TAP Vol 2 Issue 13

Renal cell carcinoma 11

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Oncology drug shortage 13

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VOLUME 2, ISSUE 13

Head and neck carcinoma 23

SEPTEMBER 1, 2011 ASCOPost.com

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

Thoracic Oncology

Fixing the Drug Shortage: It’s About Time

World Conference on Lung Cancer: Personalized Approaches to Treatment

By Caroline Helwick

T

he 14th World Conference on Lung Cancer hosted more than 7,000 attendees in Amsterdam recently, with the theme “Better Care through Personalized Medical Approaches.” The following are brief summaries of key data presented at the conference, with perspective provided by Roy S. Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut (see sidebar on page 3).

response rate was only 15.5% with chemotherapy, according to Gervais and colleagues from France.1 “We now have results for the use of first-line erlotinib in Asian and Western mutation-positive patients with NSCLC. I think EURTAC is a big step toward individualized lung cancer care,” said Radj Gervais, MD, of the Centre Francois Baclesse in Caen, France.

First-line Erlotinib

High EGFR Expression Predicts Survival

In EURTAC (n = 174), the first phase III study of erlotinib (Tarceva) to include Western patients with non–small cell lung cancer (NSCLC) who had epidermal growth factors receptor (EGFR) mutations, first-line treatment with the drug nearly doubled progression-free survival compared with chemotherapy. Progression-free survival was 9.4 months vs 5.2 months, respectively, and median overall survival was 22.9 months and 18.8 months, respectively. Although 54.5% paSEE PAGE 39 tients responded to erlotinib, the

High levels of EGFR expression predicted prolonged survival in patients with NSCLC who received cetuximab (Erbitux) in combination with chemotherapy in the first-line setting, according to a new analysis of the phase III FLEX trial.2 Among 1,121 patients, researchers found that individuals with high EGFR expression (200+ on a scale of 0–300) consistently benefited from the addition of cetuximab. Their median overall survival was 12 months, compared with 9.6 months for the chemotherapy-alone arm, a 27% reduction in risk (P = .011). The 1-year survival rates were 50% vs 37%, and continued on page 3

Increased Use of Hospital Services Boosts Oncology Spending

Cost of Care

or our ongoing series on the rising costs of cancer care, The ASCO Post spoke with Lee N. Newcomer, MD, Senior Vice President of Oncology for UnitedHealthcare. Dr. Newcomer is responsible for improving cost-effective cancer care at the nation’s largest health insurer. He shed light on areas of costs that are less transparent than drug prices, but are just as much a part of the problem of the untenable rise in health-care costs.

have spent the past 30 years trying to improve the results of treatment for advanced cancer. I had the privilege of working with Sir Michael Peckham when the late Professor Tim McElwain and he were evolving variants of the PVB (cisplatin, vinblastine, bleomycin) and PEB (cisplatin, etoposide, bleomycin) regimens for testicular cancer in the United Kingdom. This occurred soon after Drs. Larry Einhorn, John Donohue, Mel Samuels, and others had developed the final modifications of the vinblastine/bleomycin regimen with the addition of cisplatin, creating for the first time a regimen that achieved cure in more than 70% of patients with metastatic testicular cancer (as compared to the previous > 70% death rate). We took some missteps along the way, including attempts to reduce toxicity by the introduction of carboplatin into the regimen continued on page 2

Not Just About Drugs

High-priced cancer drugs tend to get the most press when it comes to rising cancer care costs. Are we missing something that could better inform the debate?

Yes. Hospital care costs are inflating as quickly as drug costs. Our cancer costs at UnitedHealthcare are driven largely by the dramatic rise in unit costs of hospital services. Even though the hospital day census for cancer cases is dropping, our overall hospital costs are increasing in In most communities, double digits because each hospital due largely to consolidation day costs more each year. With all the attention drugs are getting, this point of the hospital industry, has been lost in the debate.

Lee N. Newcomer, MD

I

Dr. Raghavan is President, Levine Cancer Institute, Carolinas HealthCare System, Charlotte, North Carolina.

By Ronald Piana

F

By Derek Raghavan, MD, PhD

the market has become an oligopoly, which diminishes our leverage to negotiate for better, more competitive pricing.

MORE IN THIS ISSUE Oncology Meetings Coverage 14th World Conference on Lung Cancer ��� 1 2011 ASCO Annual Meeting ������������ 11, 12 Institute of Medicine National Cancer Policy Forum ������������������������������ 24 Practice Guidelines ����������������������������������������� 4 Direct from ASCO ��������������������������������������� 16 Oncology Worldwide ���������������������������������� 29 FDA Update �������������������������������������������������� 34

How does that apply to the overall debate over costs?

It is a universal problem for all diseases that require hospital care.

Sure, the skyrocketing prices of cancontinued on page 8

A Harborside Press® Publication

The ASCO Post | SEPTEMBER 1, 2011

PAGE 2

Opinion

Fixing the Drug Shortage

However, in the ensuing months— and now years—it has become increasand the deletion of bleomycin. Both of ingly clear that we have a major probthese measures resulted in significant lem, and that very little has been done reductions in response rate, increase in to fix it. More to the point, people are relapse rate, and reduction in eventual at risk of dying unnecessarily of cancer cure.1,2 because of the unavailability of crucial, irreplaceable agents. This is an urgent Epidemic of Avoidable Deaths situation that requires immediate attenTiming is crucial, and some memtion. Just to be clear, some of the agents bers of ASCO will recall the untimely in shortage supply include asparaginase death of Dr. Jeff (Elspar), bleomyGottlieb, a piocin, busulfan (BuPeople are at risk of neering medical sulfex, Myleran), oncologist who cytarabine, daunodying unnecessarily succumbed to adrubicin, doxoruof cancer because of vanced testicular bicin, liposomally cancer, which had encapsulated doxothe unavailability of presented just berubicin (Doxil), crucial, irreplaceable fore the routine use paclitaxel, and of the PVB regithiotepa. Frankly, I agents. men. We lost Dr. don’t know how the Gottlieb because of hematologists who our lack of knowledge… but something treat blood cancers can sleep at night. worse is happening now. The gains in Legislative Measures the curable malignancies have resulted A meeting convened in Washingfrom a hard-fought war, and now it ton, DC, last fall, with input and leadis particularly galling to see the slow, ership from ASCO, concluded the steady, and continued emergence of a following: national travesty—the shortage of cy■■ There is an urgent need to improve totoxic drugs, which will certainly lead rapid communication between the to an epidemic of avoidable deaths. pharmaceutical supply chain and This has been going on for years, providers, so providers have more but at an insidious, almost leisurely advanced notice and better underpace. On ward service 2 to 3 years stand and manage shortages. ago, I remember being warned by our ■■ There is a crucial need to remove senior oncology pharmacist that we the barriers faced by drug manumight run out of methotrexate, and to facturers and the FDA to minimize keep an eye on the indications for prethe impact of drug shortages, such scription. That didn’t bother me too as establishing processes for potenmuch, as I believed there were situatially extending the expiration date tions where methotrexate was someof a drug in short supply if it still times used unnecessarily. For example, meets safety requirements. the use of high-dose methotrexate in ■■ The definition of “medically necesthe management of brain metastases sary,” the term that prompts advance from lung cancer is not really supportnotifications to the FDA related to ed, in my view, by level 1 data. The dedrug shortages, must be clarified to cision not to expend high doses of this ensure the FDA is aware of pending agent in a pointless exercise caused me shortages like those the oncology little concern, and I was easily able to community is experiencing. preserve methotrexate for the tumors continued on page 39 where it really makes a difference.

continued from page 1

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

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

Elizabeth Reed, MD Deputy Editor University of Nebraska Medical Center

William T. McGivney, PhD National Comprehensive Cancer Network

ASSOCIATE EDITORS Joseph S. Bailes, MD Texas Oncology Richard R. Barakat, MD Memorial Sloan-Kettering Cancer Center Charles L. Bennett, MD, PhD, MPP University of South Carolina, Columbia Douglas W. Blayney, MD Stanford University Medical Center Philip D. Bonomi, MD Rush University Medical Center Richard Boxer, MD University of Miami

James L. Mulshine, MD Rush University Medical Center Derek Raghavan, MD, PhD Levine Cancer Institute Carolinas HealthCare System 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

Harold J. Burstein, MD Dana-Farber Cancer Institute

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

Robert W. Carlson, MD Stanford University Medical Center

Lynn D. Wilson, MD Yale University School of Medicine

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

Stanley H. Winokur, MD Singer Island, Florida

Jay S. Cooper, MD Maimonides Medical Center

William C. Wood, MD Winship Cancer Institute, Emory University

John Cox, DO Texas Oncology Nancy E. Davidson, MD University of Pittsburgh Cancer Institute George D. Demetri, MD Dana-Farber Cancer Institute Paul F. Engstrom, MD Fox Chase Cancer Center David S. Ettinger, MD Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Louis B. Harrison, MD Continuum Cancer Centers of New York Jimmie C. Holland, MD Memorial Sloan-Kettering Cancer Center Nora Janjan, MD, MPSA, MBA National Center for Policy Analysis Theodore S. Lawrence, MD, PhD University of Michigan Comprehensive Cancer Center Stephen J. Lemon, MD, MPH Oncology Associates, PC, Omaha Michael P. Link, MD Stanford University Medical Center John L. Marshall, MD Ruesch Center for the Cure of GI Cancer at Georgetown University

INTERNATIONAL EDITORS Clement Adebamowo, BM, ChB (Hons), ScD University of Ibadan, Nigeria Eduardo Cazap, MD, PhD International Union Against Cancer (UICC) Buenos Aires, Argentina Mary Gospodarowicz, MD Princess Margaret Hospital Toronto, Ontario, Canada Jacek Jassem, MD Medical University of Gdansk, Poland 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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The ASCO Post Wants to Hear from You See page 13 for more on the oncology drug shortage. We encourage readers to share their opinions and thoughts on the drug shortage and other issues of interest to the oncology community.

Write to The ASCO Post at editor@ ASCOPost.com.

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PAGE 3

14th World Conference on Lung Cancer Personalized Approaches continued from page 1

2-year survival rates were 24% vs 15%, respectively. In patients with low EGFR expression, no overall survival difference was seen between the arms.

High EGFR expression is the first biomarker for overall survival in patients with advanced NSCLC who are treated with first-line chemotherapy combined with a targeted drug, noted Robert Pirker, MD, of the Medical University of Vienna.

EGFR Inhibitor Shows Promise In a phase II trial of a pan-HER tyrosine kinase inhibitor that irreversibly binds to EGFR in patients previously treated with chemotherapy, PF-299804 produced superior progression-free survival: 12.4 months vs 8.3 months with erlotinib, a 34% reduction in risk (P = .012), plus a nonsignificant trend toward improved overall survival.3 On the basis of these positive results, Pfizer is conducting the phase III ARCHER trial, which will evaluate PF-299804 vs erlotinib.

ALK Rearrangement ALK gene rearrangement was found in 9.6% of patients with lung cancer tested in the Lung Cancer Mutation Consortium and MET amplification was found in another 4.1%, reflecting a subgroup of patients who might benefit from crizotinib.4 ALK mutations were associated with younger age, nonsmoking or never-smoking status, and presence of liver metastasis.

Crizotinib investigators reported overall survival data on 82 ALK-positive patients who received the novel drug vs matched historical controls.5 Median overall survival from the firstdose data has not been reached in the crizotinib group; 1‑year overall survival was 77%, and 2-year overall survival was 64%. Among controls, median overall survival was 20 months, while 1- and 2-year survival rates were 73% and 33%, respectively.

Response Predicted by PET PET scanning with tracer [11C] erlotinib may provide a noninvasive method of identifying tumors that will respond to EGFR tyrosine kinase inhibitors. The study by Bahce et al6 included 10 NSCLC patients, 5 with wild-type EGFR and 5 with activating EGFR mutations who were scanned twice using a procedure that included a low-dose CT scan, a 10-minute [150]water dynamic PET scan, and a 1-hour [11C]erlotinib dynamic PET scan. Tumor uptake of

[11C]erlotinib was significantly higher in the group with mutated EGFR than in the wild-type group (P = .03). Only tumors with high uptake of the tracer [11C]erlotinib responded to treatment with an EGFR inhibitor.

“This new imaging PET technique may be a noninvasive predictive marker that identifies NSCLC patients who benefit from treatment with tyrosine kinase inhibitors,” said Idris Bahce, MD, of VU University Medical Center in Amsterdam.

Endoscopy More Effective than Mediastinoscopy in Staging Lung Cancer The ASTER study previously found that endosonography—combined endoscopic ultrasound/endobronchial ultrasound—followed by surgical staging when negative for malignancy, had significantly higher sensitivity and negative predictive value than surgical staging alone.7 Investigators reported that the strategy results in a cost savings ($1,210 per patient, $3,450 when mediastinoscopy is not required) and better quality of life.8 “Given that assessment of lymph glands using the endoscopic approach was more effective, better tolerated by patients, and no more expensive than the surgical approaches,” Robert Rintoul, MD, of the United Kingdom and his colleagues recommended this practice.

■

Disclosure: Dr. Pirker has received speaker’s fees and honoraria for serving on advisory boards from Merck Serono. Dr. Gervais reported no potential conflicts of interest. Dr. Rintoul’s institution, Papworth Hospital, Cambridge, UK, has received loan EBUS equipment and support for educational endosonography courses from Olympus UK

References 1. Gervais R, Rosell R, Vergnenegre A, et al. 14th World Conference on Lung Cancer.

Abstract 733. Presented July 4, 2011.

2. Pirker R, Paz Ares L, Eberhardt WEE, et al. 14th World Conference on Lung Cancer. Abstract 1557. Presented July 6, 2011.

3. Boyer M, Blackhall FH, Barrios CH, et al. 14th World Conference on Lung Cancer.

Abstract 745. Presented July 4, 2011.

4. Vella-Garcia M, Iafrate JA, Pao W, et al. 14th World Conference on Lung Cancer.

Abstract 1348. Presented July 5, 2011.

5. Shaw AT, Yeap B, Solomon B, et al.

14th World Conference on Lung Cancer.

Abstract 1348. Presented July 6, 2011.

6. Bahce I, Lubberink M, Hendrikse NH, et al. 14th World Conference on Lung Cancer. Abstract 1910. Presented July 6, 2011.

7. Annema JT, van Meerbeeck JP, Rintoul RC, et al. JAMA 304:2245-2252, 2010.

8. Rintoul RC, Annema JT, Tournoy KG, et al. 14th World Conference on Lung Cancer. Abstract 840. Presented July 6, 2011.

Expert Point of View

T

he EURTAC study provides additional evidence of the efficacy of the oral EGFR inhibitors in the first-line treatment of patients with mutated EGFR— and, importantly, in Western patients, rather than Asians, for whom data are more abundant. “The findings speak to the fact that all patients with advanced NSCLC, in my opinion, should have their tumors sequenced for EGFR mutations and, where they are mutated, be treated with an EGFR inhibitor,” said Roy S. Roy S. Herbst, MD, PhD Herbst, MD, PhD, of Yale Cancer Center in New Haven, Connecticut, in an interview with The ASCO Post.

“The caveat is that an overall survival benefit has yet to be shown, and that is unlikely, given the high crossover rates in these trials. Patients with mutations are better served by getting erlotinib (Tarceva) (or, outside of the United States, gefitinib [Iressa]) upfront, rather than second-line, given its lesser toxicity and greater efficacy than chemotherapy in this patient group.”

Cetuximab Research In the subset analysis of the FLEX trial, cetuximab (Erbitux) plus chemotherapy was most efficacious in patients with high EGFR expression, as determined by a new assay. “While the analysis of EGFR expression was prospectively planned, the type of analysis and the cutoff values that were chosen were established after the study’s completion. As such, while the data are interesting and hypothesis-generating, these results should be validated before we apply the findings in clinical practice,” Dr. Herbst said.

A prospective analysis of this variable in cetuximab-treated patients will be added as part of SWOG 0819, for which Dr. Herbst is the principal investigator.

EGFR expression determined by fluorescence in situ hybridization remains the primary endpoint of this trial, which is now accruing in the United States.

But aside from high EGFR expression and activating mutations, there are subsets of patients who will not respond to cetuximab or erlotinib. Promising results for the irreversible tyrosine kinase inhibitor PF-299804 suggest that the next generation of EGFR inhibitors coming down the pike will work by different mechanisms, potentially target more of the HER2 pathway, and possibly have increased activity in NSCLC.

Optimizing Therapy Conference attendees also heard that the subset of patients with ALK rearrangements may be larger than previously reported—10%—although as part of the Lung Cancer Mutation Consortium, some patient selection may be at play.

“But the findings indicate that mutations can be analyzed in a multicenter fashion and can be employed in future trials and in determining therapy,” Dr. Herbst said.

European investigators also reported their work with emerging imaging techniques, which offers the promise of a noninvasive means of determining likely responders to EGFR inhibitors. “This would obviate the need for biopsy, thus sparing morbidity and cost,” Dr. Herbst observed.

Lung Cancer Screening Finally, the publication of the landmark National Lung Screening Trial just prior to the Conference led to much discussion among lung cancer specialists at the meeting.1 The study found that low-dose helical CT reduces mortality from lung cancer by 20% among current and former heavy smokers.

“Based on this important trial, screening has the promise to become the standard of care, at least in the U.S. and especially in settings where multimodality approaches are in place to react to the test results,” Dr. Herbst said.

■

Disclosure: Dr. Herbst reported serving on the advisory committee for Amgen, Biothera, Genetics Squared, Med Trust, N of One, SynDevRx, Targeted Molecular Diagnostics, and Diatech.

Reference 1. The National Lung Screening Trial Research Team: N Engl J Med 365:395409, 2011.

The ASCO Post | SEPTEMBER 1, 2011

PAGE 4

Expert’s Corner Practice Guidelines

A Conversation with Samuel Silver, MD, PhD Guidelines, lessons learned, and survivorship

By Ronald Piana

Samuel Silver, MD, PhD

O

ver the past 2 decades, significant therapeutic advances have led to greater survival rates and quality of life for patients with cancer. During the same period there has been a transformation in the way oncology services are both perceived and delivered. In a recent conversation with The ASCO Post, Samuel Silver, MD, PhD, Professor of Internal Medicine, University of Michigan Medical School, and Vice Chair of the National Comprehensive Cancer Network (NCCN) Board of Directors, commented on several issues that affect the delivery of oncology services.

NCCN’s mission is to improve the quality and effectiveness of care for patients with cancer. What value do NCCN Clinical Practice Guidelines bring to achieving that mission?

NCCN Guidelines™ have filled a huge need in the provider community, the patient community, and the payer community as well. Specifically, for oncologists and hematologists, the

ucts. For instance, one could use NCCN guidelines provide a set of evidenceGuidelines to develop clinical pathways based reviews integrated with expert for the care of patients with cancer. Howmedical judgment that address more ever, pathways could also be developed than 95% of adult cancers. in a narrower scope, in which they serve Moreover, the consensus-based primarily as a cost-control mechanism process of creating and updating the stressing the use of generic cancer drugs guidelines answers many of the clinior regimens, which could unfairly restrict cal questions oncologists might have the way oncologists practice. in the treatment of adult cancers, not The value of clinical pathways deonly in areas with level 1 randomized pends on how they clinical trial–based are developed and evidence, but also The mission of the written. The misat the many node sion of the NCCN points in the care NCCN Guidelines™ Guidelines is to of these patients is to help make help make deciwhere that evisions based on dence level might decisions based on high-level evidence not be so robust. high-level evidence or expert consensus The guidelines in the best interhelp oncologists or expert consensus est of our patients. work through the in the best interest If commercial difficult clinical pathways are heavproblems they of our patients. ily weighted on the face on a daily bapayer side as a costsis, not only in the control mechanism, it could be cause for treatment of malignancies, but also in concern for the oncology community. prevention, detection, and supportive care. If you attend tumor boards at acaCautionary Tale demic institutions or in community The story of erythropoiesis-stimulating practices, one question is often heard: agents (ESAs) is well known. Looking “What did the NCCN Guidelines sugback, is there a take-away message for the gest at this juncture?” oncology community?

Guidelines vs Pathways Absolutely. We saw signals based on Could you discuss the differences bemeta-analyses that indicated a decreased tween NCCN Guidelines and some of the survival in patients receiving ESAs, but newer commercial clinical pathway proat the time there were no good randomgrams? ized trials that answered these questions In some ways, there may not be signifdefinitively. At that time, the trials that icant differences between the two prodwere being funded by Pharma were

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designed to expand the use of ESAs, as opposed to better understanding the clinical implications of ESAs in terms of patient benefit or harm.

So it was more about product expansion rather than ensuring that we had the necessary data to understand whether we were giving these drugs in the right way. From a marketing point of view, if you have a successful product, you want to find ways to expand its use for other indications. But unless we have a laserlike focus on making sure that we have good data from solid studies examining current clinical use of a product, you end up with another ESA-like situation: inadequate data to answer the possibility of harm. That’s the take-away message.

Assessing Therapeutic Value You were involved in pay-for-performance clinical trials long before the advent of comparative effectiveness research. Are we closer to having the proper methods to accurately assess value, and are guidelines a significant component for delivering value?

We actually have all the tools necessary to assess the value of various therapies. The problem is getting the funding for the trials. Studies comparing what are essentially standards of care are not attractive to Pharma. There is currently no incentive to do head-to-head trials, and you need to conduct those kinds of comparisons to show value.

That said, comparative effectiveness is the mantra du jour. The question is whether we have the fortitude to carve out the necessary funds and select which therapies and agents will

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ASCOPost.com | SEPTEMBER 1, 2011

PAGE 5

Expert’s Corner

be studied. New drugs and technologies are being developed each year, so another challenge will be to come up with an appropriate selection process, to ensure that our limited resources are used in the best way possible.

Doctor as Patient At this year’s NCCN Annual Conference, you and other survivors and caregivers spoke about your personal experiences with cancer. Could you tell us a bit about that session?

To me, what was truly enlightening about the NCCN roundtable was the focus on caregivers. Naturally, we talk about the patient and the physician, but we do not give proper attention to the role of caregivers who deal with so many of the emotional and physical needs of patients. Another interesting point that came out of the roundtable is the lack of discussion about the children of patients with cancer. We need to better understand how to talk to children about these incredibly difficult topics.

I was part of the discussion because I’m an oncologist and I’ve had a lot of experience talking to patients and caregivers during difficult times, but I also shared my experience as a cancer survivor. I was diagnosed with an aggressive form of non-Hodgkin lymphoma about 18 years ago, after I fractured my arm and went to the ER for an x-ray. The ER doc had me come back to look at my own image, and I immediately saw it was a pathologic fracture, at which point I knew I needed to see an oncologist. It was a really important moment during which I realized that I couldn’t be my own doctor and that no one is protected from cancer, not even those who treat it.

My wife, who was an amazing caregiver for me, is really the one who should have been on the roundtable. Speaking from a patient’s perspective, I realized just how important caregivers are for people battling the multitude of issues that arise with a diagnosis of cancer.

Closing Thoughts Do you have any advice for young doctors entering the field of oncology?

From my own experience as a patient, I learned how important the initial consultation is with the oncologist. This is a seminal moment for the patient and we need to truly take the time to listen and answer questions in a thoughtful manner.

Another point I’d make is that most of us are not very good at assessing our patients’ psychiatric issues, especially when depression is more than just re-

active. It’s easy to miss, so it is important to have evaluative instruments to gauge your patients’ psychological status and to have support staff intervene when appropriate.

We are in a period in which we have a multitude of new therapies that enhance our ability to tailor cancer treat-

ments on a patient-by-patient basis. It is an exciting time of scientific discovery, but the overarching question looms: How are we going to continue to pay for these very expensive therapies. As an oncologist coming into the field, you can almost become paralyzed by this conundrum. That said, the single

most important thing to remember while we advance the technical side of oncology is this: You must always place utmost value on the doctor-patient relationship; never let go of the humanity of being a doctor.

