, but treating pain should be an established priority. “If a patient has severe pain, there should be a mandatory protocol that assures that someone on the staff—a nurse practitioner 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 motivation to implement standards of operational pain control by empowering 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 welltrained nursing staff, to the relief of physical and other forms of suffering,” said Dr. Meier.

A step in that direction is the accreditation initiative by the American College of Surgeons Commission on

Diane E. Meier, MD, FACP

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.

Russell K. Portenoy, MD

Redirection of Priorities Russell K. Portenoy, MD, Chairman, Department of Pain Medicine and Palliative Care, Beth Israel Medi-

Sloan Karver, MD

Portenoy stressed education. “Basic knowledge of ‘Universal Precautions’ [in pain medicine], empowers oncologists 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

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

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 palliative medicine, Dr. Portenoy opined, “We accept that good pain management is a best practice and that oncologists are committed to it. So we have to ask the broader question: Why isn’t pain management given priority in educational 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.”

step forward in addressing undertreated 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 minimizing risk.”

Ethical Barriers In 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 hastened death. When pain is refractory to routine strategies, the ethically challenging approach of palliative sedation may be considered. Palliative sedation is an accepted therapy, but misperceptions arise when clinicians do not understand its ethical framework or standards of care, and mistakenly perceive the approach as “slow euthanasia.”

Dr. Portenoy explained that oncologists who offer sedation must appreciate both the medical and ethical implications of this intervention. “The key principle is the ‘double effect.’ Although sedation carries a risk of an earlier death, there is a clear line between sedation and physician-hastened death. The intent is to relieve suffering, and the doses of medication are appropriate for achieving that outcome,” said Dr. Portenoy, adding that the imperative to relieve symptoms when other medical strategies fail justifies the approach at the end of life.

The Patient Perception Barrier Speaking with The ASCO Post, palliative care expert Kathleen M. Foley, MD, Memorial Sloan-Kettering Cancer Center, said that patient perception 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.”

Undertreatment of Cancer Pain ■■ 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.

ASCOPost.com | APRIL 15, 2011

PAGE 37

Perspective Lessons Learned

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

Tools Help Dr. Foley said that a way to help busy community doctors manage pain is by giving them tools such as patient-reported outcomes or enlisting 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 markedly. 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-specific needs,” said Dr. Foley.

Barriers to proper cancer pain control 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 pendulum in favor of caution over aggressive 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 otherwise 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 Moffitt Cancer Center, South Florida, said that many community oncologists are hesitant about prescribing the increasingly higher doses of potentially lethal drugs necessary to control pain in ad-

Universal Precautions in Pain Medicine

Facilitating the Grieving Process

By Stanley Winokur, MD

U

niversal precautions in pain medicine include 10 steps developed to assist in managing patients with chronic pain. The goals SEE PAGE 51 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.

vanced disease, “whereas palliative care specialists are comfortable prescribing 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 paincontrol needs, not look at the clock and wait for a special time frame before taking their pain meds,” said Dr. Karver.

As Dr. Karver pointed out, breakthrough pain remains undertreated due to a number of doctor/patientdriven factors. “By providing education 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.

Conclusion The oncology community has identified undertreated cancer pain as an endemic problem. We have the pharmacotherapy tools to manage cancer pain; now we need consensus on how to best address this problem on a national scale.

■

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

G

oing through the dying process is, of course, difficult for the patient, whose loss is total and permanent. 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 facilitating the grieving process, even in the dying patient.

Showing Compassion In my experience, one of the kindest things an oncologist can say to a patient 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 differently, 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 whatever it is they are feeling, including fear, anger, relief, rage, hopelessness, or guilt, and to provide a safe environment that allows patients and loved

The ASCO Post

Wants to Hear from You

ones to freely express their truth without analysis, judgment, or criticism. It took me a long time to learn the importance 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 Dialogue For 4 years, a very close friend of mine has had to endure heavy doses of chemotherapy. Every day is a struggle 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’ questions directly gives them permission to express their feelings, whatever they may be, and allows for emotional healing, 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.

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

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

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

ASCOPost.com | APRIL 15, 2011

PAGE 39

Quality of Care Communication

Patient-centered Treatment Planning Urged to Improve Quality of Cancer Care

IOM/NCCS workshop examines the need for patient perspective in decision-making process

By Margot Fromer

W

hat 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 beginning of modern care. Although suggested answers abound, implementation has not always been successful.

This dilemma was the focus of a 2-day workshop, “Patient-centered Cancer Treatment Planning: Improving 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.

Carolyn Clancy

Dana-Farber Cancer Institute, said, “Cancer care is a two-way, poorly lit street. We need to teach both patients and caregivers how to navigate 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 little of the next few days,” he said.

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

Thomas J. Smith, MD

J. Russell Hoverman, MD, PhD

Dramatic Changes Needed

Standardized Surveys

Ellen Stovall, NCCS Senior Health Policy Advisor, said in her introduction to the workshop that although comparative effectiveness research 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 myelogenous leukemia at age 28, Richard Boyajian, RN, Clinical Director of the Adult Survivorship Program,

Carolyn Clancy, Director of the Agency for Healthcare Research and Quality (AHRQ), said, “Not only do we do a poor job of health-care communication, 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 longterm 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.”

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 problems. 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 expected to demonstrate patience, forbearance, and gratitude. Patients, of course, are the entire reason for care, but are they really at its center?

According to Patricia A. Ganz, MD, the lack Patricia A. Ganz, MD of focus on patients is a result of cancer care being complex, multimodal, multidisciplinary, toxic, expensive, 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 involved, limitations of heath literacy, patient distress that diminishes comprehension, 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 generalists rather than cancer specialists, lack of integrated electronic health records, 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

■

To this end, AHRQ has embarked on a program called Consumer Assessment of Healthcare Providers and Systems (CAHPS) to develop a set of standardized 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 information by means of scientific testing, data comparison, and other methods.

“CAHPS is one of our significant accomplishments, but by itself it cannot improve health literacy or the ability 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 University-Massey Cancer Center, said that only one-third of patients who

began cancer care with do-not-resuscitate preferences had also discussed hospice with their physician, which he said is a missed opportunity for healthcare providers and patients alike. He noted that physicians often find these discussions difficult and time-consuming. Dr. Smith pointed out that patients who have these difficult discussions 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 optimal cancer care, grouping them into 5 general categories: delivery (right treatment, safely, in a timely fashion); coverage (including direct costs); indirect costs (lost work time, child care, travel, etc); personal issues (dignity, continued on page 40

The ASCO Post | APRIL 15, 2011

PAGE 40

Quality of Care

continued from page 39

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

Even just considering this first category, physicians have their own challenges, Dr. Hoverman said. “The average 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 electronically with other specialists, laboratories, radiologists, and pathologists.

Even within practices, software programs often don’t talk to each other.”

Best Practices Speaking at the IOM/NCCS workshop, Patricia A. Ganz, MD, Director of the Division of Cancer Prevention and Control Research, UCLA Jonsson Comprehensive Cancer Center, said there is an ideal way to provide cancer care: in a multidisciplinary 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 treatment 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. “Someone has to be ultimately accountable.”

Limited Research Anthony Back, MD, Director, Program in Cancer Communication, Seattle Cancer Care Alliance and Fred Hutchinson Cancer Research Center, said that research on treatment planning is limited because of inadequate outcome measures such as satisfaction with care, regrets about decisions, and inadequate understanding

of what goes into a decision.

“Breaking bad news is part of oncology practice, but it stresses disclosure as an end rather than the beginning of a dialogue. Recent studies demonstrate 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, quality of life—and there is little research that tells us how,” Dr. Back continued.

“But we must improve communication, and we have to invite patients’ participation.”

Coverage of the NCCS/IOM workshop continues in the next issue of The ASCO Post, highlighting sessions that addressed theory and research in patient-centered care, difficulties underlying patient-informed decisions, and the challenge of discussions about death.

■

Financial Disclosure: The speakers at the NCCS/IOM workshop reported no potential conflicts of interest.