■

Disclosure: Dr. Silver serves as a consultant for Amgen and BlueCare Network of Michigan.

NOW APPROVED PREPARE FOR A NEW OPTION

ZYTIGA™ in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

Important Safety Information Contraindications ZYTIGA™ may cause fetal harm (Pregnancy Category X) and is contraindicated in women who are or may become pregnant.

Warnings and Precautions Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess—Use with caution in patients with a history of cardiovascular disease or with medical conditions that might be compromised by increases in hypertension, hypokalemia and fluid retention. Safety has not been established in patients with LVEF < 50% or NYHA Class III or IV heart failure.

Control hypertension and correct hypokalemia before and during treatment. Monitor blood pressure, serum potassium, and symptoms of fluid retention at least monthly.

Adrenocortical Insufficiency (AI) has been reported in clinical trials after an interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of AI if prednisone is stopped or withdrawn or if the patient experiences unusual stress. Perform appropriate tests, if indicated, to confirm AI. Increased dosages of corticosteroids may be used before, during and after stressful situations.

Hepatotoxicity—Increases in liver enzymes have led to drug interruption, dose modification and/or discontinuation. Monitor liver function and modify, withhold or discontinue ZYTIGA™ dosing as recommended (see Prescribing Information for more information).

Food Effect—ZYTIGA™ must be taken on an empty stomach.

Exposure of abiraterone increases up to 10-fold when abiraterone acetate is taken with meals. No food should be eaten for at least two hours before the dose of ZYTIGA™ is taken and for at least one hour after the dose of ZYTIGA™ is taken.

Adverse Reactions The most common adverse reactions (≥ 5%) reported in clinical trials were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia and upper respiratory tract infection.

Drug Interactions ZYTIGA™ is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. Avoid co-administration with CYP2D6 substrates that have a narrow therapeutic index. If an alternative cannot be used, exercise caution and consider a dose reduction of the CYP2D6 substrate. Additionally, abiraterone is a substrate of CYP3A4 in vitro. Strong inhibitors and inducers of CYP3A4 should be avoided or used with caution.

Please see adjacent page for Brief Summary of full Prescribing Information.

Contact your Centocor Ortho Biotech Sales Representative for more information.

Visit www.zytiga.com Y3294ALT_Island_7x10_v1 1

© Centocor Ortho Biotech Inc. 2011 5/11 08A11005D

5/19/11 11:05 AM

The ASCO Post | SEPTEMBER 1, 2011

PAGE 6

Spotlight on Research Genetic Profiling

Genomic Researchers Identify Weak Points in Breast Cancer Cells

By Caroline Helwick

A

large-scale project in genetic profiling has identified weak points in breast tumor cells that not only represent potentially new “druggable” targets but could lead to an entirely new classi-

fication of all cancers. The findings were recently reported in Cancer Discovery, a journal of the American Association for Cancer Research,1 and were the topic of a teleconference moderated by

Jose Baselga, MD, PhD, Co-Editor-inChief of the journal and Chief of Hematology/Oncology at the Massachusetts General Hospital.

“My own work as been in the de-

ZYTIGA™ (abiraterone acetate) Brief Summary of Prescribing Information.

INDICATIONS AND USAGE ZYTIGA in combination with prednisone is indicated for the treatment of patients with metastatic castration-resistant prostate cancer (CRPC) who have received prior chemotherapy containing docetaxel.

CONTRAINDICATIONS Pregnancy: ZYTIGA may cause fetal harm when administered to a pregnant woman. ZYTIGA is contraindicated in women who are or may become pregnant. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus.

WARNINGS AND PRECAUTIONS Hypertension, Hypokalemia and Fluid Retention Due to Mineralocorticoid Excess: Use ZYTIGA with caution in patients with a history of cardiovascular disease. ZYTIGA may cause hypertension, hypokalemia, and fluid retention as a consequence of increased mineralocorticoid levels resulting from CYP17 inhibition [see Adverse Reactions and Clinical Pharmacology (12.1) in full Prescribing Information]. Co-administration of a corticosteroid suppresses adrenocorticotropic hormone (ACTH) drive, resulting in a reduction in the incidence and severity of these adverse reactions. Use caution when treating patients whose underlying medical conditions might be compromised by increases in blood pressure, hypokalemia or fluid retention, e.g., those with heart failure, recent myocardial infarction or ventricular arrhythmia. The safety of ZYTIGA in patients with left ventricular ejection fraction <50% or NYHA Class III or IV heart failure has not been established because these patients were excluded from the randomized clinical trial. Monitor patients for hypertension, hypokalemia, and fluid retention at least once a month.

Control hypertension and correct hypokalemia before and during treatment with ZYTIGA. Adrenocortical Insufficiency: Adrenocortical insufficiency has been reported in clinical trials in patients receiving ZYTIGA in combination with prednisone, following interruption of daily steroids and/or with concurrent infection or stress. Use caution and monitor for symptoms and signs of adrenocortical insufficiency, particularly if patients are withdrawn from prednisone, have prednisone dose reductions, or experience unusual stress.

Symptoms and signs of adrenocortical insufficiency may be masked by adverse reactions associated with mineralocorticoid excess seen in patients treated with ZYTIGA. If clinically indicated, perform appropriate tests to confirm the diagnosis of adrenocortical insufficiency. Increased dosage of corticosteroids may be indicated before, during and after stressful situations [see Warnings and Precautions].

Hepatotoxicity: Marked increases in liver enzymes leading to drug discontinuation or dosage modification have occurred [see Adverse Reactions]. Measure serum transaminases (ALT and AST) and bilirubin levels prior to starting treatment with ZYTIGA, every two weeks for the first three months of treatment and monthly thereafter. In patients with baseline moderate hepatic impairment receiving a reduced ZYTIGA dose of 250 mg, measure ALT, AST, and bilirubin prior to the start of treatment, every week for the first month, every two weeks for the following two months of treatment and monthly thereafter. Promptly measure serum total bilirubin, AST, and ALT if clinical symptoms or signs suggestive of hepatotoxicity develop.

Elevations of AST, ALT, or bilirubin from the patient’s baseline should prompt more frequent monitoring. If at any time AST or ALT rise above five times the ULN, or the bilirubin rises above three times the ULN, interrupt ZYTIGA treatment and closely monitor liver function. Re-treatment with ZYTIGA at a reduced dose level may take place only after return of liver function tests to the patient’s baseline or to AST and ALT less than or equal to 2.5X ULN and total bilirubin less than or equal to 1.5X ULN [see Dosage and Administration (2.2) in full Prescribing Information].

The safety of ZYTIGA re-treatment of patients who develop AST or ALT greater than or equal to 20X ULN and/or bilirubin greater than or equal to 10X ULN is unknown.

Food Effect: ZYTIGA must be taken on an empty stomach. No food should be consumed for at least two hours before the dose of ZYTIGA is taken and for at least one hour after the dose of ZYTIGA is taken. Abiraterone Cmax and AUC0-∞ (exposure) were increased up to 17- and 10-fold higher, respectively, when a single dose of abiraterone acetate was administered with a meal compared to a fasted state. The safety of these increased exposures when multiple doses of abiraterone acetate are taken with food has not been assessed [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

ADVERSE REACTIONS The following are discussed in more detail in other sections of the labeling: Hypertension, hypokalemia, and fluid retention due to mineralocorticoid excess [see Warnings and Precautions].

Adrenocortical insufficiency [see Warnings and Precautions].

Hepatotoxicity [see Warnings and Precautions].

Food effect [see Warnings and Precautions].

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 Y3294ALT_Island_7x10_v1 2

velopment of new therapies in breast cancer. I can say that the approach put forward in this paper could be totally game-changing,” Dr. Baselga commented during the briefing.

ZYTIGA™ (abiraterone acetate) directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in clinical practice.

In a placebo-controlled, multicenter phase 3 clinical trial of patients with metastatic castration-resistant prostate cancer who were using a gonadotropin-releasing hormone (GnRH) agonist or were previously treated with orchiectomy, ZYTIGA was administered at a dose of 1,000 mg daily in combination with prednisone 5 mg twice daily in the active treatment arm (N = 791). Placebo plus prednisone 5 mg twice daily was given to control patients (N = 394). The median duration of treatment with ZYTIGA was 8 months.

The most common adverse drug reactions (≥5%) reported in clinical studies were joint swelling or discomfort, hypokalemia, edema, muscle discomfort, hot flush, diarrhea, urinary tract infection, cough, hypertension, arrhythmia, urinary frequency, nocturia, dyspepsia, and upper respiratory tract infection.

The most common adverse drug reactions that resulted in drug discontinuation were aspartate aminotransferase increased, alanine aminotransferase increased, urosepsis and cardiac failure (each in <1% of patients taking ZYTIGA).

Adverse reactions and laboratory abnormalities related to mineralocorticoid effects were reported more commonly in patients treated with ZYTIGA than in patients treated with placebo: hypokalemia 28% versus 20%, hypertension 9% versus 7% and fluid retention (edema) 27% versus 18%, respectively (see Table 1). In patients treated with ZYTIGA, grades 3 to 4 hypokalemia occurred in 5% of patients and grades 3 to 4 hypertension was reported in 1% of patients [see Warnings and Precautions].

Table 1 shows adverse reactions due to ZYTIGA that occurred with either a ≥ 2% absolute increase in frequency compared to placebo, or were events of special interest (mineralocorticoid excess, cardiac adverse reactions, and liver toxicities).

Table 1: Adverse Reactions due to ZYTIGA in a Placebo-Controlled Phase 3 Trial ZYTIGA with Placebo with Prednisone Prednisone (N=791) (N=394) System/Organ Class All Grades1 Grade 3-4 All Grades Grade 3-4 Adverse reaction % % % % Musculoskeletal and connective tissue disorders 4.2 23.4 4.1 Joint swelling/discomfort2 29.5 26.2 3.0 23.1 2.3 Muscle discomfort3 General disorders 26.7 1.9 18.3 0.8 Edema4 Vascular disorders Hot flush 19.0 0.3 16.8 0.3 Hypertension 8.5 1.3 6.9 0.3 Gastrointestinal disorders Diarrhea 17.6 0.6 13.5 1.3 Dyspepsia 6.1 0 3.3 0 Infections and infestations Urinary tract infection 11.5 2.1 7.1 0.5 Upper respiratory tract infection 5.4 0 2.5 0 Respiratory, thoracic and mediastinal disorders Cough 10.6 0 7.6 0 Renal and urinary disorders Urinary frequency 7.2 0.3 5.1 0.3 Nocturia 6.2 0 4.1 0 Cardiac disorders 7.2 1.1 4.6 1.0 Arrhythmia5 Chest pain or 3.8 0.5 2.8 0 chest discomfort 6 2.3 1.9 1.0 0.3 Cardiac failure7 1 2 3 4 5

6

7

Adverse events graded according to CTCAE version 3.0 Includes terms Arthritis, Arthralgia, Joint swelling, and Joint stiffness Includes terms Muscle spasms, Musculoskeletal pain, Myalgia, Musculoskeletal discomfort, and Musculoskeletal stiffness Includes terms Edema, Edema peripheral, Pitting edema, and Generalized edema Includes terms Arrhythmia, Tachycardia, Atrial fibrillation, Supraventricular tachycardia, Atrial tachycardia, Ventricular tachycardia, Atrial flutter, Bradycardia, Atrioventricular block complete, Conduction disorder, and Bradyarrhythmia Includes terms Angina pectoris, Chest pain, and Angina unstable.

Myocardial infarction or ischemia occurred more commonly in the placebo arm than in the ZYTIGA arm (1.3% vs. 1.1% respectively).

Includes terms Cardiac failure, Cardiac failure congestive, Left ventricular dysfunction, Cardiogenic shock, Cardiomegaly, Cardiomyopathy, and Ejection fraction decreased 5/20/11 11:13 AM

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 7

Spotlight on Research

Jose Baselga, MD, PhD

“Despite the wealth of molecular profiling data that describe breast tumors, our understanding of the fundamental genetic dependencies in this disease is relatively poor,” the investigators noted. The group, therefore, was interested in deciphering not just the location and structure of genetic mu-

tations but the “functional viability” of the mutations as well.

“Previous classification with genomics has made headway, but it catalogs structure over the activity of genes.

Many alterations are not critical for the cancer cell’s survival. They are not ‘drivers.’ We classified tumors by what drives

ZYTIGA™ (abiraterone acetate)

ZYTIGA™ (abiraterone acetate)

Cardiovascular Adverse Reactions: Cardiovascular adverse reactions in the phase 3 trial are shown in Table 1. The majority of arrhythmias were grade 1 or 2. Grade 3-4 arrhythmias occurred at similar rates in the two arms. There was one death associated with arrhythmia and one patient with sudden death in the ZYTIGA arm. No patients had sudden death or arrhythmia associated with death in the placebo arm. Cardiac ischemia or myocardial infarction led to death in 2 patients in the placebo arm and 1 death in the ZYTIGA arm.

Cardiac failure resulting in death occurred in 1 patient on both arms.

Hepatotoxicity: Drug-associated hepatotoxicity with elevated ALT, AST, and total bilirubin has been reported in patients treated with ZYTIGA. Across all clinical trials, liver function test elevations (ALT or AST increases of > 5X ULN) were reported in 2.3% of patients who received ZYTIGA, typically during the first 3 months after starting treatment. In the phase 3 trial, patients whose baseline ALT or AST were elevated were more likely to experience liver function test elevations than those beginning with normal values.

When elevations of either ALT or AST > 5X ULN, or elevations in bilirubin > 3X ULN were observed, ZYTIGA was withheld or discontinued. In two instances marked increases in liver function tests occurred [see Warnings and Precautions]. These two patients with normal baseline hepatic function, experienced ALT or AST elevations 15 to 40X ULN and bilirubin elevations 2 to 6 X ULN. Upon discontinuation of ZYTIGA, both patients had normalization of their liver function tests and one patient was re-treated with ZYTIGA without recurrence of the elevations.

In clinical trials, the following patients were excluded: patients with active hepatitis, patients with baseline ALT and/or AST ≥ 2.5X ULN in the absence of liver metastases, and patients with ALT and/or AST > 5X ULN in the presence of liver metastases. Abnormal liver function tests developing in patients participating in clinical trials were managed by treatment interruption, dose modification and/or discontinuation [see Dosage and Administration (2.2) in full Prescribing Information and Warnings and Precautions]. Patients with elevations of ALT or AST > 20X ULN were not re-treated.

Other Adverse Reactions: Adrenal insufficiency occurred in two patients on the abiraterone arm of the phase 3 clinical trial (< 1%).

Laboratory Abnormalities of Interest: Table 2 shows laboratory values of interest from the phase 3 placebo-controlled clinical trial. Grade 3-4 low serum phosphate (7.2%) and potassium (5.3%) occurred more frequently in the ZYTIGA arm.

Nursing Mothers: ZYTIGA is not indicated for use in women. It is not known if abiraterone acetate 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 ZYTIGA, a decision should be made to either discontinue nursing, or discontinue the drug taking into account the importance of the drug to the mother.

Pediatric Use: ZYTIGA is not indicated in children.

Geriatric Use: Of the total number of patients in a phase 3 trial of ZYTIGA, 71% of patients were 65 years and over and 28% were 75 years and over. No overall differences in safety or effectiveness were observed between these elderly patients and younger patients.

Patients with Hepatic Impairment: The pharmacokinetics of abiraterone were examined in subjects with baseline mild (n = 8) or moderate (n = 8) hepatic impairment (Child-Pugh Class A and B, respectively) and in 8 healthy control subjects with normal hepatic function. The systemic exposure (AUC) of abiraterone after a single oral 1,000 mg dose of ZYTIGA increased by approximately 1.1-fold and 3.6-fold in subjects with mild and moderate baseline hepatic impairment, respectively compared to subjects with normal hepatic function.

No dosage adjustment is necessary for patients with baseline mild hepatic impairment. In patients with baseline moderate hepatic impairment (ChildPugh Class B), reduce the recommended dose of ZYTIGA to 250 mg once daily. If elevations in ALT or AST >5X ULN or total bilirubin >3X ULN occur in patients with baseline moderate hepatic impairment, discontinue ZYTIGA treatment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

The safety of ZYTIGA in patients with baseline severe hepatic impairment has not been studied. These patients should not receive ZYTIGA. For patients who develop hepatotoxicity during treatment, interruption of treatment and dosage adjustment may be required [see Dosage and Administration (2.2) in full Prescribing Information, Warnings and Precautions, and Clinical Pharmacology (12.3) in full Prescribing Information].

Patients with Renal Impairment: In a dedicated renal impairment trial, the mean PK parameters were comparable between healthy subjects with normal renal function (N=8) and those with end stage renal disease (ESRD) on hemodialysis (N=8) after a single oral 1,000 mg dose of ZYTIGA. No dosage adjustment is necessary for patients with renal impairment [see Dosage and Administration (2.1) and Clinical Pharmacology (12.3) in full Prescribing Information].

OVERDOSAGE: There have been no reports of overdose of ZYTIGA during clinical studies. There is no specific antidote. In the event of an overdose, stop ZYTIGA, undertake general supportive measures, including monitoring for arrhythmias and cardiac failure and assess liver function.

Storage and Handling: Store at 20°C to 25°C (68°F to 77°F); excursions permitted to 15°C to 30°C (59°F to 86°F) [see USP controlled room temperature]. Based on its mechanism of action, ZYTIGA may harm a developing fetus. Therefore, women who are pregnant or women who may be pregnant should not handle ZYTIGA without protection, e.g., gloves [see Use in Specific Populations].

Manufactured by: Patheon Inc. Toronto, Canada

Table 2: Laboratory Abnormalities of Interest in a Phase 3 Placebo-Controlled Clinical Trial Abiraterone (N=791) Placebo (N=394) All Grades Grade 3-4 All Grades Grade 3-4 Laboratory Abnormality (%) (%) (%) (%) High Triglyceride 62.5 0.4 53.0 0 High AST 30.6 2.1 36.3 1.5 Low Potassium 28.3 5.3 19.8 1.0 Low Phosphorus 23.8 7.2 15.7 5.8 High ALT 11.1 1.4 10.4 0.8 High Total Bilirubin 6.6 0.1 4.6 0 DRUG INTERACTIONS Effects of Abiraterone on Drug Metabolizing Enzymes: ZYTIGA is an inhibitor of the hepatic drug-metabolizing enzyme CYP2D6. In a CYP2D6 drug-drug interaction trial, the Cmax and AUC of dextromethorphan (CYP2D6 substrate) were increased 2.8- and 2.9-fold, respectively, when dextromethorphan was given with abiraterone acetate 1,000 mg daily and prednisone 5 mg twice daily. Avoid co-administration of abiraterone acetate with substrates of CYP2D6 with a narrow therapeutic index (e.g., thioridazine). If alternative treatments cannot be used, exercise caution and consider a dose reduction of the concomitant CYP2D6 substrate drug [see Clinical Pharmacology (12.3) in full Prescribing Information].

Drugs that Inhibit or Induce CYP3A4 Enzymes: Based on in vitro data, ZYTIGA is a substrate of CYP3A4. The effects of strong CYP3A4 inhibitors (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or inducers (e.g., phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) on the pharmacokinetics of abiraterone have not been evaluated, in vivo. Avoid or use with caution, strong inhibitors and inducers of CYP3A4 during ZYTIGA treatment [see Clinical Pharmacology (12.3) in full Prescribing Information].

USE IN SPECIFIC POPULATIONS Pregnancy: Pregnancy Category X [see Contraindications]. ZYTIGA is contraindicated in women who are or may become pregnant while receiving the drug. If this drug is used during pregnancy, or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to the fetus and the potential risk for pregnancy loss. Women of childbearing potential should be advised to avoid becoming pregnant during treatment with ZYTIGA. Y3294ALT_Island_7x10_v1 3

Manufactured for: Centocor Ortho Biotech Inc. Horsham, PA 19044 Issued: April 2011 08Z11008

them,” explained Alan Ashworth, PhD, lead author, of the Institute for Cancer Research in London.

How Functional Screening Is Done Dr. Ashworth and colleagues performed high-throughput RNA interference screening on 34 breast cancer cell lines to identify a series of genes upon which breast cancer cells rely, ie, the novel “genetic dependencies” for “druggable” genes.

Ultimately, the research team identified 330 genes whose depletion by small interfering RNA caused loss of viability in at least one cell line and 180 genes that caused loss of viability in two or more lines. This analysis enabled the investigators to identify the predominant dependencies in each cell line.

They ultimately selected 20 breast cancer cell lines, encapsulating the major breast cancer subtypes, for subsequent interrogation. The tumor panel was further characterized by means of transcript microarrays, array-based comparative genomic hybridization, drug sensitivities for several targeted agents, and gene mutation data.

The investigators were able to validate known targets such as ERBB2 (HER2) and PIK3CA and to identify potential new therapeutic targets, including the TTK protein kinase gene for PTEN-mutated cancers. A number of oral TTK inhibitors that target PTEN deficiency are now in development.

They also showed that ADCK2 silencing is selectively lethal in estrogen receptor (ER)-positive tumor cell lines and that ADCK2 inhibition abrogates estrogen signaling. Although there are no ADCK2 inhibitors in development yet, this finding could lead to non–endocrine-based treatments for ER-positive disease.

These are just examples of the multiple vulnerabilities that can be exploited, the investigators noted. “We need to find the weaknesses in breast cancer cells and then develop drugs that hit these weak spots. With this new information we can start to do that,” said coauthor Christopher Lord, PhD, also of the Institute for Cancer Research.

Could All Cancers Ultimately Be Reclassified?

“We showed that large-scale functional profiling allows the classification of breast cancers into subgroups distinct from the established subtypes,” Dr. Ashworth said. continued on page 8

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The ASCO Post | SEPTEMBER 1, 2011

PAGE 8

Cost of Care

Oncology Spending continued from page 1

cer drugs are a real concern, but people have lost sight of other—perhaps more difficult to quantify—areas of spending, such as hospital care and overutilization of services.

Seeking Solutions How do we tackle the problem of rising hospital costs?

In today’s environment, I’d say that the hospital industry has unfettered pricing ability. In most communities, due largely to consolidation of the hospital industry, the market has become an oligopoly, which diminishes our leverage to negotiate for better, more competitive pricing. Simultaneously, the Centers for Medicare & Medicaid Services (CMS) is continuing to underpay hospitals for their services, so quite naturally the hospitals are turning to us to make up that deficit.

I sit on the board of directors for Park Nicollet Health Systems, a 700-physician, 400-bed fully integrated service. We know from our data that anytime a Medicare patient enters the Park Nicollet system, we are reimbursed at about 70% of what our costs are for that individual. The only way we can make up that shortfall is by doing what every other hospital in the United States does: We go to the private commercial insurers and overcharge them.

Park Nicollet’s dilemma is an illustration of what hospitals across the nation face. And don’t forget, the Patient Protection and Affordable Care Act is going to further decease payments to hospitals. So the fiscal pressure on hospitals is going to escalate.

Is there someway to reverse this trend?

UnitedHealthcare’s solution to the

Genomic Research continued from page 7

Another participant in the teleconference, Rene Bernards, PhD, Professor of Molecular Carcinogenesis at The Netherlands Cancer Institute in Amsterdam, added that this study lays the groundwork for discerning critical genetic profiles within a single patient’s cancer. “The investigators are making a systematic map showing the specific vulnerabilities of cancer cells with mutations in their genome. There are correlations between the mutations and their vulnerabilities. We can begin to target them where the effect will be the greatest, …and this will lead to

problem of rising hospital costs is to get more services back into community oncology practices so we do not have to pay these hospital subsidies.

The more services we redirect from the hospital setting to the community practice, the more cost-effective the care becomes. For example, you don’t have to do an infusion in a hospital clinic. Unfortunately, the current trend is exactly opposite—hospitals are acquiring oncology practices— and that trend contributes to the escalating costs of cancer care.

National Comprehensive Cancer Network (NCCN) guidelines and found that about 44% of the bevacizumab therapy we were paying for did not comply with the guidelines and recommendations. Those data prompted a claims review program that examines whether bevacizumab is being given with other recommended drugs, whether it is given for only one line of treatment, and if it is being given for the correct diagnoses.

Treatments that ignore those recommendations are a waste of valuable

Rising Cost of Cancer Care ■■ Inflation-adjusted hospital costs are rising by double digits.

■■ Hospital consolidation diminishes the ability of insurers to negotiate pricing.

■■ Community practices deliver more cost-effective care than hospitals.

■■ Evidenced-based guidelines save money, increase value of cancer care.

■■ We may see a paradigm shift, with the “buy-and-bill” model replaced by payment tied to outcomes.

We need to create a payment system that encourages physicians to work with us in a collaborative way to deliver cost-effective medicine. The payment system should share some of those savings with physicians, rather than have it all go to hospitals.

Evidence of Value The term “value over cost” has become one of the mantras in health-care reform. Is there a direct way to determine the clinical value of one therapy over another that will satisfy providers, payers, and patients?

There is, but you need high-quality evidence. At UnitedHealthcare, we are currently working on clarifying our coverage of therapy with bevacizumab (Avastin). We looked at the improvements in survival,” he predicted.

Dr. Baselga questioned whether this groundbreaking work might lead to a new classification of breast cancer based on functional categories, not histologic subtypes.

“Historically, we have categorized cancer by tissue of origin,” Dr. Bernards responded. “The significance of the current study is that we now appreciate we should begin to call cancers by the oncogenic driving lesion responsible for malignant growth… and initiate treatment based on this driver.”

According to Dr. Ashworth, this is indeed the likely direction of research.

resources and do not provide clinical benefit to patients with cancer.

Tying Payment to Outcome Fee-for-service tends to incentivize overuse of services. On the drug side, some contend that the buy-and-bill model of community oncology creates perverse incentives. Do we need to move away from that payment model?

Yes, but first we need to dispel the myth that without the buy-and-bill system, community practices will no longer be economically viable. Our challenge is to find a way that compensation is not tied directly to drug margins.

At UnitedHealthcare, we have launched a pilot program to incentivize oncologists for delivering “I envision a future where a panoply of genes will be studied for mutations, and it will be tremendously informative for treatment,” he said. Stand Up to Cancer provided funding for this research, added Dr. Ashworth, who is a principal on the Breast Cancer Subtypes Dream Team.

■

complex, comprehensive care regardless of the drugs they need to use for therapy. We are closely monitoring the quality of care we pay for and are collecting patient outcomes data to determine where we are getting the best results—think of this as real-time comparative effectiveness research. Essentially, we are asking physicians to standardize their care, measure the results, and make changes to improve the outcomes.

Their payments will be based on better outcomes and reductions in the total costs of care.

How will you evaluate the treatment regimens to determine best practices?

Over the course of the pilot, the various treatment strategies will be evaluated by the program’s physician leaders to identify the most effective regimens for a range of clinical presentations. UnitedHealthcare will play no role in determining which treatment plan the oncologists choose, but we hope the pilot will identify and reduce unnecessary drug administration that does not improve the patient’s health outcomes.

Embracing Change Do you feel that community oncologists will embrace such a sea change in the way they do business?

Absolutely. Oncologists never liked having their livelihood tied to drugs; they want to be paid for the multiple complex areas of care they deliver. We need those private practice oncologists to be able to sustain their practices in the face of changing economic times so they can continue to deliver highquality, accessible, personalized care for our patients with cancer.

■

Disclosure: Dr. Newcomer is an employee and shareholder of UnitedHealth Group.

Contact The ASCO Post EDITORIAL OFFICE

Disclosure: Drs. Baselga, Bernards, and Lord disclosed no potential conflicts of interest.

Harborside Press 37 Main Street Cold Spring Harbor, NY 11724

Reference 1. Brough R, Frankum JR, Sims D, et al: Functional viability profiles of breast cancer. Cancer Discovery. August 2, 2011 (early release online).

Phone: 631.692.0800 Fax: 631.692.0805 ASCOPost.com HarborsidePress.com

Do you recognize these patients?

Before Cycle 1, identify your patients’ individual risk factors for CINV • In addition to the emetogenic potential of a chemotherapy regimen, consider a patient’s additional risk factors for emesis.1 — Female, age <50 years, history of low alcohol intake (<1.5 oz/day), history of morning or motion sickness, and preexisting anxiety or nausea1,2 • Because with every additional risk factor, the risk of emesis increases.1,2.

• Because a 5-HT3 antagonist and a corticosteroid alone may not be enough to prevent CINV for 5 days.

Female ✔ Light drinker ✔

Motion sickness Younger than age 50 ✔ Anxiety ✔ ✔

An antiemetic regimen with a 5-HT3 antagonist, a corticosteroid, and

EMEND—Helps provide superior CINV prevention for 5 days.

References: 1. Navari RM. Pathogenesis-based treatment of chemotherapy-induced nausea and vomiting—two new agents.

J Support Oncol. 2003;1(2):89–103. 2. Osoba D, Zee B, Pater J, et al; for Quality of Life and Symptom Control Committees of the National Cancer Institute of Canada Clinical Trials Group. Determinants of postchemotherapy nausea and vomiting in patients with cancer. J Clin Oncol. 1997;15(1):116–123.

EMEND, in combination with other antiemetic agents, is indicated in adults for prevention of acute and delayed nausea and vomiting associated with initial and repeat courses of highly emetogenic cancer chemotherapy, including high-dose cisplatin; and for prevention of nausea and vomiting associated with initial and repeat courses of moderately emetogenic cancer chemotherapy.

Selected Important Safety Information (continued)

EMEND has not been studied for treatment of established nausea and vomiting.

Chronic continuous administration of EMEND is not recommended.

Chronic continuous use of EMEND for prevention of nausea and vomiting is not recommended because it has not been studied and because the drug interaction profile may change during chronic continuous use.

Selected Important Safety Information EMEND is contraindicated in patients who are hypersensitive to any component of the product.

EMEND is a dose-dependent inhibitor of cytochrome P450 isoenzyme 3A4 (CYP3A4). EMEND should not be used concurrently with pimozide, terfenadine, astemizole, or cisapride. Inhibition of CYP3A4 by aprepitant could result in elevated plasma concentrations of these drugs, potentially causing serious or life-threatening reactions.

EMEND should be used with caution in patients receiving concomitant medications, including chemotherapy agents, that are primarily metabolized through CYP3A4. Inhibition of CYP3A4 by EMEND could result in elevated plasma concentrations of these concomitant medications. Conversely, when EMEND is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is used concomitantly with medications that induce CYP3A4 activity, aprepitant plasma concentrations could be reduced, and this may result in decreased efficacy of aprepitant.

Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, vinorelbine, vinblastine, and vincristine. In clinical studies, EMEND was administered commonly with etoposide, vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions. In separate pharmacokinetic studies, EMEND did not influence the pharmacokinetics of docetaxel or vinorelbine.

Because a small number of patients in clinical studies received the CYP3A4 substrates vinblastine, vincristine, or ifosfamide, particular caution and careful monitoring are advised in patients receiving these agents or other chemotherapy agents metabolized primarily by CYP3A4 that were not studied.

Coadministration of EMEND with warfarin (a CYP2C9 substrate) may result in a clinically significant decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of EMEND with each chemotherapy cycle.

Merck Oncology Copyright © 2011 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc. All rights reserved. ONCO-1001721-0004 emend.com

The efficacy of hormonal contraceptives may be reduced during coadministration with and for 28 days after the last dose of EMEND. Alternative or backup methods of contraception should be used during treatment with and for 1 month after the last dose of EMEND.

In clinical trials of EMEND in patients receiving highly emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy, and at an incidence greater than 10% were asthenia/fatigue (17.8% EMEND vs 11.8% standard therapy), nausea (12.7% vs 11.8%), hiccups (10.8% vs 5.6%), diarrhea (10.3% vs 7.5%), and anorexia (10.1% vs 9.5%).

In clinical trials of EMEND in patients receiving moderately emetogenic chemotherapy, the most common adverse events reported at a frequency greater than with standard therapy were alopecia (12.4% EMEND vs 11.9% standard therapy), dyspepsia (5.8% vs 3.8%), nausea (5.8% vs 5.1%), neutropenia (5.8% vs 5.6%), asthenia (4.7% vs 4.6%), and stomatitis (3.1% vs 2.7%).

In clinical trials, EMEND increased the AUC of dexamethasone, a CYP3A4 substrate, by approximately 2-fold; therefore, the oral dose of dexamethasone administered in the regimen with EMEND should be reduced by approximately 50% to achieve exposures of dexamethasone similar to those obtained without EMEND. EMEND increased the AUC of methylprednisolone by 1.34-fold and 2.5-fold on Days 1 and 3, respectively. The intravenous dose of methylprednisolone should be reduced by approximately 25% and the oral dose by 50% when coadministered with EMEND. Please see Brief Summary of Prescribing Information on the following pages. For copies of the Prescribing Information, call 800-672-6372, visit emend.com, or contact your Merck representative.

CINV=chemotherapy-induced nausea and vomiting.

Persons depicted are for illustrative purposes only and are not actual patients.

An antiemetic regimen including

BriefofSummary of the Information Prescribing for Information forINDICATIONS INDICATIONS EMEND (aprepitant) capsules capsules Brief Summary the Prescribing AND USAGEAND USAGE EMEND® (aprepitant) of Chemotherapy-Induced and(CINV): Vomiting (CINV): Prevention Prevention of Chemotherapy-Induced Nausea andNausea Vomiting AST3.0, increased: 1.3 3.0, 1.3 EMEND, in combination with otheragents, antiemetic agents, for is indicated for preventionAST increased: EMEND, in combination with other antiemetic is indicated prevention followinglaboratory additionaladverse laboratory adverse experiences (incidence than standard therapy),ofregardless causality, were acute and delayed vomitingwith associated withrepeat initialcourses and repeat courses The followingThe additional experiences (incidence >0.5% and >0.5% greater and thangreater standard therapy), regardless causality,ofwere of acute andofdelayed nausea and nausea vomitingand associated initial and reportedtreated in patients with theregimen: aprepitant regimen: alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, of highly emetogenic cancer chemotherapy (HEC), includingcisplatin; high-dose cisplatin;reported in patients with treated the aprepitant alkaline phosphatase increased, hyperglycemia, hyponatremia, leukocytes increased, of highly emetogenic cancer chemotherapy (HEC), including high-dose erythrocyturia, and forofprevention of nausea vomitingwith associated withrepeat initialcourses and repeat courses erythrocyturia, leukocyturia.leukocyturia. and for prevention nausea and vomitingand associated initial and CAPSULESCAPSULES of emetogenic moderately emetogenic cancer chemotherapy (MEC).

The adverse-experience profi les in the Multiple-Cycle of HEC and MEC studies for upoftochemotherapy 6 cycles of chemotherapy were generally of moderately cancer chemotherapy (MEC).

The adverse-experience profiles in the Multiple-Cycle extensions ofextensions HEC and MEC studies for up to 6 cycles were generally similar to that of Postoperative and(PONV): Vomiting (PONV): EMEND for is indicated forofprevention of postoperative and vomiting. similar to that observed in observed Cycle 1. in Cycle 1.

Prevention Prevention of Postoperative Nausea andNausea Vomiting EMEND is indicated prevention postoperative nausea and nausea vomiting. and In well-controlled clinical studiesreceiving in patients receiving general anesthesia, patients were administered of Use: not been studied foroftreatment of established and vomiting.

PostoperativePostoperative Nausea and Nausea Vomiting: In Vomiting: well-controlled clinical studies in patients general anesthesia, 564 patients564 were administered LimitationsLimitations of Use: EMEND hasEMEND not beenhas studied for treatment established nausea and nausea vomiting.

40-mgorally aprepitant orally and 538 patients were administered 4-mg ondansetron IV. 40-mg aprepitant and 538 patients were administered 4-mg ondansetron IV. Chronic administration continuous administration is not recommended.

Chronic continuous is not recommended.

Clinical adverse experiences were reported in approximately 60%treated of patients 40-mgcompared aprepitantwith compared with approximately 64% Clinical adverse experiences were reported in approximately 60% of patients with treated 40-mg with aprepitant approximately 64% CONTRAINDICATIONS CONTRAINDICATIONS of patients with 4-mg ondansetron are the of percentage of patients receiving generalwith anesthesia clinical adverse of patients treated with treated 4-mg ondansetron IV. FollowingIV.areFollowing the percentage patients receiving general anesthesia clinical with adverse EMEND is contraindicated in patients who are hypersensitive to any of component of the product.

EMEND is contraindicated in patients who are hypersensitive to any component the product. reported at anofincidence of combined ≥3% in thestudies combined studies for40 aprepitant 40 mg and ondansetron (n=538), respectively: experiencesexperiences reported at an incidence ≥3% in the for aprepitant mg (n=564) and(n=564) ondansetron (n=538), respectively: is a dose-dependent inhibitor of cytochrome P4503A4 isoenzyme 3A4EMEND (CYP3A4).

EMEND should be used concurrently with pimozide, EMEND is a EMEND dose-dependent inhibitor of cytochrome P450 isoenzyme (CYP3A4). should not be used not concurrently with pimozide, Infections and infestations: tract infection: Infections and infestations: urinary tracturinary infection: 2.3, 3.2 2.3, 3.2 astemizole, cisapride. of CYP3A4 aprepitant resultplasma in elevated plasma concentrations of these drugs, terfenadine,terfenadine, astemizole, or cisapride.orInhibition of Inhibition CYP3A4 by aprepitantbycould result could in elevated concentrations of these drugs, Blood andsystem lymphatic systemanemia: disorders: Blood and lymphatic disorders: 3.0,anemia: 4.3 3.0, 4.3 potentially causing serious or life-threatening reactions [see Drug Interactions]. potentially causing serious or life-threatening reactions [see Drug Interactions].

Psychiatricinsomnia: disorders:2.1, insomnia: 2.1, 3.3 Psychiatric disorders: 3.3 AND PRECAUTIONS WARNINGSWARNINGS AND PRECAUTIONS Nervous systemheadache: disorders:5.0, headache: Nervous system disorders: 6.5 5.0, 6.5 CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should used with cautionreceiving in patients receiving concomitant CYP3A4 Interactions: EMEND, a dose-dependent inhibitor of CYP3A4, should be used withbecaution in patients concomitant Cardiacbradycardia: disorders: bradycardia: that are primarily metabolized through CYP3A4.inhibition Moderate of CYP3A4 by 125-mg/80-mg aprepitant, 125-mg/80-mg regimen, could Cardiac disorders: 4.4, 3.9 4.4, 3.9 medicationsmedications that are primarily metabolized through CYP3A4.

Moderate of inhibition CYP3A4 by aprepitant, regimen, could resultplasma in elevated plasma concentrations of these concomitant Vascularhypotension: disorders: hypotension: 5.7, 4.6; hypertension: result in elevated concentrations of these concomitant medications.medications.

Vascular disorders: 5.7, 4.6; hypertension: 2.1, 3.2 2.1, 3.2 Weak of CYP3A4 by a single dose ofisaprepitant is not to alter concentrations the plasma concentrations of concomitant Gastrointestinal disorders: 8.5, 8.6; constipation: 8.5, 7.6;4.1, flatulence: 4.1, 5.8; Weak inhibition of inhibition CYP3A4 by a single 40-mg dose40-mg of aprepitant not expected to expected alter the plasma of concomitant medicationsmedications Gastrointestinal disorders: nausea: 8.5,nausea: 8.6; constipation: 8.5, 7.6; flatulence: 5.8; vomiting 2.5,vomiting 3.9 2.5, 3.9 that are primarily metabolized through a clinically significant degree. that are primarily metabolized through CYP3A4 to aCYP3A4 clinicallytosignifi cant degree.

Skin and subcutaneous tissuepruritus: disorders: Skin and subcutaneous tissue disorders: 7.6,pruritus: 8.4 7.6, 8.4 When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated.

When EMEND is When aprepitant is used concomitantly with another CYP3A4 inhibitor, aprepitant plasma concentrations could be elevated. When EMEND is General general administration sitepyrexia: conditions: General disorders anddisorders general and administration site conditions: 5.9,pyrexia: 10.6 5.9, 10.6 used concomitantly with medications that induce CYP3A4 activity,plasma aprepitant plasma concentrations could and be reduced thisinmay result in used concomitantly with medications that induce CYP3A4 activity, aprepitant concentrations could be reduced this mayand result followingclinical additional clinical adverse experiences (incidence than ondansetron), causality, were The followingThe additional adverse experiences (incidence >0.5% and >0.5% greater and thangreater ondansetron), regardless ofregardless causality, ofwere reported in reported in decreased effi cacy of EMEND [see Drug Interactions]. decreased efficacy of EMEND [see Drug Interactions]. patients with aprepitant: patients treated with treated aprepitant: Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, Chemotherapy agents that are known to be metabolized by CYP3A4 include docetaxel, paclitaxel, etoposide, irinotecan, ifosfamide, imatinib, Infections and infestations: postoperative infection vinblastine, andInvincristine.

In clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, Infections and infestations: postoperative infection vinorelbine, vinorelbine, vinblastine, and vincristine. clinical studies, EMEND (125-mg/80-mg regimen) was administered commonly with etoposide, Metabolism nutritionhypokalemia, disorders: hypokalemia, Metabolism and nutritionand disorders: hypovolemiahypovolemia vinorelbine, or paclitaxel.

The doses of these agents were not adjusted to account for potential drug interactions. vinorelbine, or paclitaxel. The doses of these agents were not adjusted to account for potential drug interactions.

Nervous systemdizziness, disorders:hypoesthesia, dizziness, hypoesthesia, disorders: syncope syncope In separate pharmacokinetic studies no clinically significant change inordocetaxel orpharmacokinetics vinorelbine pharmacokinetics was observed when EMENDNervous system In separate pharmacokinetic studies no clinically signifi cant change in docetaxel vinorelbine was observed when EMEND Vascularhematoma disorders: hematoma (125-mg/80-mg regimen) was coadministered.

Vascular disorders: (125-mg/80-mg regimen) was coadministered. and disorders: mediastinaldyspnea, disorders: dyspnea, hypoxia,depression respiratory depression Due to the small numberinofclinical patients in clinical CYP3A4vinblastine, substrates vincristine, vinblastine,orvincristine, or particular ifosfamide, particular Respiratory, Respiratory, thoracic, andthoracic, mediastinal hypoxia, respiratory Due to the small number of patients studies whostudies receivedwho thereceived CYP3A4the substrates ifosfamide, and carefulare monitoring advisedreceiving in patients receiving agents or other chemotherapy agents metabolized Gastrointestinal disorders:pain, abdominal pain,pain abdominal painmouth, upper, dyspepsia dry mouth, dyspepsia caution and caution careful monitoring advised are in patients these agentsthese or other chemotherapy agents metabolized primarily by primarily CYP3A4 by CYP3A4Gastrointestinal disorders: abdominal abdominal upper, dry were [see not studied [see Drug Interactions]. that were notthat studied Drug Interactions].

Skin and subcutaneous tissueurticaria disorders: urticaria Skin and subcutaneous tissue disorders: Coadministration With(aWarfarin CYP2C9 substrate): Coadministration of EMEND result insignifi a clinically Coadministration With Warfarin CYP2C9 (a substrate): Coadministration of EMEND with warfarinwith maywarfarin result inmay a clinically cant significant General disorders General and administrative sitehypothermia, conditions: hypothermia, pain anddisorders administrative site conditions: pain decrease in international normalized ratio (INR) of prothrombin time.

In patients on chronic warfarin therapy, the INR should be closely monitored decrease in international normalized ratio (INR) of prothrombin time. In patients on chronic warfarin therapy, the INR should be closely monitored Investigations: blood pressure decreased Investigations: blood pressure decreased in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen of EMEND with each chemotherapy cycle, or following Injury,and poisoning, andcomplications: procedural complications: operative hemorrhage, wound dehiscence Injury, poisoning, procedural operative hemorrhage, wound dehiscence administration of a single dosefor of prevention EMEND forofprevention of postoperative [see Drug Interactions]. administration of a single 40-mg dose40-mg of EMEND postoperative nausea and nausea vomitingand [seevomiting Drug Interactions].

Other adverse experiences (incidence ≤0.5%) reportedtreated in patients with40 aprepitant 40 mg for postoperative Other adverse experiences (incidence ≤0.5%) reported in patients with treated aprepitant mg for postoperative nausea and nausea vomitingand vomiting Coadministration WithContraceptives: Hormonal Contraceptives: Upon coadministration efficacy ofcontraceptives hormonal contraceptives Coadministration With Hormonal Upon coadministration with EMEND,with theEMEND, efficacy the of hormonal during and during and included: included: for 28 days dosemay of EMEND may be reduced.orAlternative or backup methods of contraception should be used during treatment for 28 days following thefollowing last dosethe of last EMEND be reduced.

Alternative backup methods of contraception should be used during treatment Nervous systemdysarthria, disorders:sensory dysarthria, sensory disturbance and for 1 month dose[see of EMEND [see Drug Interactions].

Nervous system disorders: disturbance with EMENDwith andEMEND for 1 month following thefollowing last dosethe of last EMEND Drug Interactions].

Eyemiosis, disorders: acuity reduced Patients Severe Hepatic Impairment: areornopharmacokinetic clinical or pharmacokinetic datawith in patients with severe hepatic (Childimpairment (ChildEye disorders: visualmiosis, acuityvisual reduced Patients With SevereWith Hepatic Impairment: There are noThere clinical data in patients severe hepatic impairment PughTherefore, score >9).caution Therefore, caution should bewhen exercised when EMEND is administered in these patients. and disorders: mediastinalwheezing disorders: wheezing Pugh score >9). should be exercised EMEND is administered in these patients.

Respiratory, Respiratory, thoracic, andthoracic, mediastinal Chronic Continuous Chronic use continuous usefor of prevention EMEND forofprevention of nausea vomiting is not recommended because Gastrointestinal disorders: bowel soundsstomach abnormal, stomach discomfort Chronic Continuous Use: ChronicUse: continuous of EMEND nausea and vomitingand is not recommended because it has not it has notGastrointestinal disorders: bowel sounds abnormal, discomfort been studied and because the drug interaction profi le may change during chronic continuous use. been studied and because the drug interaction profile may change during chronic continuous use.

There wereadverse no serious adverse drug-related reported in the postoperative vomiting clinical studiestaking in patients taking There were no serious drug-related experiencesexperiences reported in the postoperative nausea and nausea vomitingand clinical studies in patients ADVERSE REACTIONS 40-mg aprepitant.

ADVERSE REACTIONS 40-mg aprepitant.

The overall safety ofwas aprepitant wasinevaluated in approximately 5300 individuals.

Laboratory Adverse Experiences: Oneadverse laboratory adverse experience, decreased (40-mg3.8%, aprepitant 3.8%, ondansetron The overall safety of aprepitant evaluated approximately 5300 individuals.

Laboratory Adverse Experiences: One laboratory experience, hemoglobin hemoglobin decreased (40-mg aprepitant ondansetron 4.2%), was 4.2%), was reported at an≥3% incidence ≥3% receiving in a patient receiving general anesthesia.

Because trials areunder conducted widely varying adverse conditions, adverse reaction rates the clinical trials of a drug incidence in a patient general anesthesia.

Because clinical trialsclinical are conducted widelyunder varying conditions, reaction rates observed in observed the clinicalintrials of a drug cannot be cannot bereported at an directlytocompared to clinical rates intrials the clinical trialsdrug of another drug maythe notrates reflect the rates in clinical practice. followinglaboratory additionaladverse laboratory adverse experiences (incidence than ondansetron), causality, were directly compared rates in the of another and may notand reflect observed in observed clinical practice.