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

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

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

Patient-centered Treatment

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

P<0.0001§

34%

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

Imatinib (95% CI, 28-40)

0

10

20

30

40

50 60 MMR (%)

70

80

90

100

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

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

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

ASCOPost.com | APRIL 15, 2011

PAGE 41

FDA Update

FDA Advisory Committee Finds Data Support Safety, Effectiveness of NovoTTF-100A System

N

ovocure announced that the FDA Neurological Devices Advisory Panel of the Medical Devices Advisory Committee voted (7 yes; 3 no; 2 abstain) 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 NovoTTF-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 administered as a monotherapy in place of

for Superior Response vs Imatinib in 1st Line

Start With Convenient Once-Daily Dosing

1 pill 100 mg 1 time per day

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

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

SPRYCEL Can Be Taken Either With or Without Food1

FASTING

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

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

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

§

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

standard medical therapy.

The committee’s recommendation followed a review of data from the EF-11 trial, a randomized phase III continued on page 42

The ASCO Post | APRIL 15, 2011

PAGE 42

FDA Update

NovoTTF-100A System continued from page 41

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. Patients 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 beneath the electrodes.

Indian Company Receives U.S. Orphan Drug Designation The Hyderabad, India–based NATCO 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 leukemia. 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

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

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

ASCOPost.com | APRIL 15, 2011

PAGE 43

FDA Update

India. The company has plans for further clinical trials in the United States and other countries, in addition to India.

FDA, EMA Announce Parallel Assessment of New Drugs The FDA and the European Medicines Agency (EMA) have launched

a pilot program that will allow parallel 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) submitted to the FDA and marketing authorization applications (MAAs) submitted to the EMA. However, there will be regular communication and consultation between European regulators and their U.S. colleagues throughout the

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

• Drugs that may increase SPRYCEL plasma concentrations are: — CYP3A4 inhibitors: Concomitant use of SPRYCEL and drugs that inhibit CYP3A4 should be avoided. If administration of a potent CYP3A4 inhibitor cannot be avoided, close monitoring for toxicity and a SPRYCEL dose reduction or temporary discontinuation should be considered Strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole, clarithromycin, atazanavir, indinavir, nefazodone, nelfinavir, ritonavir, saquinavir, telithromycin, voriconazole). If SPRYCEL must be administered with a strong CYP3A4 inhibitor, a dose decrease should be considered Grapefruit juice may also increase plasma concentrations of SPRYCEL and should be avoided • Drugs that may decrease SPRYCEL plasma concentrations are: — CYP3A4 inducers: If SPRYCEL must be administered with a CYP3A4 inducer, a dose increase in SPRYCEL should be considered Strong CYP3A4 inducers (eg, dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) should be avoided. Alternative agents with less enzyme induction potential should be considered. If the dose of SPRYCEL is increased, the patient should be monitored carefully for toxicity St John’s Wort may decrease SPRYCEL plasma concentrations unpredictably and should be avoided • H2 antagonists/proton pump inhibitors, such as famotidine and omeprazole. Long-term suppression of gastric acid secretion by use of H2 antagonists or proton pump inhibitors is likely to reduce SPRYCEL exposure. Therefore, concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended • Antacids. Antacids may decrease SPRYCEL drug levels. Simultaneous administration of SPRYCEL and antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL • Drugs that may have their plasma concentration altered by SPRYCEL are: — CYP3A4 substrates, such as simvastatin. CYP3A4 substrates with a narrow therapeutic index should be administered with caution in patients receiving SPRYCEL Adverse Reactions: The safety data reflect exposure to SPRYCEL in 258 patients with newly diagnosed chronic phase CML in a clinical study (median duration of therapy was 18 months).

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

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

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

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

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

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

© 2011 Bristol-Myers Squibb 729US10AB13506 1/11

review process relevant to QbD aspects of the applications. QbD in pharmaceuticals involves developing formulations and processes to help ensure product manufacturing quality. This pilot program began out of concern that certain international guidelines were being interpreted differently in Europe and the United States.

■

The ASCO Post | APRIL 15, 2011

PAGE 44

Appointments Surgical Oncology

Society of Surgical Oncology Elects President and Officers for 2011–2012 Term

T

he Society of Surgical Oncology (SSO) has elected James S. Economou, MD, as 2011– 2012 President of the Society, succeeding Mitchell C.

James S. Economou, MD

Posner, MD. Dr. Economou is Vice Chancellor for Research, the Beaumont Professor of Surgery 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

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

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

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

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

CONTRAINDICATIONS: None.

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

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

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

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

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

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

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

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

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

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

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

• Bleeding related events [see Warnings and Precautions].

• Fluid retention [see Warnings and Precautions].

• QT prolongation [see Warnings and Precautions].

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

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

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

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

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

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

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

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

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

Anne Burnett Windfohr Chair of Clinical Oncology at Memorial Sloan-Kettering Cancer Center, New York. Dr. Klimberg is the Muriel Balsam Kohn Chair in Breast Surgical Oncology at the University of Arkansas for Medical Sciences.

■

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

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

Table 1: Adverse Reactions Reported in ≥10% of Patients with Newly Diagnosed Chronic Phase CML All Grades Grade 3/4 SPRYCEL (dasatinib) Imatinib SPRYCEL Imatinib (n=258) (n=258) (n=258) (n=258) Preferred Term Percent (%) of Patients Fluid retention 23 43 1 1 Pleural effusion 12 0 <1 0 Superficial localized edema 10 36 0 <1 Generalized edema 3 7 0 0 Congestive heart failure/ 2 1 <1 <1 a cardiac dysfunction Pericardial effusion 2 <1 <1 0 Pulmonary hypertension 1 0 0 0 Pulmonary edema <1 0 0 0 Diarrhea 18 19 <1 1 Headache 12 10 0 0 Musculoskeletal pain 12 16 0 <1 11 17 0 1 Rashb Nausea 9 21 0 0 Fatigue 8 11 <1 0 Myalgia 6 12 0 0 c 6 5 1 1 Hemorrhage Gastrointestinal bleeding 2 <1 1 0 5 5 0 1 Other bleedingd CNS bleeding 0 <1 0 <1 Vomiting 5 10 0 0 Muscle inflammation 4 19 0 <1 a

Includes cardiac failure acute, cardiac failure congestive, cardiomyopathy, diastolic dysfunction, ejection fraction decreased, and left ventricular dysfunction. b Includes erythema, erythema multiforme, rash, rash generalized, rash macular, rash papular, rash pustular, skin exfoliation, and rash vesicular. c Adverse reaction of special interest with <10% frequency. d Includes conjunctival hemorrhage, ear hemorrhage, ecchymosis, epistaxis, eye hemorrhage, gingival bleeding, hematoma, hematuria, hemoptysis, intra-abdominal hematoma, petechiae, scleral hemorrhage, uterine hemorrhage, and vaginal hemorrhage.

Table 2:

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

Preferred Term

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

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

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

34 18

4 0

18 3 2 0

2 0 1 0

21 1 3 0

7 0 1 0

20 3 0 4

0 33 27 24 20 19 18 17 13 12 12

0 1 2 2 2 2 1 2 0 1 1

1 27 31 19 20 11 19 15 7 10 10

0 1 3 2 3 0 1 0 1 0 6

12 11 2 0 7 5 1

1 1 1 0 1 1 1

6 26 8 1 11 11 4

0 8 6 1 1 2 4

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

6 0

7 0 0 0

21 0 0 0

6 0 0 0

4 18 20 20 15 8 23 16 7 5 14

3 1 5 1 3 1 1 1 1 1 7

0 15 18 9 3 0 21 21 3 0 9

0 3 0 3 3 0 3 0 0 0 0

8 19 9 0 12 18 12

3 9 7 0 0 3 12

3 24 9 3 15 6 12

0 9 3 3 0 0 12

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

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

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

ASCOPost.com | APRIL 15, 2011

PAGE 45

News Leadership

AACR Officers Assume New Roles at Annual Meeting

T

he members of the American Association for Cancer Research have elected Frank McCormick, PhD, DSc (hon), as their President-elect. McCormick 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 Distinguished Professorship of Tumor Biology 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 Department of Biochemistry and Biophysics.