The followingThe additional experiences (incidence >0.5% and >0.5% greater and thangreater ondansetron), regardless ofregardless causality,ofwere reportedtreated in patients with40 aprepitant 40albumin mg: blood albumin blood decreased, blood bilirubinblood increased, blood glucoseblood increased, blood Clinical Trials Experience: Chemotherapy-Induced and Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled trials reported in in patients with treated aprepitant mg: blood decreased, bilirubin increased, glucose increased, Clinical Trials Experience: Chemotherapy-Induced Nausea and Nausea Vomiting: Highly Emetogenic Chemotherapy: In 2 well-controlled clinical trialsclinical in potassium glucose decreased, urine present. patients receiving highly emetogenic cancer chemotherapy, withduring aprepitant Cycle 1 of chemotherapy of decreased, urineglucose present. patients receiving highly emetogenic cancer chemotherapy, 544 patients544 werepatients treatedwere with treated aprepitant Cycleduring 1 of chemotherapy and 413 of and 413potassium these patientsinto continued into the Multiple-Cycle for upoftochemotherapy.

6 cycles of chemotherapy. given in combination with ondansetron adverse ofexperience increased occurred with similarinincidence in patients with40 aprepitant 40asmgin (1.1%) in patients treated these patients continued the Multiple-Cycle extension forextension up to 6 cycles EMEND wasEMEND given inwas combination with ondansetron The adverseThe experience increasedofALT occurredALT with similar incidence patients treated with treated aprepitant mg (1.1%) patientsastreated and dexamethasone. with ondansetron and dexamethasone. with ondansetron 4 mg (1.0%).4 mg (1.0%).

In Cycleadverse 1, clinical adverse experiences were reported in approximately 69%treated of patients with theregimen aprepitant regimenwith compared with Other Studies: Other Studies: 2Inserious addition, 2 serious adverse experiences were reported in postoperative vomiting (PONV) clinical studies in patients In Cycle 1, clinical experiences were reported in approximately 69% of patients with treated the aprepitant compared In addition, adverse experiences were reported in postoperative nausea and nausea vomitingand (PONV) clinical studies in patients approximately 68%treated of patients with standard therapy.areFollowing are the of percentage of patients receiving highly emetogenic taking a higher dose of 1aprepitant: 1 case of constipation, and 1 case of subileus. approximately 68% of patients with treated standard therapy.

Following the percentage patients receiving highly emetogenic taking a higher dose of aprepitant: case of constipation, and 1 case of subileus. chemotherapy in Cycle 1 with clinical adverse experiences reported at anofincidence of ≥3% for theregimen aprepitant regimen chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence ≥3% for the aprepitant (n=544) and(n=544) standardand standardAngioedemaAngioedema urticaria were as serious adverse experiences in a patient receivinginaprepitant in a non-CINV/non-PONV study. and urticariaand were reported as reported serious adverse experiences in a patient receiving aprepitant a non-CINV/non-PONV study. therapyrespectively: (n=550), respectively: therapy (n=550), Postmarketing following adverse reactions have been identifi ed during postmarketing use of Because aprepitant.

Because these Postmarketing Experience:Experience: The followingThe adverse reactions have been identifi ed during postmarketing use of aprepitant. these Body as aunspecifi whole/Site ed: asthenia/fatigue: 17.8, 11.8;6.6, dizziness: 6.6, 4.4; dehydration: 5.9, 5.1;pain: abdominal pain: 4.6,2.9, 3.3; fever: 2.9, Body as a whole/Site ed:unspecifi asthenia/fatigue: 17.8, 11.8; dizziness: 4.4; dehydration: 5.9, 5.1; abdominal 4.6, 3.3; fever: reportedfrom voluntarily from aofpopulation uncertain size, it not is generally possibleestimate to reliably estimate theirorfrequency reactions arereactions reportedare voluntarily a population uncertainofsize, it is generally possiblenot to reliably their frequency establish or establish mucousdisorder: membrane disorder: 3.5; mucous3.5; membrane 2.6, 3.1 2.6, 3.1 a causal relationship a causal relationship to the drug. to the drug.

Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; Digestive system: nausea: 12.7, 11.8; constipation: 10.3, 12.2; diarrhea: 10.3, 7.5; vomiting: 7.5, 7.6; heartburn: 5.3, 4.9; gastritis: 4.2, 3.1; Skin and subcutaneous tissuepruritus, disorders: pruritus, rash, urticaria Skin and subcutaneous tissue disorders: rash, urticaria epigastric discomfort: epigastric discomfort: 4.0, 3.1 4.0, 3.1 Immune systemhypersensitivity disorders: hypersensitivity reactions including anaphylactic Immune system disorders: reactions including anaphylactic reactions reactions Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 Eyes, ears, nose, and throat: tinnitus: 3.7, 3.8 DRUG INTERACTIONS DRUG INTERACTIONS Hemic andsystem: lymphatic system: neutropenia: 3.1, 2.9 Hemic and lymphatic neutropenia: 3.1, 2.9 is aa substrate, a weak-to-moderate (dose-dependent) andofanCYP3A4. inducer of CYP3A4.isAprepitant is alsoofanCYP2C9. inducer of CYP2C9.

Aprepitant isAprepitant a substrate, weak-to-moderate (dose-dependent) inhibitor, andinhibitor, an inducer Aprepitant also an inducer nutrition: anorexia: Metabolism Metabolism and nutrition:and anorexia: 10.1, 9.5 10.1, 9.5 Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak of CYP3A4 by a single Effect of Aprepitant on the Pharmacokinetics of Other Agents: CYP3A4 substrates: Weak inhibition of inhibition CYP3A4 by a single 40-mg dose40-mg dose Nervous system:8.5, headache: 8.5, 8.7;2.9, insomnia: Nervous system: headache: 8.7; insomnia: 3.1 2.9, 3.1 is not to alter concentrations the plasma concentrations of concomitant that are primarily metabolized through of aprepitantofisaprepitant not expected to expected alter the plasma of concomitant medicationsmedications that are primarily metabolized through CYP3A4 to aCYP3A4 to a Respiratory system: hiccups: 10.8, 5.6 clinically significant degree.

However, higherdoses aprepitant doses or repeated at anydose aprepitant dosea clinically may havesignifi a clinically significant effect.

Respiratory system: hiccups: 10.8, 5.6 clinically signifi cant degree.

However, higher aprepitant or repeated dosing at anydosing aprepitant may have cant effect.

In addition, isolated casesadverse of serious adverse experiences, of bradycardia, disorientation, and duodenal perforating duodenal ulcer As inhibitor a moderate inhibitor at of aCYP3A4 a dose of 125 mg,can aprepitant increase plasma concentrations of concomitantly In addition, isolated cases of serious experiences, regardless ofregardless causality, ofof causality, bradycardia, disorientation, and perforating ulcer As a moderate of CYP3A4 dose of at 125 mg/80 mg, mg/80 aprepitant increasecan plasma concentrations of concomitantly administeredadministered were reported in highly emetogenic clinical studies. oral medications that are metabolized through CYP3A4 [see Contraindications].

The use of fosaprepitant increase CYP3A4 substrate were reported in highly emetogenic CINV clinicalCINV studies. oral medications that are metabolized through CYP3A4 [see Contraindications].

The use of fosaprepitant may increasemay CYP3A4 substrate plasma concentrations to a lesser theaprepitant use of oral(125 aprepitant Moderately Emetogenic Chemotherapy: 1 of 2 emetogenic moderately emetogenic chemotherapy patients to a lesser degree thandegree the usethan of oral mg). (125 mg).

Moderately Emetogenic Chemotherapy: During CycleDuring 1 of 2 Cycle moderately chemotherapy studies, 868studies, patients868 were treatedwere with treated the with theplasma concentrations aprepitant and 686 of these patientsinto continued intofor extensions for upoftochemotherapy.

4 cycles of chemotherapy.

In theanalysis combined analysis of Cycle5-HT antagonists: In clinical drugstudies, interaction studies,did aprepitant not have clinicallyeffects important effects on the pharmacokinetics of 5-HT3 antagonists: aprepitant regimen andregimen 686 of these patients continued extensions up to 4 cycles In the combined of Cycle In clinical drug interaction aprepitant not havedid clinically important on the pharmacokinetics of 3 1 data for theseadverse 2 studies, adverse experiences were reported in approximately 69%treated of patients with theregimen aprepitant regimen compared or hydrodolasetron (the activeofmetabolite of dolasetron).

1 data for these 2 studies, experiences were reported in approximately 69% of patients with treated the aprepitant compared ondansetron,ondansetron, granisetron,granisetron, or hydrodolasetron (the active metabolite dolasetron). with approximately 72% of patients treated with standard therapy. with approximately 72% of patients treated with standard therapy.

Corticosteroids: Dexamethasone: EMEND, when given asofa125 regimen of 125 mg with dexamethasone coadministered 201,mg on Day 1, Corticosteroids: Dexamethasone: EMEND, when given as a regimen mg with dexamethasone coadministered orally as 20 orally mg onasDay In theanalysis combined analysis of Cycle 1 data for thesethe 2 studies, the adverse-experience profi le in both emetogenic moderately emetogenic chemotherapy and EMENDand EMEND when as with 80 mg/day with dexamethasone coadministered In the combined of Cycle 1 data for these 2 studies, adverse-experience profile in both moderately chemotherapy when given as 80 given mg/day dexamethasone coadministered orally as orally as studies was generally comparable to the highly emetogenic chemotherapy studies.

Following are the percentage of patients receiving 8 mg on Days5,2increased through 5,the increased the AUC of dexamethasone, a CYP3A4bysubstrate,

by Days 2.2-fold on 5.

Days anddexamethasone 5. The oral dexamethasone studies was generally comparable to the highly emetogenic chemotherapy studies. Following are the percentage of patients receiving 8 mg on Days 2 through AUC of dexamethasone, a CYP3A4 substrate, 2.2-fold on 1 and The1oral moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at anofincidence of ≥3% for theregimen aprepitant regimen should by be approximately reduced by approximately 50% when coadministered EMEND (125-mg/80-mg to achieveofexposures of moderately emetogenic chemotherapy in Cycle 1 with clinical adverse experiences reported at an incidence ≥3% for the aprepitant doses shoulddoses be reduced 50% when coadministered with EMENDwith (125-mg/80-mg regimen), toregimen), achieve exposures (n=868) and standard therapy (n=846), respectively: dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered (n=868) and standard therapy (n=846), respectively: dexamethasone similar to those obtained when it is given without EMEND. The daily dose of dexamethasone administered in clinical in clinical chemotherapy-induced vomiting EMEND reflects an approximate 50%of reduction of dexamethasone. the dose of dexamethasone.

A Blood andsystem lymphatic systemneutropenia: disorders: neutropenia: chemotherapy-induced nausea and nausea vomitingand studies withstudies EMENDwith reflects an approximate 50% reduction the dose of A Blood and lymphatic disorders: 5.8, 5.6 5.8, 5.6 single dose(40 of EMEND (40coadministered mg) when coadministered single dose of dexamethasone 20 mg,the increased the AUC of dexamethasone single dose of EMEND mg) when with a singlewith oraladose of oral dexamethasone 20 mg, increased AUC of dexamethasone nutritionanorexia: disorders: anorexia: Metabolism Metabolism and nutritionand disorders: 6.2, 7.2 6.2, 7.2 1.45-fold.noTherefore, no dose isadjustment is recommended. by 1.45-fold.byTherefore, dose adjustment recommended.

Psychiatricinsomnia: disorders:2.6, insomnia: Psychiatric disorders: 3.7 2.6, 3.7 Methylprednisolone: EMEND, when given asofa125 regimen 1251mg Day 1 and on 80Days mg/day on 3, Days 2 and 3,the increased Methylprednisolone: EMEND, when given as a regimen mg onofDay andon80 mg/day 2 and increased AUC of the AUC of Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4 Nervous system disorders: headache: 13.2, 14.3; dizziness: 2.8, 3.4 methylprednisolone, a CYP3A4bysubstrate, 1 and on

by Day 2.5-fold on Day 3, when methylprednisolone was coadministered methylprednisolone, a CYP3A4 substrate, 1.34-foldby on1.34-fold Day 1 andonbyDay 2.5-fold 3, when methylprednisolone was coadministered Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7 Gastrointestinal disorders: constipation: 10.3, 15.5; diarrhea: 7.6, 8.7; dyspepsia: 5.8, 3.8; nausea: 5.8, 5.1; stomatitis: 3.1, 2.7 asDay 1251mg Day 1asand 40 mg on 3.

Days 3. The IV methylprednisolone should by be approximately reduced by approximately intravenouslyintravenously as 125 mg on andonorally 40 orally mg onasDays 2 and The2IVand methylprednisolone dose shoulddose be reduced Skin and subcutaneous tissuealopecia: disorders: alopecia: the oral methylprednisolone should by be approximately reduced by approximately 50% when coadministered EMEND (125-mg/80-mg Skin and subcutaneous tissue disorders: 12.4, 11.9 12.4, 11.9 25% and the25% oral and methylprednisolone dose shoulddose be reduced 50% when coadministered with EMENDwith (125-mg/80-mg to achieveofexposures of methylprednisolone similar to those obtained when it is given without EMEND. the concomitant General general administration sitefatigue: conditions: fatigue: 15.4, 15.6; asthenia: 4.7, 4.6 regimen) to regimen) achieve exposures methylprednisolone similar to those obtained when it is given without EMEND. Although theAlthough concomitant General disorders anddisorders general and administration site conditions: 15.4, 15.6; asthenia: 4.7, 4.6 administration of methylprednisolone with40-mg the single dose ofhas aprepitant not been studied, a single doseproduces of EMEND produces administration of methylprednisolone with the single dose40-mg of aprepitant not beenhas studied, a single 40-mg dose40-mg of EMEND In aanalysis combined analysis of theseisolated 2 studies, isolated casesadverse of serious adverse experiences in the 2groups. treatment groups.

In a combined of these 2 studies, cases of serious experiences were similarwere in thesimilar 2 treatment a weak of CYP3A4 (based oninteraction midazolamstudy) interaction it is not to alter concentrations the plasma concentrations of a weak inhibition of inhibition CYP3A4 (based on midazolam and itstudy) is not and expected to expected alter the plasma of Highly and Emetogenic Moderately Emetogenic Chemotherapy: followingclinical additional clinical adverse experiences (incidence Highly and Moderately Chemotherapy: The followingThe additional adverse experiences (incidence >0.5% and >0.5% greater and thangreater than methylprednisolone to a clinically signifi cant degree.

Therefore, no dose adjustment is recommended. methylprednisolone to a clinically significant degree. Therefore, no dose adjustment is recommended. standard therapy),ofregardless causality, were reportedtreated in patients with theregimen aprepitant regimen or MEC studies: standard therapy), regardless causality, ofwere reported in patients with treated the aprepitant in either HECinoreither MECHEC studies: Chemotherapeutic [see Warnings and Precautions] In a pharmacokinetic study, EMEND (125-mg/80-mg did not Chemotherapeutic agents: [seeagents: Warnings and Precautions] Docetaxel: InDocetaxel: a pharmacokinetic study, EMEND (125-mg/80-mg regimen) didregimen) not Infections and infestations: herpes simplex, lowerinfection, respiratory infection, oral candidiasis, upper respiratory Infections and infestations: candidiasis, candidiasis, herpes simplex, lower respiratory oral candidiasis, pharyngitis, pharyngitis, septic shock,septic uppershock, respiratory uence the pharmacokinetics influence theinfl pharmacokinetics of docetaxel.of docetaxel. infection, tract infection infection, urinary tracturinary infection In a pharmacokinetic study, EMEND (125-mg/80-mg did not uence the pharmacokinetics Vinorelbine: Vinorelbine: In a pharmacokinetic study, EMEND (125-mg/80-mg regimen) didregimen) not influence theinfl pharmacokinetics of vinorelbineoftovinorelbine a clinicallyto a clinically Neoplasms benign,and malignant, unspecifiedcysts (including cysts and polyps):neoplasm, malignantnon–small-cell neoplasm, non–small-cell lung carcinoma Neoplasms benign, malignant, unspecifiand ed (including and polyps): malignant lung carcinoma significant degree. significant degree.

Blood andsystem lymphatic systemanemia, disorders: anemia, febrile neutropenia, thrombocytopenia Blood and lymphatic disorders: febrile neutropenia, thrombocytopenia CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown induce the metabolism of S(–) and tolbutamide, which CYP2C9 substrates (warfarin, tolbutamide): Aprepitant has been shown to induce thetometabolism of S(–) warfarin andwarfarin tolbutamide, which nutritionappetite disorders: appetite diabetes decreased, diabetes mellitus, hypokalemia Metabolism Metabolism and nutritionand disorders: decreased, mellitus, hypokalemia are metabolized through CYP2C9. Coadministration of EMEND with these drugs or other drugs thattoare to be metabolized are metabolized through CYP2C9.

Coadministration of EMEND with these drugs or other drugs that are known beknown metabolized

by CYP2C9,by CYP2C9, Psychiatric disorders: anxiety disorder, confusion, depression such asmay phenytoin, result in lower plasma concentrations of these drugs.

Psychiatric disorders: anxiety disorder, confusion, depression such as phenytoin, result inmay lower plasma concentrations of these drugs.

Nervous system:neuropathy, peripheral neuropathy, sensory neuropathy, taste disturbance, tremor A single 125-mg dosewas of EMEND was administered Day 1 and on 80Days mg/day on 3Days 2 and 3subjects to healthy who were stabilized Nervous system: peripheral sensory neuropathy, taste disturbance, tremor Warfarin: AWarfarin: single 125-mg dose of EMEND administered on Day 1 andon80 mg/day 2 and to healthy whosubjects were stabilized on chronic warfarin therapy.

Although was no effectonofthe EMEND on AUC the plasma of R(+) or S(–) warfarin on determined on Day 3, there Eyeconjunctivitis disorders: conjunctivitis on chronic warfarin therapy.

Although there was nothere effect of EMEND plasma of R(+)AUC or S(–) warfarin determined Day 3, there Eye disorders: was a 34% in S(–) warfarin substrate) (a CYP2C9trough substrate) trough concentration accompanied by a 14% in the prothrombin time was a 34% decrease in decrease S(–) warfarin (a CYP2C9 concentration accompanied by a 14% decrease in decrease the prothrombin time Cardiacmyocardial disorders: infarction, myocardialpalpitations, infarction, palpitations, Cardiac disorders: tachycardia tachycardia as international normalized or INR) days after of completion of dosing EMEND.on In chronic patientswarfarin on chronic warfarin (reported as(reported international normalized ratio or INR)ratio 5 days after 5completion dosing with EMEND.with In patients therapy, the therapy, the Vasculardeep disorders: venous thrombosis, hot flush, hypertension, Vascular disorders: venousdeep thrombosis, flushing, hotflflushing, ush, hypertension, hypotensionhypotension prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen prothrombin time (INR) should be closely monitored in the 2-week period, particularly at 7 to 10 days, following initiation of the 3-day regimen and disorders: mediastinalcough, disorders: cough, dyspnea, nasalpharyngolaryngeal secretion, pharyngolaryngeal pain, pneumonitis, pulmonary embolism, Respiratory, Respiratory, thoracic, andthoracic, mediastinal dyspnea, nasal secretion, pain, pneumonitis, pulmonary embolism, of EMEND with each chemotherapy cycle, or following administration of a single dosefor of prevention EMEND forofprevention of postoperative nausea of EMEND with each chemotherapy cycle, or following administration of a single 40-mg dose40-mg of EMEND postoperative nausea respiratory vocal disturbance respiratory insuffi ciency,insuffi vocalciency, disturbance and vomiting. and vomiting.

Gastrointestinal disorders:pain abdominal pain refl upper, acid reflux,disorder, deglutition dry mouth,dysphagia, dysgeusia,eructation, dysphagia,fleructation, Gastrointestinal disorders: abdominal upper, acid ux, deglutition drydisorder, mouth, dysgeusia, atulence, flatulence, Tolbutamide: Tolbutamide: EMEND, when asDay 1251mg Day 1 and on 80Days mg/day on 3, Days 2 and 3,the decreased the AUC of tolbutamide EMEND, when given as 125given mg on andon80 mg/day 2 and decreased AUC of tolbutamide (a CYP2C9 (a CYP2C9 salivation increased obstipation, obstipation, salivation increased by 23% on Day 4, 28% on15% Day 8, on Day 15, when single dose of tolbutamide mg was administered substrate) bysubstrate) 23% on Day 4, 28% on Day 8, and onand Day15% 15, when a single dosea of tolbutamide 500 mg was500 administered orally prior toorally the prior to the Skin and subcutaneous tissueacne, disorders: acne, diaphoresis, pruritus, rash administration the 3-day regimenand of EMEND Days Skin and subcutaneous tissue disorders: diaphoresis, pruritus, rash administration of the 3-dayofregimen of EMEND on Daysand 4, 8,onand 15.4, 8, and 15.

Musculoskeletal andtissue connective tissuearthralgia, disorders:back arthralgia, back pain, muscularmusculoskeletal weakness, musculoskeletal EMEND, when given as a 40-mg single on Day 1,the decreased the AUC of tolbutamide (a CYP2C9bysubstrate) by 2, 8%16% on Day Musculoskeletal and connective disorders: pain, muscular weakness, pain, myalgiapain, myalgia EMEND, when given as a 40-mg single oral dose onoral Daydose 1, decreased AUC of tolbutamide (a CYP2C9 substrate) 8% on Day on 2, 16% on 4, 15% on10% Day 8, on Day 15, when single dose of tolbutamide mg was administered prior to the administration of Renal disorders: and urinarydysuria, disorders: dysuria, renal insufficiency Day 4, 15% Day on Day 8, and onand Day10% 15, when a single dosea of tolbutamide 500 mg was500 administered orally prior toorally the administration of Renal and urinary renal insufficiency EMEND 40Days mg and 8, and 15.was Thisnot effect was not clinically considered clinically important.

EMEND 40 mg and on 2, 4,on8,Days and 2, 15.4,This effect considered important. systemdisorders: and breastpelvic disorders: ReproductiveReproductive system and breast pain pelvic pain Oral contraceptives: Aprepitant, whendaily givenforonce daily as fora14100-mg days ascapsule a 100-mg an oral contraceptive containing Oral contraceptives: Aprepitant, when given once 14 days withcapsule an oral with contraceptive containing 35 mcg of 35 mcg of General and administrative siteedema, conditions: edema, malaise, General disorders anddisorders administrative site conditions: malaise, pain, rigors pain, rigors ethinyl 1 mg of norethindrone, decreased the AUC of ethinyl 43%, andthe decreased the AUC of norethindrone by 8%. ethinyl estradiol andestradiol 1 mg ofand norethindrone, decreased the AUC of ethinyl estradiol by estradiol 43%, andbydecreased AUC of norethindrone by 8%.

Investigations: weight loss Investigations: weight loss In another dose of an oral contraceptive containing ethinyl and norethindrone was administered on Days21, 1 through 21, and In another study, a dailystudy, dose aofdaily an oral contraceptive containing ethinyl estradiol andestradiol norethindrone was administered on Days 1 through and Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another Stevens-Johnson syndrome was reported as a serious adverse experience in a patient receiving aprepitant with cancer chemotherapy in another givenregimen as a 3-day regimen 1258mg Day 8 and on 80Days mg/day on 10 Days 9 and 10 with ondansetron IV onoral Day 8 and oral EMEND wasEMEND given aswas a 3-day of 125 mg onofDay andon80 mg/day 9 and with ondansetron 32 mg IV on32 Daymg8 and CINV study. CINV study. given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11.

In the study, the AUC of ethinyl estradiol decreased by 19% dexamethasone dexamethasone given as 12 mg on Day 8 and 8 mg/day on Days 9, 10, and 11. In the study, the AUC of ethinyl estradiol decreased by 19% Laboratory Adverse Experiences: are the of percentage of patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory Laboratory Adverse Experiences: Following areFollowing the percentage patients receiving highly emetogenic chemotherapy in Cycle 1 with laboratory on there Day 10was andasthere muchdecrease as a 64% in ethinyl estradiol trough concentrations Days21.