“I am thrilled and honored to serve as President-Elect,” said Dr. McCormick.

“The AACR is a remarkable organizaFrank McCormick, PhD, DSc (hon)

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

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

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

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

Imatinib (n=258) Percent (%) of Patients

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

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

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

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

Lymphoid Blast Phase (n=33)

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

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

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

Gastrointestinal Disorders: 1%–<10% – mucosal inflammation (including mucositis/stomatitis), dyspepsia, abdominal distension, constipation, gastritis, colitis (including neutropenic colitis), oral soft tissue disorder; 0.1%–<1% – ascites, dysphagia, anal fissure, upper gastrointestinal ulcer, esophagitis, pancreatitis; <0.1% – protein losing gastroenteropathy. General Disorders and Administration Site Conditions: 1%–<10% – asthenia, pain, chest pain, chills; 0.1%–<1% – malaise, temperature intolerance. Skin and Subcutaneous Tissue Disorders: 1%–<10% – pruritus, alopecia, acne, dry skin, hyperhidrosis, urticaria, dermatitis (including eczema); 0.1%–<1% – pigmentation disorder, skin ulcer, bullous conditions, photosensitivity, nail disorder, acute febrile neutrophilic dermatosis, panniculitis, palmar-plantar erythrodysesthesia syndrome. Respiratory, Thoracic, and Mediastinal Disorders: 1%–<10% – cough, lung infiltration, pneumonitis, pulmonary hypertension; 0.1%–<1% – asthma, bronchospasm; <0.1% – acute respiratory distress syndrome. Nervous System Disorders: 1%–<10% – neuropathy (including peripheral neuropathy), dizziness, dysgeusia, somnolence; 0.1%–<1% – amnesia, tremor, syncope; <0.1% – convulsion, cerebrovascular accident, transient ischemic attack, optic neuritis. Blood and Lymphatic System Disorders: 1%–<10% – pancytopenia; <0.1% – aplasia pure red cell. Musculoskeletal and Connective Tissue Disorders: 1%–<10% – muscular weakness; 0.1%–<1% – musculoskeletal stiffness, rhabdomyolysis; <0.1% – tendonitis. Investigations: 1%–<10% – weight increased, weight decreased; 0.1%–<1% – blood creatine phosphokinase increased.

Infections and Infestations: 1%–<10% – pneumonia (including bacterial, viral, and fungal), upper respiratory tract infection/inflammation, herpes virus infection, enterocolitis infection; 0.1%–<1% – sepsis (including fatal outcomes). Metabolism and Nutrition Disorders: 1%–<10% – anorexia, appetite disturbances; 0.1%–<1% – hyperuricemia, hypoalbuminemia. Cardiac Disorders: 1%–<10% – arrhythmia (including tachycardia), palpitations; 0.1%–<1% – angina pectoris, cardiomegaly, pericarditis, ventricular arrhythmia (including ventricular tachycardia); <0.1% – cor pulmonale, myocarditis, acute coronary syndrome. Eye Disorders: 1%–<10% – visual disorder (including visual disturbance, vision blurred, and visual acuity reduced), dry eye; 0.1%–<1% – conjunctivitis. Vascular Disorders: 1%–<10% – flushing, hypertension; 0.1%–<1% – hypotension, thrombophlebitis; <0.1% – livedo reticularis. Psychiatric Disorders: 1%–<10% – insomnia,

depression; 0.1%–<1% – anxiety, affect lability, confusional state, libido decreased. Reproductive System and Breast Disorders: 0.1%–<1% – gynecomastia, menstruation irregular. Injury, Poisoning, and Procedural Complications: 1%–<10% – contusion. Ear and Labyrinth Disorders: 1%–<10% – tinnitus; 0.1%–<1% – vertigo. Hepatobiliary Disorders: 0.1%–<1% – cholestasis, cholecystitis, hepatitis. Renal and Urinary Disorders: 0.1%–<1% – urinary frequency, renal failure, proteinuria. Neoplasms Benign, Malignant, and Unspecified: 0.1%–<1% – tumor lysis syndrome. Immune System Disorders: 0.1%–<1% – hypersensitivity (including erythema nodosum).

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

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

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

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

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

Antacids: Nonclinical data demonstrate that the solubility of dasatinib is pH dependent. In a study of 24 healthy subjects, administration of 30 mL of aluminum hydroxide/magnesium hydroxide 2 hours prior to a single 50-mg dose of SPRYCEL was associated with no relevant change in dasatinib AUC; however, the dasatinib Cmax increased 26%. When 30 mL of aluminum hydroxide/magnesium hydroxide was administered to the same subjects concomitantly with a 50-mg dose of SPRYCEL, a 55% reduction in dasatinib AUC and a 58% reduction in Cmax were observed. Simultaneous administration of SPRYCEL with antacids should be avoided. If antacid therapy is needed, the antacid dose should be administered at least 2 hours prior to or 2 hours after the dose of SPRYCEL. H2 Antagonists/Proton Pump Inhibitors: Long-term suppression of gastric acid secretion by H2 antagonists or proton pump inhibitors (eg, famotidine and omeprazole) is likely to reduce dasatinib exposure. In a study of 24 healthy subjects, administration of a single 50-mg dose of SPRYCEL 10 hours following famotidine reduced the AUC and Cmax of dasatinib by 61% and 63%, respectively. In a study of 14 healthy subjects, administration of a single 100-mg dose of SPRYCEL 22 hours following a 40-mg omeprazole dose at steady state reduced the AUC and Cmax of dasatinib by 43% and 42%, respectively. The concomitant use of H2 antagonists or proton pump inhibitors with SPRYCEL is not recommended. The use of antacids (at least 2 hours prior to or 2 hours after the dose of SPRYCEL) should be considered in place of H2 antagonists or proton pump inhibitors in patients receiving SPRYCEL therapy.

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

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

Nursing Mothers: It is unknown whether SPRYCEL is excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from SPRYCEL, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother.

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

Geriatric Use: In the newly diagnosed chronic phase CML study, 25 patients (10%) were 65 years of age and over and 7 patients (3%) were 75 years of age and over. Of the 2182 patients in clinical studies of SPRYCEL with resistance or intolerance to imatinib therapy, 547 (25%) were 65 years of age and over and 105 (5%) were 75 years of age and over. No differences in efficacy were observed between older and younger patients. Compared to patients under age 65 years, patients aged 65 years and older are more likely to experience toxicity.

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

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

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

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

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

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

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

1284903

DS-B0001A-10-10

Rev October 2010

tion that continues to grow as the field evolves. We are poised to make incredible 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 Annual 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 Prevention at the Dana-Farber Cancer Institute, 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.

Judy E. Garber, MD, MPH

Dr. Garber succeeded Elizabeth H. Blackburn, PhD, Nobel Laureate and the Morris Herzstein Professor of Biology and Physiology in the Department of Biochemistry and Biophysics at University of California, San Francisco. Dr. Blackburn served with distinction as AACR President for the 2010 to 2011 term and has assumed the role of PastPresident.

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The ASCO Post | APRIL 15, 2011

PAGE 46

Awards Annual Meeting

Researchers and Scientists Honored by ASCO for Improving Prevention, Treatment, and Care of People Living with Cancer

A

physician-scientist credited with discovering the first human oncogene and isolating the first known tumor-suppressor gene is among the notable awardees to be honored by ASCO at its 2011 Annual Meeting.

Each year through its Special Awards, ASCO recognizes quality researchers, patient 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 commitment to improving the prevention, treatment, and care of people with cancer, it is our honor to bestow upon them ASCO’s highest achievement awards.”

Cancer Society Award and Lecture for her pioneering work in palliative medicine and for her substantial contributions 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

David A. Karnofsky Memorial Award and Lecture

and principles into oncology care, and breast oncology. She also has been a leading proponent for developing palliative care training for oncologists.

Kenneth C. Anderson, MD, is the recipient of the 2011 David A. Karnofsky Memorial Award and Lecture for his outstanding achievements in cancer research and for his influence on the treatment of patients with cancer. Dr. Anderson currently serves as the Director of the LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Multiple Myeloma at Dana-Farber Cancer Institute and the Kraft Family Professor of Medicine 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, Founding 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

Douglas Blayney, MD

is the recipient of the 2011 B.J. Kennedy Award and Lecture for Scientific Excellence in Geriatric Oncology. His interest in cancer in the aging population derived from studies of older patients with hematologic malignancies. Dr. Bennett was a founding member of the International Society for Geriatric Oncology and the first chair of the Myelodysplastic Syndromes Foundation, has contributed over 500 publications to medical literature.

Jamie H. Von Roenn, MD

Gianni Bonadonna Breast Cancer Award and Lecture Luca Gianni, MD, Director of the Department 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 therapies in women with breast cancer by designing and conducting the collaborative neoadjuvant trials NOAH with trastuzumab (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,

Luca Gianni, MD

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 Scientific Director for Clinical Research at the National Cancer Institute’s Center for Cancer Research, Dr. Helman’s laboratory currently focuses on the biology and treatment of pediatric sarcomas, specifically Ewing’s sarcoma, rhabdomyosarcoma, and osteosarcoma.

Partners in Progress Award Benjamin 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 practice to the care of patients with breast cancer 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 Oncology 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 Cancer Institute. His research and clinical interests focus on the development of new agents for breast cancer, colorectal cancer, lung cancer, and melanoma.

Special Recognition Award Daniel G. Haller, MD, is the recipient of the 2011 Special Recognition Award for his outstanding contributions to clinical 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 Pennsylvania. 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 official journal of the American Society of Clinical Oncology. He is the author or coauthor of more than 125 peer-reviewed publications.

Public Service Award The Honorable Sherrod Brown, senior 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 protections that require insurance plans to cover routine patient care for patients undergoing cancer clinical trials, working closely with ASCO and others in the cancer community to achieve this goal. ASCO will honor Sen. Brown for his commitment to advancing legislation in support of cancer research, treatment, and care.

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All of the above awards will be presented at the Society’s 47th Annual Meeting taking place in Chicago, June 3–7 at McCormick Place, with the exception of the Public Service 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 Symposium, taking place September 8–10 in San Francisco.

For a list of the specific dates and room locations of the awards presentations, contact Danielle Potuto at danielle.potuto@asco.org.

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ASCOPost.com | APRIL 15, 2011

PAGE 47

JCO Spotlight Breast Cancer

QOL Benefits of Capecitabine Fail to Outweigh Improved Survival with Standard Adjuvant Therapy in Older Women with Early Breast Cancer

By Matthew Stenger

he 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 relapse-free and overall survival compared with patients receving standard adjuvant chemotherapy with either CMF (cyclophosphamide/methotrexate/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.

Substudy Findings

A

Better

Capecitabine CMF or AC

100 90 80 70 60 *P < .01

50

Quality Measures

Baseline

Midtreatment

End treatment

12

18

24

Time (months)

B

Worse

Capecitabine CMF or AC

EORTC Systemic Adverse Effects

50 40

20 10 *P < .01

Baseline

Midtreatment

End treatment

12

18

24

Time (months)

C

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, indicating clinically important anxiety/ depression. Psychosocial services were used by less than 10% of patients in either group over 24 months.

Although capecitabine was associated with better QOL and reduced systemic adverse effects during treatment, differences between the two groups in global QOL, systemic adverse effects, and HADS outcome were no longer apparent at 12 months after starting treatment or thereafter (Fig. 1). Given the superiority of standard adjuvant chemotherapy 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 substitution of capecitabine for standard chemotherapy in this patient population.

‘Modest Price to Pay’

30

0

Worse

Capecitabine CMF or AC

42

“The results of the parent trial and the QOL study should be reassuring to older women who are given standard adjuvant therapy,” noted Alice B. Kornblith, PhD, of Dana-Farber Cancer Institute, Boston, and lead author of the QOL study. “Although even brief worsening of quality of life is undesirable, the goal of adjuvant therapy is to increase the chance for cure—and the brief change in quality of life with standard therapy is a modest price to pay for increased survival.”

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36 HADS Overall Score

A preplanned substudy compared quality-of-life (QOL) measures during and after treatment between 182 patients 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 Treatment of Cancer Quality of Life Questionnaire 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 receiving CMF, day 29 for those receiving AC, and day 63 for those receiving 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 measurement. The treatment schedules were: oral cyclophosphamide daily on days 1 to 14 and IV methotrexate and fluorouracil on days 1 and 8 every 28 days for six cycles for CMF; IV doxorubicin and cyclophosphamide on day 1 every 21 days for four cycles for AC; and capecitabine orally on days 1 to 14 every SEE PAGE 51 21 days for six cycles.

receiving capecitabine had significantly better EORTC role functioning (P ≤ .002) and social functioning (P < .001). There were no significant differences 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

Compared with patients receiving standard chemotherapy, patients treated with capecitabine had significantly better global QOL scores, significantly fewer systemic treatment-related adverse events, and significantly better HADS scores at midtreatment and end of treatment (Fig. 1). With regard to individual QOL domains, patients

EORTC Global Quality of Life

T

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

30 24 18 12 6 0

*P < .01

Baseline

Midtreatment

End treatment

12

18

24

Time (months)

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.

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 adjuvant chemotherapy: A companion study to Cancer and Leukemia Group B 49907.

J Clin Oncol February 22, 2011 (early release online).

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

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

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

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

The ASCO Post | APRIL 15, 2011

PAGE 50

In the Literature

Emerging Clinical Data on Cancer Management 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 neuroendocrine tumors,” suggested an editorial accompanying the articles. Both studies were phase III, double-blind, randomized, placebo-controlled trials involving sufficient numbers of patients with progressive malignant disease “to yield clear statistical results,” according to the editorial.

One study randomly assigned 171 patients to best supportive care with either continuous daily administration of the tyrosine kinase inhibitor 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 adverse 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, asthenia, and fatigue.

Sunitinib is manufactured by Pfizer, which funded the study, collected the data, performed the statistical 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-3 In the other study, RAD001 in Advanced Neuroendocrine Tumors, third trial (RADIANT-3), 410 patients were randomly assigned to best supportive care plus everolimus (Afinitor), an oral inhibitor of mammalian target of rapamycin (mTOR), or placebo. Patients receiving 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 placebo group. “It is not yet clear whether sunitinib and everolimus can be combined and, if so, whether antitumor activity would be further increased 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 everolimus than with placebo included anemia and hyperglycemia.

The study was funded by Novartis, 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 treatment interruptions.” They added that it is “unclear how the side-effect profiles 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 neuroendocrine include whether patients would “have to continue taking these drugs for years, since both drugs primarily stabilize, rather than cure, the disease” 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 364:514523, 2011.

BLADDER CANCER Bladder-sparing Approach to Metastatic Disease Features Gemcitabine and Radiotherapy

© J.C. Duffy/The New Yorker Collection/www.cartoonbank.com

A bladder-sparing approach using concurrent gemcitabine and hypofractionated radiotherapy in 50 patients with muscle-invasive bladder cancer showed a complete response rate of 88% among the 47 participants who had cystoscopy 3 months after treatment. The overall survival rate at 3 years was 75%, and diseasespecific 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 Journal of Clinical Oncology.

All participating patients completed radiotherapy, and 46 tolerated all four cycles of gemcitabine given intravenously 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-associated deaths. Four patients underwent cystectomy—three because of recurrent disease and one because of toxicity. 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 cystectomy (eg, those with poor bladder function or extensive carcinoma in situ),” the authors noted. “Nonetheless, with good patient selection, a proportion of patients can be offered the opportunity of cure while they retain a well-functioning bladder and sexual function. It is, therefore, vital to continue 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 additional 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 menopause 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

ASCOPost.com | APRIL 15, 2011

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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 postmenopausal women in the United Kingdom “who provided prospective information on hormonal therapy use and other factors relevant for breast cancer risk,” the authors explained.