9 through 21. was Whilenothere was no on Day 10 and muchwas as as a 64% in decrease ethinyl estradiol trough concentrations during Days during 9 through While there adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: adverse experiences reported at an incidence of ≥3% for the aprepitant regimen (n=544) and standard therapy (n=550), respectively: effectonofthe EMEND onnorethindrone the AUC of norethindrone on Day 10,asthere muchdecrease as a 60% in norethindrone trough concentrations during effect of EMEND AUC of on Day 10, there was muchwas as as a 60% in decrease norethindrone trough concentrations during Days21.

9 through 21.

Proteinuria: Proteinuria: 6.8, 5.3 6.8, 5.3 Days 9 through ALT6.0, increased: In another dose of an oral contraceptive containing ethinyl and norgestimate (which istoconverted to norelgestromin) was ALT increased: 4.3 6.0, 4.3 In another study, a dailystudy, dose aofdaily an oral contraceptive containing ethinyl estradiol andestradiol norgestimate (which is converted norelgestromin) was on Days21, 1 through 21, and EMEND 40 mgonwas 8. Inthe theAUC study, the AUC of ethinyl estradiolbydecreased Blood urea nitrogen4.7, increased: 4.7, 3.5 administeredadministered on Days 1 through and EMEND 40 mg was given Daygiven 8. Inon theDay study, of ethinyl estradiol decreased 4% and by 4% and Blood urea nitrogen increased: 3.5 Day12, 8 and Day 12, respectively, while the AUC of norelgestromin by 18% Day 8 andbydecreased by 10% 29% on Day29% 8 andonDay respectively, while the AUC of norelgestromin increased byincreased 18% on Day 8 andondecreased 10% on Day 12. Inon Day 12. In Serumincreased: creatinine3.7, increased: 3.7, 4.3 Serum creatinine 4.3 ®

EMEND® (aprepitant) EMEND® (aprepitant) capsules capsules the trough concentrations of ethinyl and norelgestromin on Days218 were through 21 were generally lower following coadministration addition, theaddition, trough concentrations of ethinyl estradiol andestradiol norelgestromin on Days 8 through generally lower following coadministration of the oral contraceptive EMEND 408mg on Day 8tocompared the trough levels following administration of the oral contraceptive alone. of the oral contraceptive with EMENDwith 40 mg on Day compared the troughtolevels following administration of the oral contraceptive alone.

The coadministration of EMEND reduce efficacy ofcontraceptives hormonal contraceptives (these can pills, skin patches, The coadministration of EMEND may reduce may the effi cacy the of hormonal (these can include birthinclude controlbirth pills,control skin patches, implants, and certain during and after for 28administration days after administration of the dose Alternative of EMEND.orAlternative or backup implants, and certain IUDs) duringIUDs) and for 28 days of the last dose of last EMEND. backup methods of methods of contraception should be used duringwith treatment and for 1 month dose of EMEND. contraception should be used during treatment EMENDwith andEMEND for 1 month following thefollowing last dosethe of last EMEND. EMENDthe increased the AUC of midazolam, a sensitive CYP3A4bysubstrate,

by Day 2.3-fold Day 1 and 3.3-fold on Day 5, when a single Midazolam:Midazolam: EMEND increased AUC of midazolam, a sensitive CYP3A4 substrate, 2.3-fold on 1 andon3.3-fold on Day 5, when a single oral dose of2midazolam 2 mg was coadministered Day5 1ofand Day 5 ofofaEMEND regimen125 of EMEND 1251mg Day 1 and on 80Days mg/day on Days 2 through oral dose of midazolam mg was coadministered on Day 1 andonDay a regimen mg on Day andon80 mg/day 2 through 5. The potential effects ofplasma increased plasma concentrations midazolam or other benzodiazepines CYP3A4 (alprazolam, 5. The potential effects of increased concentrations of midazolamofor other benzodiazepines metabolizedmetabolized via CYP3A4via (alprazolam, triazolam) should be when considered when coadministering single dose(40 of EMEND (40 mg) increased triazolam) should be considered coadministering these agentsthese with agents EMENDwith (125EMEND mg/80(125 mg).mg/80 A singlemg). doseA of EMEND mg) increased the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND the AUC of midazolam by 1.2-fold on Day 1, when a single oral dose of midazolam 2 mg was coadministered on Day 1 with EMEND 40 mg; this 40 mg; this effect was not clinically considered clinically important. effect was not considered important.

In another study with intravenous administration of midazolam, asDay 1251mg Day 1 and on 80Days mg/day on 3, Days In another study with intravenous administration of midazolam, EMEND wasEMEND given aswas 125given mg on andon80 mg/day 2 and and2 and 3, and mg IVprior wastogiven prior to the administration the 3-day regimenand of EMEND onand Days 8, and 15.

EMENDthe increased midazolam 2midazolam mg IV was2given the administration of the 3-dayofregimen of EMEND on Daysand 4, 8, 15.4,EMEND increased AUC the AUC of by midazolam by 25% ondecreased Day 4 andthe decreased the AUC of by midazolam by 19% on Dayto8the relative dosingon of Days EMEND on Days 1 through of midazolam 25% on Day 4 and AUC of midazolam 19% on Day 8 relative dosingtooftheEMEND 1 through 3. These were not clinically considered clinicallyThe important.

AUC of on midazolam on Day 15 was similar to thatatobserved 3. These effects wereeffects not considered important.

AUC of The midazolam Day 15 was similar to that observed baseline. at baseline. additional study waswith completed with intravenous administration midazolam EMEND. Intravenous 2 mg1 was An additionalAnstudy was completed intravenous administration of midazolamofand EMEND.and Intravenous midazolam 2midazolam mg was given hourgiven 1 hour after oral administration of a of single dose125 of EMEND mg. The AUC ofwas midazolam wasbyincreased 1.5-fold.on Depending after oral administration of a single dose EMEND mg. The125 plasma AUCplasma of midazolam increased 1.5-fold. by Depending clinical on clinical situations (eg, elderly andmonitoring degree ofavailable, monitoring available, dosage for adjustment for intravenous midazolam may bewhen necessary situations (eg, elderly patients) andpatients) degree of dosage adjustment intravenous midazolam may be necessary it is co-when it is coEMEND for the chemotherapy-induced vomiting(125 indication on Dayby1 80 followed 80 mg on 3).

Days 2 and 3). administeredadministered with EMENDwith for the chemotherapy-induced nausea and nausea vomitingand indication mg on (125 Day 1mg followed mg onbyDays 2 and Effect of Other Agents on the Pharmacokinetics of Aprepitant: a substrate CYP3A4;coadministration therefore, coadministration of Effect of Other Agents on the Pharmacokinetics of Aprepitant: Aprepitant isAprepitant a substrateis for CYP3A4;for therefore, of withinhibit drugsCYP3A4 that inhibit CYP3A4 result inplasma increased plasma concentrations aprepitant. Consequently, EMEND withEMEND drugs that activity may activity result inmay increased concentrations of aprepitant.of Consequently, concomitantconcomitant administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, troleandomycin, clarithromycin, administration of EMEND with strong CYP3A4 inhibitors (eg, ketoconazole, itraconazole,itraconazole, nefazodone,nefazodone, troleandomycin, clarithromycin, ritonavir, ritonavir, nelfinavir) should be approached caution.

BecauseCYP3A4 moderate CYP3A4 inhibitors (eg,result diltiazem) resultincrease in a 2-fold increase in plasma nelfinavir) should be approached with caution.with Because moderate inhibitors (eg, diltiazem) in a 2-fold in plasma concentrations aprepitant, concomitant administration should also be approached concentrations of aprepitant,of concomitant administration should also be approached with caution.with caution. a substrate CYP3A4;coadministration therefore, coadministration of EMEND withstrongly drugs that strongly induce CYP3A4 Aprepitant isAprepitant a substrateis for CYP3A4;for therefore, of EMEND with drugs that induce CYP3A4 activity (eg, activity rifampin,(eg, rifampin, carbamazepine, phenytoin) resultplasma in reduced plasma concentrations aprepitant thatinmay result ineffi decreased efficacy of EMEND. carbamazepine, phenytoin) may result inmay reduced concentrations of aprepitantofthat may result decreased cacy of EMEND. Ketoconazole: When a single 125-mg dosewas of EMEND was administered Day 5 of a 10-day regimen of 400 mg/day of ketoconazole, a Ketoconazole: When a single 125-mg dose of EMEND administered on Day 5 of aon10-day regimen of 400 mg/day of ketoconazole, a strong CYP3A4 the AUC ofincreased aprepitantapproximately increased approximately 5-fold andterminal the mean terminal half-life ofincreased aprepitant increased strong CYP3A4 inhibitor, theinhibitor, AUC of aprepitant 5-fold and the mean half-life of aprepitant approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached approximately 3-fold. Concomitant administration of EMEND with strong CYP3A4 inhibitors should be approached cautiously. cautiously.

Rifampin: When a single 375-mg dosewas of EMEND was administered Day 9 of a 14-day regimen of 600 mg/day aofstrong rifampin, a strong Rifampin: When a single 375-mg dose of EMEND administered on Day 9 of aon14-day regimen of 600 mg/day of rifampin, CYP3A4 the AUC ofdecreased aprepitantapproximately decreased approximately 11-fold andterminal the mean terminal half-lifeapproximately decreased approximately 3-fold.

CYP3A4 inducer, the inducer, AUC of aprepitant 11-fold and the mean half-life decreased 3-fold.

Coadministration of EMEND withinduce drugs CYP3A4 that induce CYP3A4 resultplasma in reduced plasma concentrations andeffi decreased Coadministration of EMEND with drugs that activity may activity result inmay reduced concentrations and decreased cacy of efficacy of EMEND. EMEND. Additional Interactions: EMENDtoisinteract unlikelywith to interact withare drugs that arefor substrates for the P-glycoprotein as demonstrated by the Additional Interactions: EMEND is unlikely drugs that substrates the P-glycoprotein transporter, transporter, as demonstrated by the lack ofofinteraction of EMEND digoxin drug in a clinical drugstudy. interaction study. lack of interaction EMEND with digoxin with in a clinical interaction Diltiazem: In patients mild tohypertension, moderate hypertension, administration aprepitant once daily,formulation as a tablet formulation to Diltiazem: In patients with mild to with moderate administration of aprepitantofonce daily, as a tablet comparablecomparable to 230capsule mg of the capsule formulation, with diltiazem 120 mg times daily resulted for 5 days, in a 2-fold increase ofAUC aprepitant 230 mg of the formulation, with diltiazem 120 mg 3 times daily3 for 5 days, in aresulted 2-fold increase of aprepitant and a AUC and a simultaneous 1.7-fold increase of diltiazem These pharmacokinetic effects result meaningful in clinically meaningful changes in ECG, heart simultaneous 1.7-fold increase of diltiazem AUC. TheseAUC. pharmacokinetic effects did not resultdidinnot clinically changes in ECG, heart rate, or blood pressure beyond those changes induced by diltiazem alone. rate, or blood pressure beyond those changes induced by diltiazem alone.

Coadministration once-daily doses of as aprepitant, as a tablet comparable formulation comparable 85mg mgoforthe 170capsule mg of the capsule Paroxetine:Paroxetine: Coadministration of once-dailyofdoses of aprepitant, a tablet formulation to 85 mg or to 170 with20 paroxetine mgresulted once daily, in AUC by approximately 25% and C max by approximately by approximately 20% of both20% of both formulation, formulation, with paroxetine mg once 20 daily, in aresulted decreaseinina decrease AUC by approximately 25% and C max aprepitant and paroxetine. aprepitant and paroxetine.

USE INPOPULATIONS SPECIFIC POPULATIONS USE IN SPECIFIC effects:Category Pregnancy B: Reproduction have beeninperformed rats atup oral up to 1000 mg/kg Pregnancy:Pregnancy: Teratogenic Teratogenic effects: Pregnancy B: Category Reproduction studies havestudies been performed rats at oralindoses to doses 1000 mg/kg of 31.3 mcg•hr/mL, about timesexposure the human at the recommended and rabbits twice daily AUC 0–24hr mcg•hr/mL, about 1.6 times the1.6 human at exposure the recommended dose) and indose) rabbits at inoral dosesat oral doses twice daily (plasma AUC(plasma 0–24hr of 31.3 of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed up to 25 mg/kg/day (plasma AUC 0–24hr up to 25 mg/kg/day (plasma AUC 0–24hr of 26.9 mcg•hr/mL, about 1.4 times the human exposure at the recommended dose) and have revealed of impaired fertility or harm to the due to There aprepitant.

There are, adequate and well-controlled studies in pregnant no evidenceno of evidence impaired fertility or harm to the fetus due to fetus aprepitant. are, however, nohowever, adequateno and well-controlled studies in pregnant women.

Because animal reproduction studies arepredictive not alwaysofpredictive of humanthis response, this drug should be used duringonly pregnancy only if women. Because animal reproduction studies are not always human response, drug should be used during pregnancy if clearly needed. clearly needed.

NursingAprepitant Mothers:isAprepitant excreted the milk of rats.

It iswhether not known this druginis human excreted in human milk.

Because Nursing Mothers: excreted inis the milk ofinrats.

It is not known thiswhether drug is excreted milk.

Because many drugs many drugs excreted in human milk and because of the possible serious adverse in nursing fromand aprepitant are excretedare in human milk and because of the potential for potential possible for serious adverse reactions in reactions nursing infants frominfants aprepitant becauseand of because of for tumorigenicity shown forinaprepitant in rodent carcinogenicity studies,should a decision should be made whether to discontinue nursing the potentialthe for potential tumorigenicity shown for aprepitant rodent carcinogenicity studies, a decision be made whether to discontinue nursing or to discontinue the drug, taking into the importance the mother. drug to the mother. or to discontinue the drug, taking into account the account importance of the drug toof the Pediatric Safety and effectiveness EMEND patients in pediatric have not been established.

Pediatric Use: Safety Use: and effectiveness of EMEND inofpediatric havepatients not been established.

Geriatric Use: In 2 well-controlled chemotherapy-induced vomiting clinical studies, of the total number(N=544) of patientstreated (N=544) treated Geriatric Use: In 2 well-controlled chemotherapy-induced nausea and nausea vomitingand clinical studies, of the total number of patients EMEND, 31% and5% over, while over. In well-controlled postoperative vomiting clinical studies, of the with EMEND,with 31% were 65 andwere over,65 while were 755% andwere over.75 In and well-controlled postoperative nausea and nausea vomitingand clinical studies, of the number(N=1120) of patientstreated (N=1120) and2% over, while over.differences No overall in differences total numbertotal of patients with treated EMEND,with 7%EMEND, were 657% andwere over,65 while were 752% andwere over.75 Noand overall safety or in safety or were observed between these younger subjects.

Greaterofsensitivity of individuals some oldercannot individuals cannot effectivenesseffectiveness were observed between these subjects andsubjects youngerand subjects.

Greater sensitivity some older be ruled out.be ruled out.

Dosage in adjustment is not necessary.

Dosage adjustment the elderlyinisthe notelderly necessary.

NONCLINICAL TOXICOLOGY NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Fertility: Carcinogenicity wereinconducted in Sprague-Dawley rats and Carcinogenesis, Mutagenesis, ImpairmentImpairment of Fertility:of Carcinogenicity studies werestudies conducted Sprague-Dawley rats and in CD-1 micein CD-1 mice forthe 2 years.

In the rat carcinogenicity studies, withranging oral doses to 1000 twicehighest daily. The highest for 2 years. In rat carcinogenicity studies, animals wereanimals treatedwere with treated oral doses fromranging 0.05 tofrom 10000.05 mg/kg twicemg/kg daily. The ) oftimes 0.7 to timesexposure the human exposure (AUCmcg•hr/mL) at dosea systemic producedexposure a systemic aprepitant 0–24hr =19.6 mcg•hr/mL) 0.7 0–24hr to 1.6 the1.6 human (AUC at dose produced to exposure aprepitantto(plasma AUC(plasma 0–24hr ) ofAUC 0–24hr =19.6 the recommended of 125 mg/day.with Treatment withataprepitant 5 to 1000 twice daily caused an increase in the incidences the recommended dose of 125 dose mg/day.

Treatment aprepitant doses of 5attodoses 1000ofmg/kg twicemg/kg daily caused an increase in the incidences of thyroid celland adenomas and carcinomas rats.

In female rats, hepatocellular it produced hepatocellular 5 to 1000 of thyroid follicular cellfollicular adenomas carcinomas in male rats.inInmale female rats, it produced adenomas atadenomas 5 to 1000atmg/kg twicemg/kg twice daily and hepatocellular and thyroid cellatadenomas at 125 to 1000 twice daily. Incarcinogenicity the mouse carcinogenicity daily and hepatocellular carcinomas carcinomas and thyroid follicular cellfollicular adenomas 125 to 1000 mg/kg twicemg/kg daily. In the mouse studies, studies, withranging oral doses from 2.5 to 2000 mg/kg/day. dosea systemic producedexposure a systemic the animals the wereanimals treatedwere with treated oral doses fromranging 2.5 to 2000 mg/kg/day.

The highest The dosehighest produced of exposure about 2.8oftoabout 2.8 to timesexposure the human at the recommended dose.with Treatment withproduced aprepitantskin produced skin fibrosarcomas at 125 and 500 mg/kg/day 3.6 times the3.6 human at exposure the recommended dose. Treatment aprepitant fibrosarcomas at 125 and 500 mg/kg/day doses in male mice. doses in male mice.

Aprepitant was notingenotoxic thethe Ames test,lymphoblastoid the human lymphoblastoid cell (TK6) mutagenesis the rat DNA hepatocyte Aprepitant was not genotoxic the Ames intest, human cell (TK6) mutagenesis test, the rat test, hepatocyte strand DNA breakstrand break test, the Chinese hamster (CHO) cell chromosome aberration andmicronucleus the mouse micronucleus test. test, the Chinese hamster ovary (CHO)ovary cell chromosome aberration test, and thetest, mouse test.

Aprepitant affectorthegeneral fertilityreproductive or general reproductive of malerats or at female up to thefeasible maximum dose of Aprepitant did not affectdidthenotfertility performanceperformance of male or female dosesrats up at to doses the maximum dosefeasible of twice dailyexposure (providing malethan ratsthe lower than the at the recommended dose and in female rats 1000 mg/kg1000 twicemg/kg daily (providing in exposure male rats in lower exposure at exposure the recommended human dosehuman and exposure in exposure female rats at about 1.6 times the human exposure). at about 1.6 times the human exposure).

PATIENT COUNSELING INFORMATION PATIENT COUNSELING INFORMATION [See FDA-Approved PatientInstructions: Labeling.] Instructions: Physicians should patients to readpackage the patient package before starting [See FDA-Approved Patient Labeling.]

Physicians should instruct theirinstruct patientstheir to read the patient insert beforeinsert starting to reread each time the prescription therapy withtherapy EMENDwith andEMEND to rereadand it each time itthe prescription is renewed. is renewed.

Patients should betoinstructed to take only as For prescribed.

Forofprevention of chemotherapy-induced vomiting (CINV), patients Patients should be instructed take EMEND onlyEMEND as prescribed. prevention chemotherapy-induced nausea and nausea vomitingand (CINV), patients shouldtobetake advised take their firstmg) dose mg)1ofhour EMEND prior to chemotherapy treatment.

Forofprevention of postoperative nausea should be advised their tofirst dose (125 of (125 EMEND prior 1tohour chemotherapy treatment. For prevention postoperative nausea vomiting (PONV), patients should their (40-mg medication (40-mg capsule within of EMEND) within prior to of anesthesia. and vomitingand (PONV), patients should receive theirreceive medication capsule of EMEND) 3 hours prior3 tohours induction of induction anesthesia.

Allergicwhich reactions, which may and be serious, and may include rash, and andculty cause difficulty inorbreathing or swallowing, Allergic reactions, may be serious, may include hives, rash, hives, and itching, and itching, cause diffi in breathing swallowing, have been have been reporteduse in general use with EMEND.should Physicians should patients to EMEND stop taking call their reported in general with EMEND. Physicians instruct theirinstruct patientstheir to stop taking andEMEND call theirand doctor right doctor away ifright they away if they experience an allergic reaction. experience an allergic reaction. with some drugs including chemotherapy; therefore, patients shouldtobereport advised to report to their doctor the use of any EMEND mayEMEND interactmay withinteract some drugs including chemotherapy; therefore, patients should be advised to their doctor the use of any other prescription or nonprescription medication or herbal products. other prescription or nonprescription medication or herbal products.

Patientswarfarin on chronic warfarin therapy should betoinstructed have their clotting status closelyinmonitored in period, the 2-week period, at particularly at 7 Patients on chronic therapy should be instructed have theirtoclotting status closely monitored the 2-week particularly 7 to 10 days, following initiation the 3-day regimen125 of EMEND mg/80 mgchemotherapy with each chemotherapy cycle, or following administration of a to 10 days, following initiation of the 3-dayofregimen of EMEND mg/80 125 mg with each cycle, or following administration of a single dosefor of prevention EMEND forofprevention of postoperative and vomiting. single 40-mg dose40-mg of EMEND postoperative nausea and nausea vomiting.

Administration of EMEND reduce efficacy ofcontraceptives. hormonal contraceptives.

Patients shouldtobeuse advised to useoralternative or backup methods Administration of EMEND may reduce may the effi cacy the of hormonal Patients should be advised alternative backup methods of contraception duringwith treatment and for 1 month dose of EMEND. of contraception during treatment EMENDwith andEMEND for 1 month following thefollowing last dosethe of last EMEND. detailed information, read the Information.

Prescribing Information.

For detailed For information, please read please the Prescribing Rx only Rx only

© 2011 Sharp & Dohme Corp., aofsubsidiary Merck Copyright ©Copyright 2011 Merck SharpMerck & Dohme Corp., a subsidiary Merck &ofCo., Inc. & Co., Inc. All rightsONCO-1001721-0004 reserved. ONCO-1001721-0004 All rights reserved.

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 11

News Genitourinary Cancer

Adjuvant Immunotherapy Provides No Clinical Benefit in Patients with High‑risk Renal Cell Carcinoma

By Larry J. Rosenberg, PhD

F

or renal cell carcinoma patients at high risk of relapse following nephrectomy, adjuvant therapy with the combination of interleukin-2 (Proleukin), interferon alfa, and fluorouracil (5-FU) provides no survival benefit over observation alone, according to a phase III trial conducted by the European Organisation for Research and Treatment of Cancer (EORTC).

Michael Aitchison, MD, of the Beatson Oncology Centre in Glasgow, presented the final results of the trial at the 2011 ASCO Annual Meeting.1

Michael Aitchison, MD

Atzpodien Regimen Previous studies demonstrated high response rates with the combination of interleukin-2, interferon alfa, and 5-FU as first-line therapy in patients with metastatic renal cell carcinoma. Known as the Atzpodien regimen (after Dr. Jens

Atzpodien, who developed it), the combination was considered the optimal adjuvant therapy in 1995, when the present trial was initiated. This EORTC/ NCRI study funded by CR-UK was designed to determine if adjuvant therapy with the Atzpodien regimen improves survival compared with observation alone in patients who are at high risk of relapse following nephrectomy.

Patients were eligible for this randomized phase III trial if they were 8 weeks postnephrectomy with no macroscopic residual disease, had stage T3b-c, T4, or any pT and pN1 or pN2 or positive microscopic margins or microscopic vascular invasion, and had no metastases. The trial SEE PAGE 39 was designed to detect an increase in 3-year disease-free survival from 50% in the control arm to 65% with treatment (HR = 0.63), with 90% power and 2-sided alpha of 0.05. Quality of life was assessed using the EORTC QLQ C-30 instrument.

No Significant Differences A total of 309 patients were enrolled in the trial (68% male), including 155 on the control arm (median age, 55 years) continued on page 12

Expert Point of View

C

ommenting on the renal cell carcinoma study presented in abstract 4505 at the 2011 ASCO Annual Meeting, Walter M. Stadler, MD, of The University of Chicago, said, “The EORTC and investigators should be congratulated for conducting and completing this extremely difficult trial.”