Using 2D Barcodes

What’s this?

Beral V, et al: J Natl Cancer Inst 103:296-305, 2011.

Chlebowski RT, Anderson G: J Natl Cancer Inst 103:284-285, 2011.

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There are three ways to download the ScanLife application:

1

Simply text the word “scan” to 43588.

2

Go to www.getscanlife. com on your phone’s Web browser. The application will attempt to determine which model phone you have. If it’s successful, simply select “Download”.

3

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

Submit an abStract

Comparisons to WHI Findings In 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 substantial 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 differences between” the MWS and the WHI, “the similarity of results is remarkable 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 increases in breast cancer risk among women, 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 menopause, the magnitude of the effects was greater in the MWS trial.

“Although the similarities between the patterns of breast cancer risk observed in these two methodologically 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-only users, for which the interpretation is still unclear.” They add that conflicting data may be due to methodologic differences between the studies and that additional postintervention follow-up of the WHI estrogen-only trial should lead to further clarification.

The 2D barcodes found in this issue of The ASCO Post will connect readers to further information about the articles they are reading using the ScanLife application.

Getting the Application

Breast Cancer Symposium 2011 T h e Co n Ti n u u m o f B r e asT Ca r e : sC i e n Ce To su rvi vo r shi p

September 8-10, 2011 San FranciSco marriott marquiS San FranciSco, caLiFornia

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.

Topic caTegories • • • •

Detection/Screening/imaging Systemic therapy prevention, Survivorship & Health policy Local/regional therapy

may 10, 2011 at 11:59 pm (eDt): abstract Submission Deadline august 3, 2011 at 11:59 pm (eDt): Housing and early registration Deadline

To submit an abstract or to view guidelines, visit breastcasym.org.

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

TARG E T I NG

C A NC E R

C A RE

Primary Supporter

The ASCO Post | APRIL 15, 2011

PAGE 52

In the News

Results of Breast Cancer Lymph Node Dissection Study Are Already Changing Standard Medical Practice

By Charlotte Bath

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

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

P

ractice-changing is how many media 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 earlystage 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 practice on its head,” according to the account in the New York Times.2 In commenting on the study to The ASCO Post, William C. Wood, MD, of Winship Cancer Institute, Emory University, 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 covering 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 Cancer Center in New York, M.D. Anderson 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 position 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 American Society of Clinical Oncology expert 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 Removed The American College of Surgeons Oncology Group Z0011 trial was a phase III noninferiority trial involving 891 women at 115 sites. Targeted enrollment was 1,900 women, but the trial was closed early because the mortality rate was lower than expected. Eligible patients were women with clinical 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

Expect Questions from Your Patients

W

ith 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 encourages 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 Armando E. Giuliano, MD this point, he added, people need to understand what group of patients the study applies to—women 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, radiation oncologists—have to be careful that we apply these findings only to the types of patients who were included in the study.”

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frozen section, touch preparation, or hematoxylin and eosin staining on permanent section.

All patients underwent lumpectomy and tangential whole-breast irradiation.

Those identified by sentinel lymph node dissection (SLND) as having sentinel lymph node metastases were randomly assigned to undergo no further axillary treatment or axillary lymph node dissection (ALND) of 10 or more nodes. “Disease characteristics at baseline 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% anticipated at protocol design,” the investigators reported. The 5-year diseasefree survival was 82.2% with ALND and 83.9% with SLND alone.

Patients Dread Lymphedema It 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 fewer nodes is the reduced rate of complications with sentinel lymph node dissection. In this study, the rate of wound infections, axillary seromas, and paresthesias was 70% for the ALND group vs 25% for the SLND-alone group.

“Lymphedema in the ALND group was significantly more common by subjective 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 randomized comparisons of SLND with vs without ALND.” When it comes to the benefits of avoiding complications, particularly lymphedema, “you don’t have to convince patients,” Dr. Giuliano said. “Patients dread lymphedema.” And physicians will do what they can to prevent or minimize lymphedema from occurring in their patients with breast cancer.

The complications and the lack of

proof that axillary dissection improved survival were what inspired Dr. Giuliano 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 Morning Edition the day after the report was published.5 “Back in the mid-1990s,” he commented, “Dr. Giuliano was instrumental in establishing the current practice of sampling one or two sentinel lymph nodes and then using those results to determine whether other lymph nodes in the area should be excised.”

Revisiting NSABP B04 In the current era, with breast cancer being diagnosed earlier, “fewer women have positive nodes, and women who do have positive nodes have fewer positive nodes,” Dr. Giuliano said. “So it seemed like a good idea to reexamine

Oncologists have to be careful to apply these findings only to the types of patients who were included in the study.

NSABP B04.” The National Surgical Adjuvant Breast and Bowel Project B04 study randomly assigned women with clinically negative nodes to treatment with radical mastectomy, total mastectomy plus nodal irradiation, or total mastectomy with delayed ALND if nodal recurrence was observed. “Initially and at each interim analysis for up to 25 years of follow-up, no statistically significant survival differences were observed between any of the groups,” the investigators wrote.

“For patients treated in the modern era, the relevance of the B04 study, which included patients with larger tumors undergoing mastectomy without adjuvant systemic therapy, is uncertain, because an axillary recurrence after SLND in patients with a lowSEE PAGE 51 er risk of death from

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In the News

distant disease might negatively affect survival. The findings from Z0011 document the high rate of locoregional control achieved with modern multimodality therapy, even without ALND,” they added.

“The excellent local and distant outcomes in this study highlight the effects of multiple changes in breast cancer management during the interval between the two studies,” the investigators continued. “These changes, which include improved imaging, more detailed pathologic evaluation, improved planning of surgical and radiation approaches, and more effective systemic therapy, emphasize the need for ongoing reevaluation of ‘standard’ local therapy.”

The Next Step Several 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 longterm follow-up on this study and to determine whether the findings are appropriate for other patients,” Dr. Giuliano 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 neoadjuFDA Update

Peginterferon alfa-2b Approved for Postsurgical Melanoma with Nodal Involvement

O

n March 29, the FDA approved peginterferon alfa-2b (Sylatron), for the treatment of patients with melanoma with microscopic or gross nodal involvement within 84 days of definitive surgical resection including complete lymphadenectomy.

The approval was based on an openlabel, 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 peginterferon alfa-2b or observation for 5 years.

An improvement in relapse-free survival for peginterferon-treated patients was observed (median of 34.8 and 25.5 months in the peginterferon and observation arms, respectively). Following 525 deaths, there was no difference in overall survival between the two arms.

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vant chemotherapy, but these studies have yet to be formalized.

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

References 1. Giuliano AE, Hunt KK, Ballman KV, et al: Axillary dissection vs no axillary dis-

section in women with invasive breast cancer 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: Management of axillary lymph node metastasis

in breast cancer: Making progress. JAMA 305(6):606-607, 2011.

4. Stein R: Breast-cancer study questions lymph node removal. Washington Post. February 9, 2011. Available at www. washingtonpost.com.

5. Knox R: Certain breast cancer patients may nix node surgery. NPR. February 9, 2011. Available at www.npr.org.

The ASCO Post | APRIL 15, 2011

PAGE 54

Perspective

Japan and Radiation continued from page 1

also be suspended in reaction to the tragedy in Japan.

Advances in Radiation Oncology

Nora Janjan, MD, MPSA, MBA

In contrast, just 7 years later in 1986, the Chernobyl incident in the former Union of Soviet Socialist Republics released massive amounts of radioactive material into the environment.2 Boron and sand, poured from the air, was not effective in containing 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 developed acute radiation sickness.

More than 600,000 workers were involved in the Chernobyl cleanup, and 200,000 recovery workers continue to be monitored for late radiation effects. About 4,000 cases of thyroid cancer were diagnosed among children who drank contaminated milk; 99% of these children have been successfully 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 development 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 reactors have been built, and only 1 is under construction. Despite this, in 2009 the United States produced more than 30% of the worldwide nuclear generation of electricity, with 104 nuclear reactors in 31 states producing 799 billion kWh, representing 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

In the context of these events, the use of nuclear power continues to be debated, but meanwhile, the diagnosis and treatment of cancer with radiation has made tremendous technologic progress. The radiographic early detection of cancer, particularly with mammography, has significantly improved cancer survival rates. Technologic improvements in computed tomography (CT) and the development of magnetic resonance imaging (MRI) and positron-emission tomography (PET) have transformed oncologic practice.

For radiation oncology, there have been three major advances. First, the use of radiation therapy has expanded, in conjunction with more conservative surgical approaches to accomplish organ preservation.

Second, multidisciplinary care has expanded to include multimodality cancer therapy, particularly the administration of chemotherapy during

restrict mammography for women under the age of 50 years. In February 2010, the FDA published a policy paper entitled, “Initiative to Reduce Unnecessary Radiation Exposure from Medical Imaging,” which included three recommendations.4 In order to promote safe use of medical imaging devices, the FDA will: 1. Establish requirements for manufacturers of CT and fluoroscopic 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 assurance practices into accreditation and participation criteria for imaging facilities and hospitals.

3. Recommend that the healthcare professional community, in collaboration with FDA, continue efforts to develop diagnostic reference levels for CT, fluoroscopy, and nuclear medicine procedures locally and also through a national radiation dose registry.

The FDA emphasized the “appropriate justification for ordering and

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. the course of radiation. Third, radiation 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 accelerators, radiation treatment planning, and verification of the delivered radiation dose, which ushered in intensity-modulated radiation therapy (IMRT) and proton therapy.

Debates and Recommendations Despite these advances in oncologic care, disagreements about the risks of radiation used in medicine are ongoing. In particular, the risks of radiation administered during mammography continue to be debated, although mammography has been routinely 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

performing each procedure” and the “careful optimization of the radiation dose during each procedure” in December 2010. The aim is to record the radiation dose from each CT, fluoroscopy, and nuclear medicine procedure (including PET).

These records of radiation dose will then be sent to a radiation dose registry for the collection, initially, of de-identified patient radiation dose data. Pooling dose data across imaging 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 development 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 questions about how the patient and nonradiologist physicians will interpret the data (particularly in differentiating localized vs whole-body radiation exposure) and whether the data will be used to limit future radiation procedures (which could be especially problematic for cancer diagnosis, treatment, and follow-up).

Conclusions 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. Risks associated with nuclear energy, like those with radiology in medicine, are well controlled, and these applications of radiation improve and save lives. Nevertheless, policymaking must always consider unintended consequences. With potential significant restrictions looming in nuclear energy and the medical application of radiation, we hope that we will not also see risks resulting from significant energy shortages, like frail individuals dying in their homes from excessive heat without air conditioning, and a reversal of the improvements achieved in cancer survival.

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References 1. U.S. Nuclear Regulatory Commission: Backgrounder on the Three Mile Island accident. August 2009. Available at www.nrc.gov. Accessed March 21, 2011.

2. U.S. Nuclear Regulatory Commission: Backgrounder on Chernobyl nuclear power plant accident. April 2009. Available at www.nrc.gov. Accessed March 21, 2011.

3. World Nuclear Association: Nuclear power in the USA. Updated March 2011. Available at www.world-nuclear. org. Accessed March 21, 2011.

4. U.S. Food and Drug Administration: 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 established in 1983 and headquartered in Dallas.

AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin‑treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).]

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

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

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

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

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

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

[See Dosage and Administration (2.4).]

6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: • Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).]

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

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

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

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

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

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

• Proteinuria [See Dosage and Administration (2.4), Warnings and Precautions (5.8).]

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

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

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

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

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

Among patients requiring surgery on or within 60 days of receiving study treatment, wound healing and/or bleeding complications occurred in 15% (6/39) of patients receiving bolus‑IFL plus Avastin as compared to 4% (1/25) of patients who received bolus‑IFL alone.

In Study 7, events of post‑operative wound healing complications (craniotomy site wound dehiscence and cerebrospinal fluid leak) occurred in patients with previously treated glioblastoma: 3/84 patients in the Avastin alone arm and 1/79 patients in the Avastin plus irinotecan arm. [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).]

Hemorrhage The incidence of epistaxis was higher (35% vs. 10%) in patients with mCRC receiving bolus‑IFL plus Avastin compared with patients receiving bolus‑IFL plus placebo. All but one of these events were Grade 1 in severity and resolved without medical intervention. Grade 1 or 2 hemorrhagic events were more frequent in patients receiving bolus‑IFL plus Avastin when compared to those receiving bolus‑IFL plus placebo and included gastrointestinal hemorrhage (24% vs. 6%), minor gum bleeding (2% vs. 0), and vaginal hemorrhage (4% vs. 2%). [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).]

Venous Thromboembolic Events The incidence of Grade 3–4 venous thromboembolic events was higher in patients with mCRC or NSCLC receiving Avastin with chemotherapy as compared to those receiving chemotherapy alone. The risk of developing a second subsequent thromboembolic event in mCRC patients receiving Avastin and chemotherapy was increased compared to patients receiving chemotherapy alone. In Study 1, 53 patients (14%) on the bolus‑IFL plus Avastin arm and 30 patients (8%) on the bolus‑IFL plus placebo arm received full dose warfarin following a venous thromboembolic event. Among these patients, an additional thromboembolic event occurred in 21% (11/53) of patients receiving bolus‑IFL plus Avastin and 3% (1/30) of patients receiving bolus‑IFL alone.

The overall incidence of Grade 3–4 venous thromboembolic events in Study 1 was 15.1% in patients receiving bolus‑IFL plus Avastin and 13.6% in patients receiving bolus‑IFL plus placebo. In Study 1, the incidence of the following Grade 3–4 venous thromboembolic events was higher in patients receiving bolus‑IFL plus Avastin as compared to patients receiving bolus‑IFL plus placebo: deep venous thrombosis (34 vs. 19 patients) and intra‑abdominal venous thrombosis (10 vs. 5 patients).

Neutropenia and Infection The incidences of neutropenia and febrile neutropenia are increased in patients receiving Avastin plus chemotherapy compared to chemotherapy alone. In Study 1, the incidence of Grade 3 or 4 neutropenia was increased in mCRC patients receiving IFL plus Avastin (21%) compared to patients receiving IFL alone (14%). In Study 4, the incidence of Grade 4 neutropenia was increased in NSCLC patients receiving paclitaxel/carboplatin (PC) plus Avastin (26.2%) compared with patients receiving PC alone (17.2%). Febrile neutropenia was also increased (5.4% for PC plus Avastin vs. 1.8% for PC alone). There were 19 (4.5%) infections with Grade 3 or 4 neutropenia in the PC plus Avastin arm of which 3 were fatal compared to 9 (2%) neutropenic infections in patients receiving PC alone, of which none were fatal. During the first 6 cycles of treatment, the incidence of serious infections including pneumonia, febrile neutropenia, catheter infections and wound infections was increased in the PC plus Avastin arm [58 patients (13.6%)] compared to the PC alone arm [29 patients (6.6%)].

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

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

Congestive Heart Failure The incidence of Grade ≥ 3 left ventricular dysfunction was 1.0% in patients receiving Avastin compared to 0.6% in the control arm across indications. In patients with MBC, the incidence of Grade 3‑4 congestive heart failure (CHF) was increased in patients in the Avastin plus paclitaxel arm (2.2%) as compared to the control arm (0.3%). Among patients receiving prior anthracyclines for MBC, the rate of CHF was 3.8% for patients receiving Avastin as compared to 0.6% for patients receiving paclitaxel alone. The safety of continuation or resumption of Avastin in patients with cardiac dysfunction has not been studied.

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

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

All Grade 3–4 adverse events and selected Grade 1–2 adverse events (hypertension, proteinuria, thromboembolic events) were collected in the entire study population. Severe and life‑threatening (Grade 3–4) adverse events, which occurred at a higher incidence (≥ 2%) in patients receiving bolus‑IFL plus Avastin as compared to bolus‑IFL plus placebo, are presented in Table 1.