Unfortunately, he noted, no long-term benefit was observed, which parallels the observations of a Medical Research Council (MRC) trial in the metWalter M. Stadler, MD astatic renal cell carcinoma setting of interferon vs the same combination.1 Thus, the current standard of care for locally advanced, high-risk but completely resected renal cancer remains observation.

■

Disclosure: Dr. Stadler has served as a consultant for Genentech and has received research funding from Genentech and Eli Lilly.

Reference 1. Gore ME, Griffin CL, Hancock B, et al: Interferon alfa-2a versus combination therapy with interferon alfa-2a, interleukin-2, and fluorouracil in patients with untreated metastatic renal cell carcinoma (MRC RE04/EORTC GU 30012): An openlabel randomised trial. Lancet 375:641-648, 2010.

The ASCO Post | SEPTEMBER 1, 2011

PAGE 12

News Gynecologic Oncology

Screening for Ovarian Cancer Does Not Reduce Mortality and Leads to Unnecessary Tests for False-Positives

By Alice Goodman

U

sing a CA-125 blood test combined with transvaginal ultrasound for early detection of ovarian cancer failed to reduce the risk of mortality associated with the disease and led to a large number of false-positive tests with unnecessary related biopsies and other follow-up procedures in the large, long-term Prostate, Lung, Colorectal, and Ovarian (PLCO) Screening Trial sponsored by the NCI. The authors said that although CA-125 and transvaginal ultrasound are appropriate for widespread use

to evaluate symptoms, assess disease status, and determine the effectiveness of treatments in women already diagnosed with the disease, this study shows that the tests are not useful for general screening in women without the disease. They presented their findings at the ASCO Annual Meeting.1

Screening for Ovarian Cancer ■■ Screening for ovarian cancer with CA-125 plus transvaginal ultrasound did not reduce the risk of mortality compared with usual care.

■■ Screening was associated with increased risks of false-positive test results leading to unnecessary invasive procedures.

■■ More sensitive and specific screening measures are needed for ovarian cancer detection.

Precise Screening Tools Needed “In the absence of a good method for diagnosing ovarian cancer, we hypothesized that these two tests—which

Expert Point of View

are useful to measure disease—would identify ovarian cancer at an early stage when it is more likely to be cured,” stated lead author Saundra S. Buys, MD, Professor of Medicine at the University of Utah and Huntsman Cancer Institute

F

ormal discussant of this trial, Usha Menon, MD, Professor of Gynecological Oncology at the Institute for Women’s Health, University College, London, raised several important issues about the design of the PLCO trial particularly related to the dilution of the screening effect due to prolonged follow-up of women after the end of screening and the lack of a well-defined screening strategy with both first- and second-line tests, fixed timelines, and protocol-driven management, which has been repeatedly shown to play a crucial role in attaining a mortality impact in cervical cancer. Most of the deaths occur in women with type II ovarian cancer (high-grade serous, high-grade endometrioid, and undifferentiated cancers). She said that it is questionable whether screening can have an impact on mortality in ovarian cancer unless effective treatment strategies are found for the 80% that recur in this group. A better understanding of the natural history of the disease is therefore crucial.

Based on current evidence, ovarian screening cannot be recommended in the general population, and “opportunistic” screening of asymptomatic lowrisk women with CA-125 is not advisable, Prof. Menon stated.

“This does not mean that screening for ovarian cancer will not work. We just have not yet found a screening strategy that can impact mortality,” she told the audience.

She said that future screening trials should incorporate serial changes when measuring markers as well as quality assessment. “The search for better biomarkers should continue. Also, we need a better understanding of the natural history of the disease, because it is unclear if ovarian cancer is amenable to screening,” she stated.

■

Disclosure: Prof. Menon is joint principal investigator on the UK Ovarian Cancer Screening Trial. Her group has a research collaboration with Becton Dickinson, which has an interest in tumor markers and ovarian cancer. She has a financial interest through UCL Business and Abcodia Ltd in the third-party exploitation of clinical trials biobanks, which have been developed through the research at UCL.

Adjuvant Immunotherapy continued from page 11

and 154 on the treatment arm (median age, 57 years). However, 35% of patients who received the combination regimen were unable to complete therapy, largely due to treatment-related toxicity (at least grade 2 in 92% of patients, and at least grade 3 in 41%). At 6 months, no statistically significant differences were observed in any quality-of-life param-

eters between the two treatment arms.

With a median follow-up of 5.9 years (maximum 12.1 years), the investigators found no statistically significant survival benefit for the treatment regimen arm compared with the control arm. The 3-year disease-free survival was 61% on the treatment arm and 50% on the control arm (overall HR = 0.84; 95% CI = 0.63–1.12).

Overall survival at 5 years was also

Saundra S. Buys, MD

in Salt Lake City. She said the results were disappointing, “but not necessarily surprising.” Also, Dr. Buys continued, “they show that the tests can actually cause harm, due to the high number of false-positives necessitating surgical biopsies and other related procedures.

These results underscore the need for a continuing search to find precise screening tools for the early identification of ovarian cancer.”

Study Design and Results The randomized multicenter study included 78,216 women aged 55 to 74 years screened at 10 screening centers across the United States. They were randomly assigned in a 1:1 ratio to annual screening similar (70% vs 63%; HR = 0.86; 95% CI = 0.60–1.22). Post hoc exploratory analysis suggested a possible difference in survival between pT1 and pT2 patients, which needs to be confirmed in additional trials.

■

Disclosure: Dr. Aitchison is a consultant for and has received honoraria from Novartis and Pfizer.

Dr. Rosenberg is an employee of UBC Scientific Solutions and has previously provided medical writing support, which was funded by Pfizer.

(CA-125 testing for 6 years, transvaginal ultrasound for 4 years, and follow-up for 13 years) or usual care (no annual screening tests) between 1993 and 2001.

No statistically significant difference was found between the two arms for ovarian cancer cases or related mortality. Ovarian cancer was diagnosed in 212 women in the screening arm compared with 176 in the usual care arm.

118 deaths were reported in the screenSEE PAGE 39 ing arm and 100 in the usual care arm. A total of 2,924 and 2,914 deaths from causes other than ovarian, colorectal, and lung cancer occurred in the two arms, respectively.

In the screening arm, there were 3,285 false-positive tests compared with 212 true-positives. About onethird of the women with false-positive tests (n = 1,080) had surgical biopsy; serious complications were reported in 163 of these women.

■

Disclosure: Dr Buys reported no potential conflicts of interest.

Reference 1. Buys SS, Partridge E, Black A, et al: Effect of screening on ovarian cancer mortality in the prostate, lung, colorectal, and ovarian (PLCO) cancer randomized screening trial. 2011 ASCO Annual Meeting. Abstract 5001. Presented June 4, 2011.

Reference 1. Aitchison M, Bray CA, Van Poppel H, et al: Final results from an EORTC (GU Group)/NCRI randomized phase III trial of adjuvant interleukin-2, interferon alpha, and 5-fluorouracil in patients with a high risk of relapse after nephrectomy for renal cell carcinoma (RCC). 2011 ASCO Annual Meeting. Abstract 4505. Presented June 6, 2011.

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 13

News Issues in Oncology

Congressional Hearing Highlights Oncology Drug Shortages

By Margot Fromer

S

ome oncology drugs are in such short supply that the situation is now critical, with almost 200 drugs affected—triple that of 2003. This was the background described by speakers at a July 2011 congressional briefing sponsored by the Association of Community Cancer Centers (ACCC), ASCO, and other cancer organizations.

use, and when one [company] decides to discontinue a drug, there is no one to take up the slack,” said Dr. Link.

Consequences for Patients Drug shortages pose devastating problems for patients and providers. “There are treatment delays, which are never a good idea. Often we have to substitute a less effective drug, and sometimes there is no substitute,” said Dr. Link.

includes drugs that are in short supply.

As Dr. Link noted, we treat some cancers with an expectation of cure: leukemia, lymphoma, testis cancer, and sarcoma of bone and soft tissue. “If we can’t get the drugs, a disease we’ve treated successfully for many years is now rendered incurable, or significantly more difficult to treat. It is terribly discouraging and dispiriting.”

This is particularly evident in child-

Would a New Law Help?

T

wo bills introduced in Congress this year address the drug shortage problem. They are S296, introduced by Sen. Amy Klobuchar (D-MN) and Sen. Robert Casey (D-PA), and HR2245, introduced by Rep. Diana DeGette (D-CO) and Rep. Thomas Rooney (R-FL). In brief, they:

Matthew Farber, MA

In the past 2 years, according to a survey conducted by ACCC, Community Oncology Alliance, and Association of Oncology Social Work, almost every facility (94.4%) that provides cancer care experienced a drug shortage, said Matthew Farber, MA, ACCC Director of Provider Economics and Public Policy. Further, 84% of institutions said they had to temporarily suspend or modify a treatment regimen as a result of the shortage, and 63% spent more time and effort procuring drugs in 2010 than during the previous year.

All providers have been affected, said Ali McBride, PharmD, Barnes Jewish Hospital, St. Louis, although it isn’t as bad in large cancer centers as in smaller community ones. Moreover, every type of cancer has been affected, and many of the difficult-to-obtain drugs are the standard of care.

Problem Is Increasing ASCO President Michael P. Link, MD, Lydia J. Lee Professor of Pediatrics, Stanford University School of Medicine, said that the shortage is not improving and noted that in addition to antineoplastic agents, some anesthetic and antibiotic drugs are in short supply. Dr. Link added that “70% of the 2010 shortages were sterile injectable agents, for which there is usually no alternative.” These drugs, especially older generics, are made by only a few companies. The manufacturing process is complex and costly— therefore not an economically attractive endeavor—and when a problem occurs, it is expensive to fix. “Companies want to put their resources to more profitable

■■ Require a manufacturer to notify FDA 6 months before discontinuing or interrupting distribution of a drug such that a shortage will ensue.

■■ Set forth the conditions under which a manufacturer must submit such notice.

■■ Define “drug shortage” by a period of time during which the supply will not meet the demand.

■■ Require that FDA inform providers about drug shortages and publish them on its website.

■■ Require the Government Accountability Office to study the causes of drug shortages.

■

At the briefing was Tom Kornberg, PhD, a research biologist at the University of California, San Francisco, who was diagnosed with Hodgkin lymphoma and scheduled to be treated with ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine). The vinblastine was unavailable, however. Dr. Kornberg said he called on some of his contacts in the science community and eventually he located the agent.

Dr. Kornberg is in remission now.

He is lucky to have the wherewithal and tenacity that enabled him to obtain the drug himself. The vast majority of patients with cancer, however, may not be so fortunate.

Dr. McBride added that in addition to treatment delays (affecting 80% of patients, according to a University of Utah survey), doses have been reduced, and medication errors are common. For example, when busulfan is unavailable, stem cell transplant cannot proceed, and when an oral drug is substituted for a parenteral one, errors are more likely.

In addition, the effect on clinical trials can be significant if the standard of care cannot be administered to act as the control because the standard regimen

hood acute lymphoblastic leukemia, which is curable in almost 90% of cases. The same is true for osteosarcoma, which is 65% curable with surgery and chemotherapy. All the drugs used for these two common childhood cancers are in short supply.

Causes Are Many, Solutions Needed The causes of drug shortages are multiple and varied. Manufacturing difficulties, compliance problems, and obtaining raw materials can create significant delays. “For instance, if a company needs to change something in the production process, they can’t proceed until FDA approves,” Dr. Link said.

“But it takes a while for FDA inspectors to visit the factory, so everything stops until the agents get there. And patients wait—and wait.”

Corporate decisions to discontinue a drug, most likely because of insufficient profit, is a leading factor, as are changes in the industry itself, notably mergers. “Health care is a business, drug manufacturing is private enterprise, and there’s only so much that government and health-care providers can do to

influence them,” said Dr. Link. “What kinds of incentives would encourage the industry to make drugs that are not so profitable? Tax breaks? Changing patent laws or distribution methods? Additional market exclusivity? Any of these might be worth thinking about.”

Aside from being expensive to research and bring to market, oncology drugs are unprofitable because of poor reimbursement. “Perhaps if CMS rethought its reimbursement policies, things might improve,” said Dr. Link.

Would legislation help? “It might, but it could backfire. Six-month notification by FDA that a drug was to be discontinued temporarily or permanently would give providers warning of a shortage [see sidebar, “Would a New Law Help?”], but it also could lead to hoarding or stockpiling. And in the end, the agency has no real control over what the industry chooses to produce, or not.”

Financial Effect The financial impact of drug shortages is also an issue. Substituting other medications may be more costly (and produce unexpected side effects, which are expensive to treat), and locating drugs that are in short supply is timeconsuming and expensive. Stockpiling and hoarding by hospitals and distributors have become problems, both of which result in increased shortages elsewhere and “scalper” prices everywhere.

Further disturbing is the gray market that has emerged. Almost half (43%) of provider facilities said they have been contacted by gray market suppliers, although it is unknown how many hard-to-find drugs are “real” and how many are “gray.” If the latter, they may be counterfeit and possibly adulterated or weakened. Moreover, drugs on the gray market are always more expensive—often much more than the usual cost.

It’s impossible to be sure where gray market drugs come from, who manufactures them, how they are distributed, and how many hands they pass through before being administered to patients.

Pharmacists cannot assay each dose, and although FDA has jurisdiction over counterfeit drugs, the agency cannot control widespread illegal activity.

■

Disclosure: Drs. Farber, McBride, Kornberg, and Link reported no potential conflicts of interest.

Editor’s note: See page 1 of this issue of The ASCO Post for more on the drug shortage in oncology.

ns o i t a lic App Open Now

2012 Career Development Award (CDA) and Young Investigator Award (YIA) Career Development Award: Provides research funding to clinical investigators in the first to third year of faculty appointment to establish an independent clinical cancer research program.

Young Investigator Award: Provides research funding to promising young physicians during the final years of training to support the transition to a faculty appointment and to encourage quality research in clinical oncology.

Applications Close September 28, 2011 www.conquercancerfoundation.org

GRANTS AND AWARDS PROGRAM

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 15

Spotlight on Research

A Conversation with Constance M. Chen, MD, MPH

Autologous lymph node transfer for lymphedema: First U.S. clinical trial launched

By Jo Cavallo

Constance M. Chen, MD, MPH

A

lthough incidence data vary widely, breast cancer–related lymphedema may affect as many as 54% of the 2.3 million survivors of breast cancer in the United States. The condition is often disabling and can result in both long-term devastating physical consequences for survivors, including the loss of strength and functional limitation of the affected arm, as well psychosocial consequences, such as poor body image and loss of self-esteem.

While the current standard of care for breast cancer–related lymphedema is complete decongestive therapy— which only slows the progression of disease but does not reverse it—more effective treatments have been elusive.

Now, a surgical procedure pioneered

by French surgeon Corinne Becker, MD, called autologous lymph node transfer, is being studied in the United States as a potential long-term remedy—and possible cure—for lymphedema sufferers.

The procedure involves taking superficial lymph nodes from a patient’s groin and transplanting them to her axilla to replace the ones removed or damaged during breast cancer treatment. Although the operation has been used in France for 20 years as a treatment for lymphedema, the sur-

gery is rare in the United States, and few hospitals offer it.

To test the effectiveness and potential side effects of lymph node transfer in patients suffering from breast cancer–related lymphedema, Constance M. Chen, MD, MPH, a reconstructive plastic surgeon in New York who specializes in microsurgical breast reconstruction for patients with cancer, has just launched the first double-blind randomized controlled clinical trial of the procedure. Recruitment is taking place at the New York Center for Advancement of Breast Reconstruction, part of the New York Eye and Ear Infirmary.

The ASCO Post talked with Dr. Chen about the benefits and risks of the procedure and the launch of her clinical study.

microsurgery into the axilla of the affected arm.

The first step in this procedure is preparing the axillary recipient site.

The axilla in an arm affected by lymphedema is typically scarred and has an extremely hollow appearance because the axillary skin is stuck to the dome of the axilla. This axillary scar tissue needs to be dissected and released, because the scar tissue is blocking the lymphatic channels and preventing lymphatic flow.

After scar release, the second step is microsurgical transfer of healthy, vascularized tissue containing lymph nodes. Without transfer of healthy tissue into the freed-up axillary space, it is hypothesized that the skin would just scar back down to the

We are launching the clinical trial precisely because we need better data to determine the risks and benefits of autologous lymph node transfer.

How the Procedure Is Done Explain how the autologous lymph node transfer is performed.

Dr. Corinne Becker has done 4,000 lymph node transfers in the treatment of both upper- and lower-extremity lymphedema over the last 20 years in Paris. My clinical trial is for patients with breast cancer who have undergone mastectomy and are suffering from chronic recalcitrant upper-extremity lymphedema. Autologous lymph node transfer is performed by harvesting an average of three superficial inguinal lymph nodes from the groin region on a vascular pedicle, and then transferring the nodes using

base of the wound. Bringing in living tissue that comes with its own blood supply creates a healthy environment for the transferred lymph nodes to take up lymphatic flow.

Success Rate and Risks How successful is lymph node transfer?

According to Dr. Becker’s data, 40% of her patients had complete resolution to lymphedema, meaning their affected arm looked and felt normal without using compression garments.

About 28% of her patients had greater than a 50% reduction of arm volume, 28% had less than 50% of arm volume, and 2% had no resolution.

What are the risks?

The most worrisome risk is lowerextremity lymphedema. While Dr. Becker claims that this is not a significant risk in her patients, it seems reasonable that if a patient can develop upper-extremity lymphedema from a sentinel node biopsy then she could also develop lower-extremity lymphedema from the removal of even one lymph node from the groin.

The more common risk is a postoperative seroma from the groin donor site. Drains and a bolster dressing need to be used in the groin postoperatively to avoid this complication. Finally, there is always the risk that after lymph node transfer there will not be improvement in arm lymphedema. Indeed, we are launching the clinical trial precisely because we need better data to determine the risks and benefits of autologous lymph node transfer.

The procedure seems to show promise as a potential solution to reverse and even cure the long-term effects of chronic recalcitrant lymphedema. More data are needed, however, to make a definitive statement about outcomes. We are currently recruiting patients who suffer from chronic upper-extremity lymphedema following a mastectomy with either no breast reconstruction or implant-based breast reconstruction and who have failed a complete course of complex decongestive therapy. In order to test the hypothesis that autologous lymph node transfer improves upper-extremity lymphedema, we plan to enroll 88 women over a 5-year period. Potential candidates or physicians interested in learning more about this study can either contact me (212-792-6378) or my coinvestigator, Mei Fu, PhD, RN, at NYU Cancer Center (212-998-5314).

■

Disclosure: Dr. Chen reported no potential conflicts of interest.

Contact The ASCO Post EDITOR IAL CORR ESPONDENCE James O. Armitage, MD Editor-in-Chief

Cara H. Glynn Director of Editorial

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The ASCO Post | SEPTEMBER 1, 2011

PAGE 16

Direct from ASCO

ASCO Connection Adds New Columnists, Launches Group Creation Option

A

SCO’s professional networking site, ASCOconnection.org, continues to build depth in areas of interest to the oncology community, adding as its newest commentator ASCO President Michael P. Link, MD, the Lydia J. Lee Professor in Pediatric Oncology at Stanford University School of Medicine, as well as the Society’s first pediatric oncologist to hold the office. Dr. Link’s initial topics have included the application of lessons learned from successes in pediatric oncology to other areas of cancer care and research, a look at the growing force of ASCO’s international initiatives and membership, and a personal look at the need for greater compassion and clarity when communicating with patients and families.

Don S. Dizon, MD, FACP, an Associate Professor of Obstetrics/Gynecology and Medicine at the Warren Alpert Medical School of Brown University and Co-Chair of ASCO’s Integrated Media and Technology Committee, is another new voice on the site, providing insight into gynecologic cancer care. Beverly Moy, MD, MPH, Clinical Director of the Breast Oncology Program and a medical oncologist at the Massachusetts General Hospital, is also slated to join

the site. Dr. Moy serves as the Chairman of ASCO’s Advisory Group on Health Disparities and Chair-Elect of the Ethics Committee.

These latest commentators join Immediate Past President George W. Sledge, Jr, MD, who continues to write about breakthroughs in research, and Past President Douglas W. Blayney, MD, who raises issues in practice and quality. Health information and technology topics are covered by Peter P. Yu, MD, and Robert S. Miller, MD. Other columnists and their specialties include ASCO Connection Editor-in-Chief Jonathan S. Berek, MD, MMS (gynecologic cancer); Clement Adabamowo, MD, ScD (international issues); Anees B. Chagpar, MD (breast surgery oncology); John V. Cox, DO, MBA, FACP (Editor-inChief, Journal of Oncology Practice); L. Michael Glodé, MD (medical oncology); Heather M. Hylton, MS, PA-C (physician assistant); and Jamie H. Von Roenn, MD (palliative care).

New Option for Creating Groups ASCOconnection.org recently launched new group functionality, enabling ASCO members and guest

account holders to create and join working groups of varying security levels—private, closed, or open. The security level is designated by the group’s creator.

The group tool has been streamlined for ease of use. It avoids Facebook-style social networking and instead focuses on easy ways to post messages and receive group updates by email. An additional advantage to members and guests is the ability to host a working group on the world’s most prestigious oncology site, with ready access to ASCO’s many programs, services, and resources, including ASCO’s Membership Directory (member login required).

Opportunities to Share Accomplishments, Viewpoints ASCOconnection.org always features the latest interactive electronic version of ASCO’s official member magazine, ASCO Connection, with hyperlinks to references and resources, as well as a complete archive of past issues. Logged-in users are invited to comment on all content (some content is for members only), including new articles on the debate surrounding resident duty hours, breast can-

cer surveillance for childhood cancer survivors, and ASCO’s new Cancer Survivorship Committee. In addition, ASCO University has launched Tumor Board discussions in the Forum section of ASCOconnection.org.

The site provides a platform for sharing the latest member news, from professional accolades to behind-the-scenes stories, including an online exclusive interview with five-time Jeopardy! winner and ASCO member, Jay Rhee, MD, a medical oncologist from Annapolis, Maryland. ASCO members are invited to submit news and article ideas to ascoconnection@asco.org.

Free Subscriptions by E-mail or RSS Readers can keep abreast of new content on the site by subscribing to a weekly digest via RSS feed or e-mail (scroll down to the footer on ASCOconnection.org for links to the subscription center). Visitors also have the option to subscribe to RSS feeds to individual bloggers and to specific interest categories, such as international or practice-related content.

■

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

Measures of Success for Cooperative Group Reorganization

A

SCO continues to work with the NCI and others to transform the Cooperative Group Program through implementation of recommendations of the 2010 Institute of Medicine (IOM) report, “A National Cancer Clinical Trials System for the 21st Century: Reinvigorating the Cooperative Group Program.”

Five Goals ASCO believes it is essential that NCI define specific metrics for determining the success of the reorganization. An ASCO letter to NCI outlined five broad goals that could be used as the basis for reorganizing the Cooperative Group Program: ■■ Enhance inclusion of innovative and clinically meaningful science and decrease duplication across all

NCI-supported clinical trials.

■■ Improve timeliness of concept development and scientific review.

■■ Promote efficiency across the network.

■■ Increase funding for NCI-supported clinical trials.

■■ Ensure continuation of a national infrastructure to enable physician participation.

ASCO’s recommendations were highlighted in a presentation by Jeff Abrams, MD, Associate Director of the NCI Cancer Therapy Evaluation Program, to the NCI Clinical Trials and Translational Research Advisory Committee in July 2010. Dr. Abrams and CTAC members discussed ASCO’s letter and ways to help ensure that the reorganized system is best equipped to promote scientific innovation and effi-

ciently administer clinical trials.