1 INDICATIONS AND USAGE 1.1 Metastatic Colorectal Cancer (mCRC) Avastin is indicated for the first‑ or second‑line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5‑fluorouracil–based chemotherapy.

1.2 Non‑Squamous Non–Small Cell Lung Cancer (NSCLC) Avastin is indicated for the first‑line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

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

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

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

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

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

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

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

4 CONTRAINDICATIONS None.

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

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

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

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

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

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

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

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

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

[See Adverse Reactions (6.1).]

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

In clinical studies in non–small cell lung cancer where patients with CNS metastases who completed radiation and surgery more than 4 weeks prior to the start of Avastin were evaluated with serial CNS imaging, symptomatic Grade 2 CNS hemorrhage was documented in one of 83 Avastin‑treated patients (rate 1.2%, 95% CI 0.06%–5.93%).

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

Do not administer Avastin to patients with recent history of hemoptysis of ≥1/2 teaspoon of red blood. Discontinue Avastin in patients with hemorrhage. [See Boxed Warning, Dosage and Administration (2.4).]

5.4 Non‑Gastrointestinal Fistula Formation Serious and sometimes fatal non‑gastrointestinal fistula formation involving tracheo‑esophageal, bronchopleural, biliary, vaginal, renal and bladder sites occurs at a higher incidence in Avastin‑treated patients compared to controls. The incidence of non‑gastrointestinal perforation was ≤0.3% in clinical studies. Most events occurred within the first 6 months of Avastin therapy.

Discontinue Avastin in patients with fistula formation involving an internal organ. [See Dosage and Administration (2.4).]

5.5 Arterial Thromboembolic Events Serious, sometimes fatal, arterial thromboembolic events (ATE) including cerebral infarction, transient ischemic attacks, myocardial infarction, angina, and a variety of other ATE occurred at a higher incidence in patients receiving Avastin compared to those in the control arm.

Across indications, the incidence of Grade ≥ 3 ATE in the Avastin containing arms was 2.4% compared to 0.7% in the control arms. Among patients receiving Avastin in combination with chemotherapy, the risk of developing ATE during therapy was increased in patients with a history of arterial thromboembolism, or age greater than 65 years. [See Use in Specific Populations (8.5).]

The safety of resumption of Avastin therapy after resolution of an ATE has not been studied.

Discontinue Avastin in patients who experience a severe ATE. [See Dosage and Administration (2.4).]

5.6 Hypertension The incidence of severe hypertension is increased in patients receiving Avastin as compared to controls. Across clinical studies the incidence of Grade 3 or 4 hypertension ranged from 5‑18%.

Table 1 Monitor blood pressure every two to three weeks during treatment with Avastin. Treat with NCI‑CTC Grade 3−4 Adverse Events in Study 1 appropriate anti‑hypertensive therapy and monitor blood pressure regularly. Continue to (Occurring at Higher Incidence [≥ 2%] Avastin vs. Control) monitor blood pressure at regular intervals in patients with Avastin‑induced or ‑exacerbated Arm 1 Arm 2 hypertension after discontinuation of Avastin.

IFL + Placebo IFL + Avastin Temporarily suspend Avastin in patients with severe hypertension that is not controlled with medical management. Discontinue Avastin in patients with hypertensive crisis or hypertensive (n = 396) (n = 392) encephalopathy. [See Dosage and Administration (2.4).]

NCI‑CTC Grade 3‑4 Events 74% 87% 5.7 Reversible Posterior Leukoencephalopathy Syndrome (RPLS) RPLS has been reported with an incidence of <0.1% in clinical studies. The onset of symptoms Body as a Whole Asthenia 7% 10% occurred from 16 hours to 1 year after initiation of Avastin. RPLS is a neurological disorder Abdominal Pain 5% 8% which can present with headache, seizure, lethargy, confusion, blindness and other visual and Pain 5% 8% neurologic disturbances. Mild to severe hypertension may be present. Magnetic resonance imaging (MRI) is necessary to confirm the diagnosis of RPLS. Cardiovascular Hypertension 2% 12% Discontinue Avastin in patients developing RPLS. Symptoms usually resolve or improve within days, although some patients have experienced ongoing neurologic sequelae. The safety of Deep Vein Thrombosis 5% 9% reinitiating Avastin therapy in patients previously experiencing RPLS is not known. [See Intra‑Abdominal Thrombosis 1% 3% Dosage and Administration (2.4).]

Syncope 1% 3% 5.8 Proteinuria Digestive The incidence and severity of proteinuria is increased in patients receiving Avastin as Diarrhea 25% 34% compared to controls. Nephrotic syndrome occurred in < 1% of patients receiving Avastin in Constipation 2% 4% clinical trials, in some instances with fatal outcome. [See Adverse Reactions (6.1).] In a Hemic/Lymphatic published case series, kidney biopsy of six patients with proteinuria showed findings Leukopenia 31% 37% consistent with thrombotic microangiopathy.

14% 21% Neutropeniaa Monitor proteinuria by dipstick urine analysis for the development or worsening of proteinuria with serial urinalyses during Avastin therapy. Patients with a 2 + or greater urine aCentral laboratories were collected on Days 1 and 21 of each cycle.

Neutrophil counts are available in 303 patients in Arm 1 and 276 in Arm 2. dipstick reading should undergo further assessment with a 24‑hour urine collection.

71819ge_c 1

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

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

System Organ Class/ IFN‑α + Placebo IFN‑α + Avastin (n = 304) (n = 337) Preferred terma Table 2 Gastrointestinal disorders NCI‑CTC Grade 1‑4 Adverse Events in Study 1 Diarrhea 16% 21% (Occurring at Higher Incidence [≥ 5%] in IFL + Avastin vs. IFL) General disorders and administration Arm 1 Arm 2 Arm 3 site conditions IFL + Placebo IFL + Avastin 5‑FU/LV + Avastin Fatigue 27% 33% (n = 98) (n = 102) (n = 109) Investigations Weight decreased 15% 20% Body as a Whole Metabolism and nutrition disorders Pain 55% 61% 62% Anorexia 31% 36% Abdominal Pain 55% 61% 50% Musculoskeletal and connective Headache 19% 26% 26% tissue disorders Cardiovascular Myalgia 14% 19% Hypertension 14% 23% 34% Back pain 6% 12% Hypotension 7% 15% 7% Nervous system disorders Deep Vein Thrombosis 3% 9% 6% Headache 16% 24% Digestive Renal and urinary disorders Vomiting 47% 52% 47% Proteinuria 3% 20% Anorexia 30% 43% 35% Respiratory, thoracic and Constipation 29% 40% 29% mediastinal disorders Stomatitis 18% 32% 30% Epistaxis 4% 27% Dyspepsia 15% 24% 17% Dysphonia 0% 5% GI Hemorrhage 6% 24% 19% Vascular disorders Weight Loss 10% 15% 16% Hypertension 9% 28% Dry Mouth 2% 7% 4% a Adverse events were encoded using MedDRA, Version 10.1.

Colitis 1% 6% 1% Hemic/Lymphatic The following adverse events were reported at a 5‑fold greater incidence in the IFN‑α plus Thrombocytopenia 0% 5% 5% Avastin arm compared to IFN‑α alone and not represented in Table 4: gingival bleeding Nervous (13 patients vs. 1 patient); rhinitis (9 vs.0 ); blurred vision (8 vs. 0); gingivitis (8 vs. 1); Dizziness 20% 26% 19% gastroesophageal reflux disease (8 vs.1 ); tinnitus (7 vs. 1); tooth abscess (7 vs.0); mouth ulceration (6 vs. 0); acne (5 vs. 0); deafness (5 vs. 0); gastritis (5 vs. 0); gingival pain (5 vs. 0) Respiratory and pulmonary embolism (5 vs. 1).