More on Group Consolidation Also in July, the IOM issued a summary of a March 21st workshop on this issue sponsored by the IOM’s National Cancer Policy Forum and ASCO. The report summarizes how to increase efficiency and productivity, including efforts to consolidate the Cooperative Groups, public-private collaboration, funding, and ensuring broad involvement of patients and health-care providers.

Other Developments

■■ The American College of Surgeons Oncology Group, Cancer and Leukemia Group B, and North Central Cancer Treatment Group formed the Alliance for Clinical Trials in

Oncology. Monica Bertagnolli, MD, was elected Group Chair.

■■ The National Surgical Adjuvant Breast and Bowel Project and the Radiation Therapy Oncology Group are developing plans to consolidate some activities, and the Gynecologic Oncology Group announced negotiations with these two groups. Also, the Eastern Cooperative Oncology Group and the American College of Radiology Imaging Network are discussing an alliance.

■■ ASCO has developed a report tracking progress of all stakeholders in implementing the IOM report’s recommendations.

■

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

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 17

Direct from ASCO

UN Summit to Focus on Noncommunicable Diseases This Month ASCO pressing President Obama to attend.

F

or the second time since its inception 65 years ago, the United Nations General Assembly is holding a “High-level Meeting” that will focus on health. During the September 19–20 meeting, world leaders will shine a spotlight on the devastation that noncommunicable diseases are causing and have caused across the developed and underdeveloped world in recent decades, and what exactly needs to be done about it.

It is estimated that noncommunicable diseases (cancer, heart diseases, diabetes, and lung diseases) cause 60% of all deaths in the world each year. And cancer is chief among them. According to the World Health Organization, 7.6 million people die of cancer annually, which is more than HIV/AIDS, malaria, and tuberculosis combined. And yet, noncommunicable diseases receive less than 3% of global development assistance.

Cancer Incidence Highest in Developing Nations A recent UN report concluded that the cancer rate will reach more than 20 million annual cases by 2030, most of which are expected to occur in low- and middle-income countries. As people in these countries consume more tobacco products, adopt a Western diet, migrate to urban centers, and live longer (due in part to infection control), their cancer rate has increased, recently surpassing that of more developed nations.

In the United States and other more developed nations, access to care is widespread, but less-developed countries have a dearth of oncologists and treatments options.

ASCO and many other organizations that focus on noncommunicable diseases see the summit as an opportunity to change all that.

The summit, to be held in New York, will be attended by heads of state, ministers, and other government representatives, representatives from civil society, the private sector and academia, and other stakeholders. As a member of the Union for International Cancer

Control (UICC), ASCO has been working to try to persuade President Barack Obama to be there. ASCO has also worked to raise awareness among the Society’s members about the summit and its purpose, and has come up with recommendations for outcomes it would like to see from the meeting.

rum has highlighted these diseases as one of the three most likely and most severe risks to the global economy.

“This is not only a question of making noncommunicable diseases part of a health-care agenda globally, but rather of making it a development issue,” said Dr. Cazap. “Instead of vertical action through the ministers of health, it is important to develop a horizontal agenda that includes ministers of economics.

Otherwise, it will be difficult for the ministers of health to face the situation alone.”

The only other health-related UN High-level Meeting, held in 2001,

focused on HIV/AIDS. That summit ultimately led to the creation of the Global Fund to Fight AIDS, Tuberculosis and Malaria, with positive results seen worldwide.

According to Dr. Cazap, this month’s meeting has the potential to garner commitment from heads of government for a coordinated global response to noncommunicable diseases, increasing financial resources to combat them, and saving millions of people from early death and devastating health complications.

■

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

Eduardo Cazap, MD, PhD

Cancer Needs to Be Political Priority Eduardo Cazap, MD, PhD, President of the UICC, Chair of the UN Civil Society Task Force, and an ASCO board member, said that cancer care leaders want reduction of the incidence of cancer and other noncommunicable diseases to be added to the UN’s Millennium Development Goals. These goals constitute a blueprint for development priorities about which all the world’s countries and leading development institutions agree. The Millennium Development Goals range from reducing extreme poverty to halting the spread of HIV/AIDS and are up for renewal in 2015.

“The main issue is that cancer is not on the political agenda in the majority of countries around the world,” said Dr. Cazap. “It’s not a priority. Diseases included in the Millennium Development Goals have far more opportunities for funding from the World Bank and many other sources.”

Economic Impact of Noncommunicable Disease Dr. Cazap added that having a broad focus—looking at noncommunicable diseases as an economic issue as well as a health issue—is key. And noncommunicable diseases clearly are an economic issue.

After all, the World Economic Fo-

Volume 29, Issue 15

May 20, 2011

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

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

www.jco.org

What’s Hot in

JCO

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

JCO.org 1. Palliative Care and the Quality of Life Diane E. Meier, et al 29(20): 2750 2. Is Breast Conservation Therapy Superior to Mastectomy for Women With Triple-Negative Breast Cancers?

Jean-Philippe Pignol, et al 29(21): 2841 3. Rectal Cancer Trials: No Movement Martin R. Weiser 29(20): 2746

6. Presurgical Progesterone in Early Breast Cancer: So Much for So Little?

Mitch Dowsett, et al 29(21): 2839 7. Gain of Function: Empathy for the Uncertain Patient With Cancer Mark A. Lewis 29(22): 3103 8. Estrogen Receptor: A Never Ending Story?

Antonio C. Wolff, et al 29(22): 2955

4. Molecular Selection Trumps Clinical Selection Frances A. Shepherd 29(21): 2843

9. Prediction Models: Revolutionary in Principle, But Do They Do More Good Than Harm?

Andrew J. Vickers 29(22): 2951

5. Newly Diagnosed Acute Promyelocytic Leukemia: Arsenic Moves Front and Center Elihu H. Estey 29(20): 2743

10. Clinical Development of Vascular Disrupting Agents: What Lessons Can We Learn From ASA404?

Patricia M. LoRusso, et al 29(22): 2952

The ASCO Post | SEPTEMBER 1, 2011

PAGE 18

Direct from ASCO

ASCO Examines Impact of Health-care Reform on Cancer Care Disparities Makes recommendations for closing gaps

I

n a new policy statement, ASCO outlines specific provisions of the 2010 Patient Protection and Affordable Care Act that have the potential to reduce cancer care dis-

parities. ASCO’s statement makes recommendations to ensure that such provisions are carried out effectively, and urges additional steps to address systemic issues in-

cluding insurance reform, quality of care, prevention, research, and diversity in the health-care workforce.

ASCO’s statement, published

in the Journal of Clinical Oncology,1 identifies specific measures to help eliminate cancer care disparities: ■■ Adopt patient-centered quality improvement initiatives.

■■ Attract more minority physicians and improving the training of the oncology workforce to meet the needs of racially and ethnically diverse patients with cancer.

■■ Improve data collection on cancer disparities.

■■ Ensure access to cancer specialists for all patients who seek treatment at federally qualified community health centers.

■■ Allow for cancer-centered services to be at the direction of oncology professionals in community health centers and medical homes where many seek medical care.

What role may MUC1 play in NSCLC Michael P. Link, MD

ASCO President Michael P. Link, MD, explained, “The Affordable Care Act provides a foundation for meaningful progress in eliminating disparities in health care.

However, many of its provisions are vague and open for interpretation.

In addition, significant progress requires added measures that are not in the new law.”

It’s well-known that mucins protect healthy cells, but did you know that aberrant overexpression of mucin 1 (MUC1) by tumor cells may play a role in tumor cell survival?1-3 At EMD Serono, we’re investigating the significance of MUC1 and its impact on your patients with NSCLC.

Improve Insurance Coverage By increasing Medicaid eligibility, the Affordable Care Act has the potential to reduce the number of uninsured by 59%. However, an estimated 23 million individuals will be uninsured by 2019. Moreover, ASCO remains concerned about evidence showing that with low reimbursement, cancer patients on Medicaid fare no better than patients who have no health insurance.

To ensure that Medicaid pa-

110715-130123

Visit www.emdserono.com to learn more about EMD Serono Oncology.

1. Ahmad R, Raina D, Joshi MD, et al. MUC1-C oncoprotein functions as a direct activator of the NF-κB p65 transcription factor. Cancer Res. 2009;69(17):7013-7021.

2. Behrens ME, Grandgenett PM, Bailey JM, et al. The reactive tumor microenvironment: MUC1 signaling directly reprograms transcription of CTGF. Oncogene. 2010;29(42): 5667-5677. 3. Raina D, Kosugi M, Ahmad R, et al. Dependence on the MUC1-C oncoprotein in non-small cell lung cancer cells. Mol Cancer Ther. 2011;10(5):806-816.

EMD Serono Oncology | Combination is key™

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

003296_emddsa_dsa_tea_fa2.indd 1

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ASCOPost.com | SEPTEMBER 1, 2011

PAGE 19

Direct from ASCO

tients have consistent access to quality cancer care, ASCO asks policymakers to: ■■ Provide Medicaid patients diagnosed with cancer with immediate, presumptive eligibility for Medicare.

■■ Reimburse doctors who treat cancer patients on Medicaid at Medicare rates.

Enhance Prevention and Screening Follow-up Although the health-care reform legislation mandates that insurers cover certain cancer screenings, it does not expressly require insurers to cover follow-up tests if an abnormality is found. For example, if a polyp is found during a colonoscopy, insurers are not required by law to cover follow-up diagnostic examinations and biopsies. ASCO is calling for Congress to require insurers to cover appropriate followup testing without patient deductibles or copays.

Meet the Needs of Diverse Patients Provisions in the Act direct the Secretary of Health and Human Services to support the develop-

ment of curricula for cultural competency programs. In addition, effective in 2012, health plans’ summary of benefits and appeals processes are expressly required to be presented in a culturally and linguistically sensitive manner. For example, summaries must be written in plain language to be understood by those with limited English proficiency.

Develop Quality-of-care Measures The new law also authorizes development of a strategy to develop and test measures to improve quality of care as a means to reduce disparities in health care.

ASCO strongly supports this measure, and has made great progress in improving the quality of cancer care over the past 10 years.

ASCO’s Quality Oncology Practice Initiative (QOPI®) is the first national program to help practices improve the quality of care they deliver and to certify outpatient oncology offices for meeting the highest national standards for cancer care delivery. Today, nearly 700 oncology practices participate in QOPI.

Pick up Cancer.Net Materials for Your Patients at the Breast Cancer Symposium

S

top by the ASCO booth in the Exhibit Hall at the Breast Cancer Symposium, September 8–10 in San Francisco, to pick up samples of some of the materials Cancer.Net has available for your patients. At the booth, you can learn about the Cancer.Net Guide to Breast Cancer and pick up fact sheets about breast cancer, as well as other educational and promotional materials. You can

also learn how to order these materials for your practice at www.cancer. net/estore.

The Exhibit Hall will be located in the Yerba Buena Ballroom and will be open September 8 from 7:00 AM until 6:30 PM and September 9 from 7:00 AM until 5:45 PM.

Dr. Link explained, “When it comes to closing the disparities gap, quality does matter. A meaningful quality initiative must be based on best practices derived from clinical guidelines, published measures, and collective expert consensus. Care minus quality isn’t much better than no care at all.”

Reference 1. Moy B, Polite BN, Halpern MT, et al: American Society of Clinical Oncology Policy Statement: Opportunities in the Patient Protection and Affordable Care Act to reduce cancer care disparities. J Clin Oncol. August 1, 2011 (early release online).

■

■

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

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

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 23

Journal Spotlight Biomarkers

Circulating Tumor Cell Assay Shows Potential for Predicting Prognosis in Head and Neck Carcinoma

By Matthew Stenger

A

ccording to the NCI, an estimated 49,260 new cases of oral cavity, pharyngeal, and laryngeal cancers occurred in the United States in 2010, and approximately 11,480 deaths were attributed to these cases. It is estimated that 95% or more of these cases are squamous cell carcinomas. Currently, the presence of lymphatic metastasis is the best predictor of prognosis in squamous cell carcinoma of the head and neck. There is a need for reliable serologic markers of prognosis, particularly markers that can identify patients at risk for locoregional or distant recurrence.

Novel Technique In a recent article in Archives of Otolaryngology—Head & Neck Surgery, Jatana and colleagues, from The Ohio State University in Columbus, describe the performance of a novel technique for detecting and measuring circulating tumor cells (CTCs) to predict prognosis in patients with squamous cell carcinoma of the head and neck.1 Techniques for isolating and measuring CTCs have generally involved depleting blood samples of red blood cells and positively selecting CTCs for measurement by using an antiepithelial antibody bound to a magnetic particle. Positive selection methods may be prone to bias due to selection of only those circulating tumor cells bearing the surface markers for which the antibodies are specific.

Currently, the only FDA-cleared system for detecting CTCs in peripheral blood is the CellSearch system (Veridex LLC), which is used for detecting CTCs in patients with metastatic breast, prostate, and colorectal cancer. This system uses immunomagnetic labeling and automated digital microscopy to capture and count CTCs, with the CTCs being bound by monoclonal epithelial cell adhesion molecule antibodies.

Method and Criteria Jatana and colleagues developed a negative depletion method in which samples are enriched for CTCs by depletion of normal blood cells.2,3 In this technique, blood samples undergo red blood cell lysis followed by labeling using an antiCD45 tetrameric antibody complex SEE PAGE 39 and dextran-coated

magnetic nanoparticles; CD45 is exes between patients with CTCs and pressed at high levels on the surface of those without CTCs with regard to all nucleated hematopoietic cells. The age, gender, proportion with smoking labeled cells are then passed through history of at least 15 pack-years, proa magnetic deposition sorting system, portion with at least moderate alcohol resulting in depletion of peripheral consumption, tumor site, proportion blood leukocytes. who had received adjuvant therapy, or To test for the mean nucleated or presence of cirtotal cell log depleAt a mean followculating tumor tion. Of particular cells, the enriched interest was the up of 19 months, samples undergo finding that the patients with no CTCs cytospin for imtwo groups also had significantly munocytochemisdid not differ with try staining. Initial regard to stage of longer disease-free staining consists disease or proporsurvival. of incubation tion with nodal with a dilution of involvement, sugant ic y tokerat in gesting that presfluorescien isothiocyanate conjugated ence of CTCs may be an independent (FITC) antibody CK3-6H5, which risk factor for poorer prognosis. recognizes cytokeratins (8, 18, and 19) Further Analysis present on epithelial cells. Additional Follow-up of this cohort of patients staining is performed with 4,6-diamidcontinues, and circulating tumor cells ino-2-phenylindole (DAPI), which from these patients have been lysed stains cell nuclei, with specimens then to obtain RNA for further molecular being analyzed by fluorescent microsanalysis. Potential advantages of the copy. negative enrichment system are that The criteria for CTCs in the study it can eliminate bias for certain types were that cells had to be positive for of cancer (eg, those that express the both FITC and DAPI staining, have an epithelial cell adhesion molecule) and intact membrane, and have a high nuallow analysis of multiple markers on clear to cytoplasmic ratio while being at individual samples of CTCs, including least as large as surrounding peripheral markers that are not typically associated blood leukocytes. Since CD45-positive with epithelial cells. cells were removed via magnetic sortDisclosure: Dr. Jatana reported no potential ing, it was assumed that all remaining conflicts of interest. cells in the sample were CD45-negative.

The concentration of CTCs per milliliReferences ter of peripheral blood was calculated 1. Jatana KR, Balasubramanian P, Lang using the numbers of CTCs on the cyJC: Significance of circulating tumor cells tospin, with appropriate dilution factors in patients with squamous cell carcinoma applied during the depletion process.

■

Key Correlations Initially, testing in 48 patients with squamous cell carcinoma of the head and neck showed that this technique resulted in mean total cell depletion of 5.32 log10 and mean nucleated cell depletion of 2.53 log10. At that time, a mean follow-up of 19 months, patients with no CTCs had significantly longer disease-free survival (P = .01). More recently, presented at ASCO with additional prospective follow-up of 50 patients, at a mean of 26.6 months, the trend has continued (P = .045). Of these 50 patients, 70% had CTCs present.4 There were no significant differenc-

of the head and neck. Arch Otolaryngol Head Neck Surg 136:1274-1279, 2010.

2. Yang L, Lang JC, Balasubramanian P, et al: Optimization of an enrichment process for circulating tumor cells from the blood of head and neck cancer patients through depletion of normal cells. Biotechnol Bioeng 102:521-534, 2009.

3. Balasubramanian P, Yang L, Lang JC, et al: Confocal images of circulating tumor cells obtained using a methodology and technology that removes normal cells. Mol Pharm 6:1402-1408, 2009.

4. Jatana K, Balasubramanian P, Lang JC, et al: Correlation of circulating tumor cells in SCCHN patients to cancer reoccurence using a negative enrichment technology. 2011 ASCO Annual Meeting. Abstract 5511. Presented June 3, 2011.

PAGE 24

The ASCO Post | SEPTEMBER 1, 2011

Drug Development

Research in Combining Targeted Agents Faces Numerous Challenges

By Margot J. Fromer

I

f the clinical trials endeavor in oncolingly sophisticated targeted therapies, ogy is falling short of its goals and but cellular pathways contain redunif targeted agents have not kept their dancies that can be activated in repromise, can a new approach to drug sponse to inhibition of one or another development provide a solution? pathway, thus promoting emergence Very possibly, said John Hohneker, of resistant cells and clinical relapse.

MD, Chair of the Workshop Planning The traditional path to drug develCommittee for the conference, “Faopment, even targeted therapy, has cilitating Collaborations to Develop been one at a time. Sometimes a new Combination Investigational Cancer drug is added to a standard regimen and Therapies,” held in Washington in midthen compared to the standard alone, June and sponsored by the Institute of Medicine (IOM) National Cancer Policy Forum. He is also Senior Vice President and Global Head of Development, Integrated Hospital Care, Novartis.

Dr. Hohneker said that the purpose of the workshop was to talk about the many barriers to this new approach John Hohneker, MD Jane Perlmutter, PhD to cancer treatment. “Combut regardless of how or with what it is bining investigational products early used, it has to work on its own. in their development is thought to be a promising strategy, especially when they Cooperative Development target multiple pathways (or more than This system is no longer comone step in a pathway), thus conferring pletely viable in cancer and needs greater benefit than therapy directed at a to be modernized. A new approach single target.” would provide the flexibility to evaluUnfulfilled Promise ate combination regimens in a single Jane Perlmutter, PhD, founder of development program that can screen the Gemini Group, a consulting compaall tumors for their pathway depenny, added, “The problem with the way dencies, resulting in efficacy based on cancer research is conducted is that the screening results and experience with biology of the disease is so complicated patterns of resistance. that, although technology keeps adHowever, despite the potential benvancing, personalized medicine is still efits of such a scheme, uncertainty and mostly only a promise.” risk abound. First, it is usually imposTargeted agents for cancer haven’t sible to characterize the effects of the panned out to the extent hoped. Alindividual components. Second, comthough a few might work sometimes or binations would probably yield considfor a short time, the effects have not been erably less information about safety and significant or durable. And many are efficacy than would have been available more toxic than expected. “Their reguhad they been developed individually. lation is confusing and/or interpreted Third, patients and physicians must not too conservatively, and despite the great only be informed of more-than-usual need, there is limited incentive for pharrisk, they must be willing to accept it. maceutical companies to collaborate Fourth, there should be a compelling with each other,” said Dr. Perlmutter. biologic rationale for their use and subAdvances in genomics and cell bistantial reasons why the agents cannot ology have paved the way for increasbe developed individually.

Visit

The Science Is Complex

Dr. Doroshow. “This is a huge undertaking, and unfortunately it is not necessarily predictive of clinical benefit.

That requires larger, later-stage trials.”

Michael T. Barrett, PhD, Associate Professor and Head of the Oncogenomics Laboratory, TGen, added that cancer is extremely genetically unstable, resulting in highly karyotypically and biologically individual malignancies. Thus, each patient’s cancer could require its own specific therapy. Even if this were possible and practical, the treatment could ultimately be thwarted by emergence of a resistant variant genetic subline.

Dr. Barrett also noted that each genome has unique sets of selected aberrations and mutations, of which multiple popuJames Doroshow, MD Michael T. Barrett, PhD lations can be present at biopsy.

These mutations can be asymtools means inability to assess the metric; they can progress and metastarget effect of many agents, and astasize, and thus resist treatment. He says are not standardized. warned that application of genomic ■■ Preclinical models to evaluate eftools to combination therapy has to be ficacy, dosing schedule effects, biobased on unbiased profiling of biopmarker utility, and toxicity are not sies, as well as identification of theraavailable for combination therapies. peutic vulnerabilities in all patients.

■■ Clinical trials methodology reKurt Bachman, PhD, Head of mains unclear with regard to Translational Medicine and Biology, numbers of patients, tumor biopGlaxoSmithKline, added, “The chalsies, relevance of histologic holenge is to identify the tumor types mogeneity, and pharmacokinetic most likely to respond, to find biointeractions. markers that predict a response, and to ■■ Intellectual property and reguladefine the relationship of the predictory matters are daunting. tors to the biology of the inhibitors.”

Disclosure: Dr. Hohneker is employed by Dr. Doroshow also discussed and owns stock in Novartis. Dr. Barrett has a mechanism of action (or mechanism current research contract with AstraZeneca. of resistance) studies in early-phase Dr. Bachman is employed by GlaxoSmithKline. trials. Problems include the evaluaDr. Perlmutter reported no potential conflicts of interest. Dr. Doroshow reported no potential tion of actual vs presumed sites of tarconflicts of interest. get engagement, evidence to support further development, demonstration of the relationship between dosing In the next issue of The ASCO schedule and systemic exposure to Post, we will consider further istarget effects, and relevance of biosues raised at the IOM conference, markers. including business, regulatory, and “In addition, we need to investilegal concerns in the development of gate the molecular effects, toxicology, targeted-agent combination theraand other safety signals of combinapies for patients with cancer. tion agents in surrogate tissues,” said

James Doroshow, MD, Deputy Director for Clinical and Translational Research, NCI, discussed the scientific challenges facing development of combination targeted therapeutics: ■■ The mechanisms of action for a growing number of targeted agents that are available for trials are not completely understood.

■■ Lack of the right assays or imaging

■

website at ASCOPost.com

To confront a

Common Threat in the 2 leading causes of cancer death1...

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.

Please see accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

Think Avastin First-line metastatic non-squamous NSCLC: 19% increase in median OS in combination with PC (Study E4599)2

1-year survival:

Percentage Surviving

100

51% vs 44%2

80

2-year survival:

23% vs 15%2

60 40

Avastin + PC (n=434) PC alone (n=444)

20 0

10

20

30

40

50

OS (Months)

NSCLC=non-small cell lung cancer; PC=paclitaxel/carboplatin; HR=hazard ratio; CI=confidence interval.

Median OS with Avastin plus PC was 12.3 months vs 10.3 months with PC alone (HR=0.80 [95% CI, 0.68–0.94], P=0.013)2 Patients receiving Avastin plus PC vs PC alone were 16% more likely to be alive at 1 year (51% vs 44%) and 53% more likely to be alive at 2 years (23% vs 15%)3

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 Gastrointestinal (GI) perforation — Serious and sometimes fatal GI perforation occurs at a higher incidence (up to 2.4%) in Avastin-treated patients compared to controls. Discontinue Avastin for 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 — Discontinue in patients with wound dehiscence.

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

©2011 Genentech USA, Inc.

All rights reserved.

AVA0000488100

Printed in USA.