Upper Respiratory Infection 39% 47% 40% 6.2 Immunogenicity Epistaxis 10% 35% 32% As with all therapeutic proteins, there is a potential for immunogenicity. The incidence of antibody Dyspnea 15% 26% 25% development in patients receiving Avastin has not been adequately determined because the assay Voice Alteration 2% 9% 6% sensitivity was inadequate to reliably detect lower titers. Enzyme‑linked immunosorbent assays Skin/Appendages (ELISAs) were performed on sera from approximately 500 patients treated with Avastin, primarily Alopecia 26% 32% 6% in combination with chemotherapy. High titer human anti‑Avastin antibodies were not detected.

Skin Ulcer 1% 6% 6% Immunogenicity data are highly dependent on the sensitivity and specificity of the assay.

Special Senses Additionally, the observed incidence of antibody positivity in an assay may be influenced by Taste Disorder 9% 14% 21% several factors, including sample handling, timing of sample collection, concomitant medications, Urogenital and underlying disease. For these reasons, comparison of the incidence of antibodies to Avastin Proteinuria 24% 36% 36% with the incidence of antibodies to other products may be misleading.

6.3 Postmarketing Experience Avastin in Combination with FOLFOX4 in Second‑line mCRC The following adverse reactions have been identified during post‑approval use of Avastin.

Only Grade 3‑5 non‑hematologic and Grade 4–5 hematologic adverse events related to Because these reactions are reported voluntarily from a population of uncertain size, it is not treatment were collected in Study 2. The most frequent adverse events (selected Grade 3–5 always possible to reliably estimate their frequency or establish a causal relationship to non‑hematologic and Grade 4–5 hematologic adverse events) occurring at a higher incidence drug exposure. (≥ 2%) in 287 patients receiving FOLFOX4 plus Avastin compared to 285 patients receiving Body as a Whole: Polyserositis FOLFOX4 alone were fatigue (19% vs. 13%), diarrhea (18% vs. 13%), sensory neuropathy Cardiovascular: Pulmonary hypertension, RPLS, Mesenteric venous occlusion (17% vs. 9%), nausea (12% vs. 5%), vomiting (11% vs. 4%), dehydration (10% vs. 5%), Eye disorders (reported from unapproved use for treatment of various ocular disorders): hypertension (9% vs. 2%), abdominal pain (8% vs. 5%), hemorrhage (5% vs. 1%), other Endophthalmitis; Intraocular inflammation such as iritis and vitritis; Retinal detachment; Other neurological (5% vs. 3%), ileus (4% vs. 1%) and headache (3% vs. 0%). These data are likely retinal disorders; Increased intraocular pressure; Hemorrhage following intraocular injection to under‑estimate the true adverse event rates due to the reporting mechanisms used including conjunctival, vitreous hemorrhage or retinal hemorrhage; Vitreous floaters; Visual in Study 2. disturbances; Ocular hyperemia; Ocular pain and/or discomfort Unresectable Non‑Squamous Non‑Small Cell Lung Cancer (NSCLC) Gastrointestinal: Gastrointestinal ulcer, Intestinal necrosis, Anastomotic ulceration Only Grade 3‑5 non‑hematologic and Grade 4‑5 hematologic adverse events were collected Hemic and lymphatic: Pancytopenia in Study 4. Grade 3–5 non‑hematologic and Grade 4–5 hematologic adverse events (occurring Renal: Renal thrombotic microangiopathy (manifested as severe proteinuria) at a higher incidence (≥2%) in 427 patients receiving PC plus Avastin compared with 441 patients receiving PC alone were neutropenia (27% vs. 17%), fatigue (16% vs. 13%), hypertension Respiratory: Nasal septum perforation, dysphonia (8% vs. 0.7%), infection without neutropenia (7% vs. 3%), venous thrombus/embolism (5% vs. 3%), 7 DRUG INTERACTIONS febrile neutropenia (5% vs. 2%), pneumonitis/pulmonary infiltrates (5% vs. 3%), infection with Grade 3 A drug interaction study was performed in which irinotecan was administered as part of the or 4 neutropenia (4% vs. 2%), hyponatremia (4% vs. 1%), headache (3% vs. 1%) and proteinuria FOLFIRI regimen with or without Avastin. The results demonstrated no significant effect of bevacizumab on the pharmacokinetics of irinotecan or its active metabolite SN38.

(3% vs. 0%).

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

163 patients were bleeding/hemorrhage (2%), CNS hemorrhage (1%), hypertension (5%), venous thromboembolic event (7%), arterial thromboembolic event (3%), wound‑healing complications (3%), proteinuria (1%), and gastrointestinal perforation (2%).

Metastatic Renal Cell Carcinoma (mRCC) All grade adverse events were collected in Study 9. Grade 3–5 adverse events occurring at a higher incidence (≥ 2%) in 337 patients receiving interferon alfa (IFN‑α) plus Avastin Avastin® (bevacizumab) compared to 304 patients receiving IFN‑α plus placebo arm were fatigue (13% vs. 8%), 02/11 AVA0000306600 asthenia (10% vs. 7%), proteinuria (7% vs. 0%), hypertension (6% vs. 1%; including Manufactured by: 10127309 hypertension and hypertensive crisis), and hemorrhage (3% vs. 0.3%; including epistaxis, Initial U.S.Approval: February 2004 small intestinal hemorrhage, aneurysm ruptured, gastric ulcer hemorrhage, gingival bleeding, Genentech, Inc. haemoptysis, hemorrhage intracranial, large intestinal hemorrhage, respiratory tract A Member of the Roche Group Code Revision Date: February 2011 hemorrhage, and traumatic hematoma).

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

3/8/11 11:24 PM

In first-line metastatic NSCLC and first- and second-line MCRC

To reach beyond convention…

Indications Avastin is indicated for the first-line treatment of unresectable, locally advanced, recurrent or metastatic non–squamous non–small cell lung cancer in combination with carboplatin and paclitaxel.

Avastin is indicated for the first- or second-line treatment of patients with metastatic carcinoma of the colon or rectum in combination with intravenous 5-fluorouracil–based chemotherapy.

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade ≥3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (≥1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention) Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation (≤0.3%), arterial thromboembolic events (grade ≥3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions In NSCLC, grade 3–5 (nonhematologic) and grade 4–5 (hematologic) adverse events in Study E4599 occurring at a ≥2% higher incidence in Avastin-treated patients vs controls were neutropenia (27% vs 17%), fatigue (16% vs 13%), hypertension (8% vs 0.7%), infection without neutropenia (7% vs 3%), venous thrombus/embolism (5% vs 3%), febrile neutropenia (5% vs 2%), pneumonitis/pulmonary infiltrates (5% vs 3%), infection with grade 3 or 4 neutropenia (4% vs 2%), hyponatremia (4% vs 1%), headache (3% vs 1%), and proteinuria (3% vs 0%) In first-line MCRC, the most common grade 3–4 events in Study 2107, which occurred at a ≥2% higher incidence in the Avastin plus IFL vs IFL groups, were asthenia (10% vs 7%), abdominal pain (8% vs 5%), pain (8% vs 5%), hypertension (12% vs 2%), deep vein thrombosis (9% vs 5%), intra-abdominal thrombosis (3% vs 1%), syncope (3% vs 1%), diarrhea (34% vs 25%), constipation (4% vs 2%), leukopenia (37% vs 31%), and neutropenia (21% vs 14%) In second-line MCRC, the most common grade 3–5 (nonhematologic) and 4–5 (hematologic) events in Study E3200, which occurred at a higher incidence (≥2%) in the Avastin plus FOLFOX4 vs FOLFOX4 groups, were diarrhea (18% vs 13%), nausea (12% vs 5%), vomiting (11% vs 4%), dehydration (10% vs 5%), ileus (4% vs 1%), neuropathy–sensory (17% vs 9%), neurologic–other (5% vs 3%), fatigue (19% vs 13%), abdominal pain (8% vs 5%), headache (3% vs 0%), hypertension (9% vs 2%), and hemorrhage (5% vs 1%) Please see following brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

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