(06/11)

Hemorrhage — Severe or fatal hemorrhage, hemoptysis, GI bleeding, CNS hemorrhage, and vaginal bleeding are increased in Avastin-treated patients. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis

Additional serious adverse events Additional serious and sometimes fatal adverse events with increased incidence in the Avastin-treated arm vs control included: — Non-GI fistula formation (≤0.3%) — Arterial thromboembolic events (grade ≥3, 2.4%) — Proteinuria including nephrotic syndrome (<1%) Additional serious adverse events with increased incidence in the Avastin-treated arm vs control included: — Hypertension (grade 3–4, 5%–18%) — Reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%)

Most common adverse events Most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate: — Epistaxis — Proteinuria — Lacrimation disorder — Headache — Taste alteration — Back pain — Hypertension — Dry skin — Exfoliative dermatitis — Rhinitis — Rectal hemorrhage

Because overall survival matters Proven to extend overall survival (OS) in the 2 cancers with the highest mortalities1

Percentage Surviving

First-line MCRC: 30% increase in median OS in combination with IV 5-FU–based chemotherapy (Study 2107)4,5

100

First-line median OS:

80

(HR=0.66 [95% CI, 0.54–0.81], P<0.001)

20.3 vs 15.6 months

60 40 20

Avastin + IFL (n=402) Placebo + IFL (n=411)

0 6

18 12 OS (Months)

24

30

MCRC=metastatic colorectal cancer; IV=intravenous; 5-FU=5-fluorouracil; IFL=5-FU/leucovorin (LV)/irinotecan.

OS in second-line MCRC Study E3200: Median OS of 13.0 months with Avastin plus 5-FU/LV/oxaliplatin (FOLFOX4) vs 10.8 months with FOLFOX4 alone (HR=0.75 [95% CI, 0.63–0.89], P=0.001)2,6

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

Pregnancy warning Based on animal data, Avastin may cause fetal harm and may impair fertility Advise patients of the potential risk to the fetus during and following Avastin and the need to continue adequate contraception for at least 6 months following the last dose of Avastin For nursing mothers, discontinue nursing or Avastin, taking into account the importance of Avastin to the mother 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%), intraabdominal 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 accompanying brief summary of Prescribing Information, including Boxed WARNINGS, for additional important safety information.

References: 1. American Cancer Society. Cancer Facts and Figures 2010. http://www.cancer. org/acs/groups/content/@nho/documents/document/acspc-024113.pdf. Accessed April 21, 2011. 2. Avastin Prescribing Information. Genentech, Inc. February 2011. 3. Sandler A, Gray R, Perry MC, et al. N Engl J Med. 2006;355:2542-2550. 4. Data on file. Genentech, Inc. 5. Hurwitz H, Fehrenbacher L, Novotny W, et al. N Engl J Med. 2004;350:2335-2342.

6. Giantonio BJ, Catalano PJ, Meropol NJ, et al. J Clin Oncol. 2007;25:1539-1544.

www.avastin.com

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.

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.

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 29

OncologyWorldwide Cancer Care in the UK: A Conversation with Chris Parker, MD

By Ronald Piana

ceive a fixed salary no matter how many men with prostate cancer I treat or, for that matter, what modality of treatment they receive. I have no incentive to impose my treatment preference on patients, so they are free to make their own informed decisions. Maybe the decisions by our patients in the UK better reflect their own personal values rather than the prejudices of their physicians.

Chris Parker, MD

I

n the contentious debate over rising health-care spending, the cancer care policies of the British National Health Service (NHS) are often cited by U.S. policymakers as an example of how health-care rationing denies patients lifeprolonging treatments based on costs.

The ASCO Post recently spoke with prostate cancer specialist, Chris Parker, MD, Academic Urology Unit, The Royal Marsden NHS Foundation Trust, about the realities of oncology services in the United Kingdom.

Active Surveillance Most prostate cancer experts in the United States agree that active surveillance is underutilized in managing disease.

Is this an issue in the United Kingdom?

Unlike the U.S., active surveillance is widely accepted by both doctors and their patients in the UK. Our latest data suggest that about 40% of men diagnosed with low-risk prostate cancer are managed by active surveillance.

The comparable figure in the U.S. is much less. It is difficult to understand why that discrepancy in treatment choices exists between the two nations; one factor could be a difference in patient attitudes. UK patients might place more emphasis on avoiding the side effects from prostate cancer treatment, while their counterparts in the US might be more focused on minimizing risk from the cancer.

Health-care Policy The fee-for-service system in the U.S. provides doctors with an incentive to use expensive reimbursable treatments. Would you please contrast the UK’s system?

In the National Health Service, I re-

In our current debate on health-care spending, the UK’s National Health Service and National Institute for Health and Clinical Excellence (NICE) are often used as examples of health-care rationing that limits cancer care services. What’s your response?

I am a staunch supporter of the UK’s National Health Service and I would point out that medical services here are universally available to all people from whatever walk of life. No matter what your role in British society is, you are entitled to high-quality, timely medical care, which I believe is a huge strength of the UK system. It is taxpayer funded, free at the point of need. And to my mind, that makes a great deal of sense when you’re talking about a basic

as a taxpayer, I want the government to make wise use of the health-care budget. So I want NICE to approve costeffective treatments, but I don’t want exorbitantly expensive treatments that offer very little in return.

NICE does have one shortcoming.

Since the agency places great importance on making high-quality decisions based on an exhaustive review of the evidence, the decision-making process can be slow. This often leads to a significant delay in getting promising new drugs into the clinic. A topical example would be abiraterone for prostate cancer, which is now routinely available in the U.S. (as Zytiga) but not yet in the UK. I guess that is the price one pays for having such a rigorous examination process. Overall, I think NICE does an excellent job.

Prostate Cancer Overtreatment Is there a central issue in prostate cancer that guides treatment decisions in the UK? We know that certain men with prostate cancer benefit from curative treatment—especially those with high-risk disease. Conversely, we know

As a prostate cancer clinician, I want my patients to have the best possible therapy. As a taxpayer, I want the government to make wise use of the health-care budget.

point to the European Screening Trial that shows a reduction in the risk of prostate cancer death. Those who feel PSA does more harm than good cite data showing the huge problems of overdiagnosis and overtreatment. The take-up rate of PSA testing is certainly far lower than in the United States; only a small minority of UK men have their PSA checked on a regular basis.

Clinical Trials What role do trials play in clinical practice in the UK? We place a great deal of importance on clinical trials, and the UK system is conducive to patient participation in trials. The National Cancer Research Network (NCRN) provides centrally funded research nurses throughout the UK to facilitate clinical trials. The UK has a culture that promotes participation in clinical trials. My patients typically expect to be offered the chance to enroll in a trial. In fact, about 50% of patients with prostate cancer in our center are on trials.

One important UK prostate cancer trial is ProtecT, in which about 2,000 men have been randomly assigned to surgery, radiotherapy, or active monitoring. In time, this trial will yield the best-quality evidence concerning the relative merits of those three options.

Without such well-constructed randomized trials, clinical decision-making will always be a matter of guesswork; these trials are the key to making progress in treating prostate cancer.

Closing Thoughts human need, such as health care.

In recent years we have had an abundance of new cancer drugs, and that can only be a good thing. However, the new drugs are increasingly costly and, for the most part, their benefits are measured in small increments. Taken together with the fact that our medical resources are finite, it seems obvious that we need some form of thoughtful rationing to ensure sustainability.

To that end, NICE has an extremely difficult job in determining which drugs should be approved, and, in my view, they do it pretty well. As a prostate cancer clinician, I want my patients to have the best possible therapy. But

that very few men with low-risk disease will benefit from treatment. A key unmet need is to better distinguish which men need treatment and which men do not. By doing so, we could not only deliver more cost-effective care, but also avoid the harms associated with unnecessary treatment.

Overtreatment of prostate cancer begins with screening. Some experts assert that prostate-specific antigen (PSA) testing leads to many unnecessary biopsies.

What’s the UK experience with PSA? The debate over the pros and cons of PSA screening is highly controversial. Those in favor of PSA screening

Any last thoughts on the state of cancer care in the UK? Cancer care in the UK is often criticized as inferior to that in other parts of the world. I beg to differ. NHS oncology services have improved considerably in recent years, and, in my experience, are now excellent. When it comes to prostate cancer, our outcomes are comparable to those anywhere in the world. My concern would be that the level of funding that the NHS currently enjoys might be threatened given the global economic malaise we are facing.

■

Disclosure: Dr. Parker reported no potential conflicts of interest.

The ASCO Post | SEPTEMBER 1, 2011

PAGE 30

Psychosocial Oncology

Experts Address Cancer-related Distress—the ‘Sixth Vital Sign’

M

ore research is needed to investigate the effects of screening and treatment for distress in cancer care, according to a recent issue of the international journal Psycho‑Oncology.

This special edition of the journal includes a review of screening for dis-

tress and depression over 40 years in cancer care, 10 new papers examining aspects of cancer-related distress, and two brief reports on studies of screening for distress in inpatient and outpatient settings. The issue is available at no cost online (http://onlinelibrary.

wiley.com/doi/10.1002/pon.v20.6/ issuetoc).

Next Obstacle Coeditor of the journal, Jimmie C. Holland, MD, said a global focus on distress as the “sixth vital sign” could

greatly improve the experience of patients with cancer worldwide, enhancing patient care. Dr. Holland is the Wayne E. Chapman Chair in Psychiatric Oncology at Memorial SloanKettering Cancer Center in New York.

“The next obstacle to overcome for psycho-oncology is to address the social, organizational, and economic challenges that prevent patients with cancer from being routinely screened and treated for distress,” Dr. Holland said. “We have a long way to go in understanding the effects distress can have on patients, and much more research is required to build scientific knowledge that can be translated into effective practice,” she commented.

“Psycho-oncologists have a critical role to play in developing clinical guidelines that identify distressed patients, by routinely implementing a new screening standard for distress integrated with cancer care systems in all nations,” she added.

Global Effort In June 2009, the International Psycho-Oncology Society (IPOS) first made the recommendation to revise cancer care standards and clinical practice guidelines by ranking distress as the sixth vital sign in cancer care.

“The high prevalence of distress in patients with cancer worldwide has been well documented, with significant impact on patients’ basic functioning,” said Maggie Watson, PhD, President of IPOS and coeditor of Psycho-Oncology.

The IPOS recommendation was officially endorsed by the Union for International Cancer Control (UICC) at the World Cancer Congress in August 2010. President of the UICC, Eduardo Cazap, MD, PhD, said progress was being made in countries such as Australia, the United Kingdom, the United States, and Canada, but more could be done on a global scale.

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ASCOPost.com | SEPTEMBER 1, 2011

PAGE 31

JCO Spotlight Genitourinary Cancer

At 5 Years, Brachytherapy Shows Quality-of-life Advantages over Radical Prostatectomy for Favorable-risk Prostate Cancer

By Charlotte Bath

F

ive years after treatment for favorable-risk prostate cancer, men who either chose or were randomly assigned to receive brachytherapy reported quality-of-life advantages in urinary and sexual domains and in patient satisfaction compared to men who received radical prostatectomy, according to a study recently reported in the Journal of Clinical Oncology.1 Favorable risk prostate cancer was defined as Gleason score ≤ 6, prostatespecific antigen (PSA) < 10 ng/mL, stage T1 to T2a.

diation oncologist. All were considered “equally appropriate” for both treatments, lead investigator Juanita Mary Crook, MD, told The ASCO Post. She said that although only a minority of the individuals were randomly assigned to treatment, the study represents a direct comparison of the long-term effects of brachytherapy and radical prostatectomy. Dr. Crook is Professor of Radiation Oncology at the University of British Columbia, British Columbia Cancer Agency, Center for the Southern Interior, Kelowna, Canada.

Table 1: Health-related Quality of Life by Interventiona

Juanita Crook, MD, FRCPC

The men were originally approached at the University Health Network and Princess Margaret Hospital in Toronto for participation in the phase III Surgical Prostatectomy versus Interstitial Radiation Intervention Trial (SPIRIT).

The trial was closed due to poor accrual, but 168 trial-eligible men who received either radical prostatectomy or brachytherapy completed health-related quality of life (HRQOL) assessments 3.2 to 6.5 years later.

A “unique” feature of the study was that all men enrolled had received identical balanced information about radical prostatectomy and brachytherapy in small-group educational sessions given jointly by a urologist and a ra-

The Anonymity Advantage

“T

his study has the advantage of not only being patient-reported but also of patient anonymity; the questionnaires were not administered or discussed with the patients by any of the treating physicians,” the study authors reported.

“I know that patients often want to please their doctor. They don’t want to say something that is going to get their doctor upset,” lead investigator Juanita Mary Crook, MD, explained. “If patients are reporting to you face to face, they may minimize symptoms or dissatisfaction simply because they are a little bit dependent on you for their ongoing care. If patients report anonymously, I think they are more likely to be honest and say exactly how things are affecting them.”

■

Intervention

Mean

SD

P

Urinary

Brachytherapy Prostatectomy Brachytherapy Prostatectomy Brachytherapy Prostatectomy Brachytherapy Prostatectomy Brachytherapy Prostatectomy

91.82 88.15 93.0 94.37 52.54 39.22 93.52 89.98 93.63 76.89

8.53 11.47 11.62 8.91 24.06 25.35 8.27 12.79 12.03 27.49

.02

Brachytherapy Prostatectomy Brachytherapy Prostatectomy

55.88 55.42 44.72 43.19

9.69 8.85 5.28 5.81

Bowel Sexual Hormonal Patient satisfaction SF-12-PCS

Statistically Significant Domain Differences At a median follow-up of 5.2 years, the investigators found a statistically significant difference in the urinary domain, favoring the men treated with brachytherapy (P = .02). Questions about the degree and frequency of urine leakage all showed a P value of < .001 in favor of brachytherapy, whereas none of the questions on irritative and obstructive symptoms (which might persist after brachytherapy) revealed a significant difference. The authors also reported highly significant differences in the sexual domain (P = .001) and in patient satisfaction score (P = .001), all favoring brachytherapy. They observed no differences in the scores for bowel or hormonal domains (see Table 1). The HRQOL instruments used were the prostate cancer–specific 50-item Expanded Prostate Cancer Index Composite (EPIC) and short-form measurements of physical and mental components.

Highly significant differences in favor of brachytherapy in the sexual domain involved the ability to have an erection (P < .001), the quality of erec-

Domain

SF-12-MCS

.34 .001 .1 < .001 .38 .04

Based on the EPIC, SF-12 PCS, and SF-12 MCS instruments. For each domain, higher total scores imply a better health-related quality of life. EPIC = Expanded Prostate Cancer Index Composite; SD = standard deviation; SF-12 MCS = Short Form 12 Mental Component Score; SF-12 PCS = Short Form 12 Physical Component Score.

Reprinted, with permission, from Crook JM, et al.1 Copyright © 2011 by the American Society of Clinical Oncology. All rights reserved. a

tions (P < .001), the frequency of erections (P = .003), awakening with an erection (P = .002), and the ability to function sexually (P = .003). Overall, 79% of men treated with brachytherapy reported erections firm enough for sexual activity, compared with 48% of those treated by radical prostatectomy (P < .001), and 66% of men after brachytherapy “had erections at least half the time when they wanted as compared with 40% after surgery (P = .003),” the researchers wrote.

“The associated degree of the problem with these changes, as evaluated by the ‘bother’ scores of EPIC, also reached significance but at levels of P = .02 to P = .049,” the authors reported. The bother score is important because otherwise people assessing treatment side effects will make decisions about what effects might be generally troublesome, rather than what actually bothers an individual patient. “That is what quality of life is all about—the individual’s perception,” Dr. Crook noted.

Brachytherapy Chosen for Potency Advantages The men had attended educational sessions comparing and contrasting brachytherapy and radical prostatectomy, including the specifics of the procedures and the impact on urinary and sexual function, and then had in-

dividual specialty consultations with a urologist and a radiation specialist. “If either specialist felt that on the basis of prostate size, voiding function, comorbidities, or patient preference, an individual was more suited to one treatment or the other (or neither), the patient was informed of the SEE PAGE 39 recommendation and was not offered participation in the trial,” the investigators explained.

Of the 268 men attending the sessions, 34 chose random assignment.

Another 62 men chose radical prostatectomy and 94 chose brachytherapy.

The others were directed toward external-beam radiation therapy or surveillance, the authors reported.

“The reasons for selecting one treatment over another are complex, but many men chose brachytherapy because of a perceived advantage in maintenance of potency, which was acknowledged by the urologist,” Dr. Crook said. The less invasive nature of brachytherapy was also more appealing to the men. “Since you are not having major surgery,” she stated, “the initial recovery period tends to be easier after brachytherapy.”

Asked if unwillingness to be randomly assigned to radical prostatectomy continued on page 36

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

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

•

•

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

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

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

Peripheral Neuropathy • Patients should be monitored closely for signs of peripheral • •

motor and sensory neuropathy Grade 3 peripheral neuropathy occurred in 8% of patients, and Grade 4 in 0.4% of patients who received Halaven. Delay administration of Halaven until resolution to Grade 2 or less Neuropathy lasting more than 1 year occurred in 5% of patients. Twenty-two percent of patients developed a new or worsening neuropathy that had not recovered within a median follow-up duration of 269 days (range 25-662 days)

•

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

Avoid in patients with congenital long QT syndrome

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

Please see accompanying brief summary of Halaven full Prescribing Information.

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

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

Referenced with permission from the NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines™) for Breast Cancer V.2.2011. © 2011 National Comprehensive Cancer Network, Inc. All rights reserved. Accessed February 2, 2011. To view the most recent and complete version of the NCCN Guidelines, go online to NCCN.org. NATIONAL COMPREHENSIVE CANCER NETWORK®, NCCN®, NCCN GUIDELINES™, and all other NCCN Content are trademarks owned by the National Comprehensive Cancer Network, Inc.

HALAVEN™ is a trademark used by Eisai Inc. under license from Eisai R&D Management Co., Ltd. © 2011 Eisai Inc. All rights reserved. Printed in USA/June 2011 ERI 81R1

Scan this code to visit www.halaven.com

A preferred single agent in the NCCN Guidelines™1

DISCOVER

OVERALL SURVIVAL

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

TPC Arm (n=254)

Median OS (months [95% Cl])

13.2 (12.1, 14.4)

10.6 (9.2, 12.0)

Deaths

386

203

1.0 0.9

PROPORTION OF PATIENTS ALIVE

0.8 0.7 0.6

RESULTS CONSISTENT WITH PRIMARY ANALYSIS2

Halaven

0.5

Control Arm

0.4 0.3 0.2 0.1 0.0

0

6

12

18

24

30

36

54 26

11 5

0 0

TIME (MONTHS) Number of patients at risk

508 254

406 178

274 106

142 61

Halaven TPC Arm

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

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

CI=confidence interval; HR=hazard ratio.

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

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

• The most common serious adverse reactions reported in patients receiving Halaven were febrile neutropenia (4%) and neutropenia (2%)

• Peripheral neuropathy (5%) was the most common adverse reaction resulting in discontinuation

ADVANCING SURVIVAL

The ASCO Post | SEPTEMBER 1, 2011

PAGE 34

FDA Update

Updated Drug Label Approved for Pioglitazone after Safety Review

T

he FDA recently approved updated drug labels for pioglitazone (Actos) and other pioglitazone-containing medicines (in combination with metformin, Actoplus Met and Actoplus Met XR; and

with glimepiride, Duetact) to include safety information that the use of pioglitazone for more than 1 year may be associated with an increased risk of bladder cancer.

The updated drug labels recom-

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

mend that health-care professionals should not use pioglitazone in patients with active bladder cancer, and use pioglitazone with caution in patients with a prior history of bladder cancer. The new labels also recommend that pa-

Table 2 (cont’d) MedDRA ver 10.0

HALAVEN (n=503) Control Group (n=247) All Grades ≥ Grade 3 All Grades ≥ Grade 3 Respiratory, thoracic, and mediastinal disorders Cough 14% 0 9% 0 Dyspnea 16% 4% 13% 4% Skin and subcutaneous tissue disorders Alopecia 45% NAc 10% NAc Infections and Infestations Urinary Tract Infection 10% 1% 5% 0 a Based upon laboratory data. b Includes neuropathy peripheral, neuropathy, peripheral motor neuropathy, polyneuropathy, peripheral sensory neuropathy, and paraesthesia. c Not applicable; (grading system does not specify > Grade 2 for alopecia).

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

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

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

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

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

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

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

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

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

There is no known antidote for HALAVEN overdose.

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

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

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

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

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

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

tients should contact their health-care professional if they experience any sign of blood (or a red color) in the urine or other symptoms such as new or worsening urinary urgency or pain on urination since starting pioglitazone, as these may be due to bladder cancer.

Pioglitazone is used along with diet and exercise to improve control of blood sugar in adults with type 2 diabetes mellitus. From January 2010 through October 2010, approximately 2.3 million patients filled a prescription for a pioglitazone-containing product from outpatient retail pharmacies

Safety Announcement The FDA had issued a safety announcement in June to inform the public about the possible association between pioglitazone use and bladder cancer risk. The safety information was based on FDA’s review of data from a planned 5-year interim analysis of an ongoing, 10-year epidemiologic study.

The 5-year results showed that although there was no overall increased risk of bladder cancer with pioglitazone use, an increased risk of bladder cancer was noted among patients with the longest exposure to pioglitazone, and in those exposed to the highest cumulative dose of pioglitazone.

The FDA safety announcement also mentioned an epidemiologic study conducted in France that suggests an increased risk of bladder cancer with pioglitazone. Based on the results of this study, France has suspended the use of pioglitazone and Germany has recommended not starting pioglitazone in new patients.

FDA will continue to evaluate data from the ongoing 10-year epidemiologic study. The Agency will also conduct a comprehensive review of the results from the French study. FDA will update the public when more information becomes available.

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ASCOPost.com | SEPTEMBER 1, 2011

PAGE 35

Clinical Trials Ethics

‘Unrealistic Optimism’ Poses Ethical Challenges, May Affect Informed Consent Process

Study findings show patients in early-phase oncology trials have an optimistic bias.

By Jo Cavallo

D

oes a patient’s optimistic expectation of reaping a health benefit from participating in phase I and phase II oncology studies, even when he understands that these early trials are not designed to provide direct therapeutic benefit, compromise the informed consent process? And, does that optimistic expectation for benefit merely reflect the patient’s natural disposition to think positively when facing a life-threatening medical situation, or is it the result of a distortion in how that patient is assessing the potential risks and benefits of early-phase clinical trials?

patients enrolled in early-phase clinical trials confuse the purpose of such studies, which is to advance generalized scientific knowledge and not provide individual therapeutic benefit—is an ongoing concern for physicians and medical ethicists. Nevertheless, the majority of the participants in these early trials said they understood the purpose of the trial was to gain research knowledge and not to treat them for their cancer. Despite this understanding, a significant number of respondents had what the researchers call “unrealistic optimism,” or an optimistic bias, when it came to applying that knowledge to their personal situation.

Benign Hopefulness?

Lynn A. Jansen, PhD, RN

Those are some of the questions researchers sought to answer in their study published in the January/February issue of IRB: Ethics & Human Research.1 The study was funded by an NIH/NCI grant (R21CA131601).

The researchers surveyed 72 patients with cancer enrolled in phase I, phase I/II, and phase II trials at St. Vincent’s Medical Center in New York. The study volunteers were given a comparative risk/benefit assessment questionnaire, which asked: Compared to other patients participating in the same cancer research trial you are participating in, what are the chances ■■ Your cancer will be cured with existing drugs or treatments (not those being tested in the trial)?

■■ Your cancer will be controlled by the drugs you get in the trial?

■■ You will experience a health benefit from participating in the trial?

■■ You will experience a health problem from the drugs being tested in the trial?

■■ Your cancer will be cured by the drugs you get in the trial?

Therapeutic misconception—a widely recognized problem in which

The survey results found three areas where a majority of study participants believed they were more likely than other volunteers in the trial to have a positive outcome: their cancer would be controlled with the experimental drug; they would experience a health benefit; and they would not experience adverse health effects from the trial drugs.

“Over the past 5 years, researchers have started to realize that patients in early-phase clinical trials often do understand the purpose of those trials, so there’s not a therapeutic misunderstanding,” said Lynn A. Jansen, PhD, RN, Madeline Brill Nelson Chair of Ethics Education and Associate Director of the Center for Ethics in Health Care at Oregon Health and Science University in Portland, and lead author of the study. “Still, many of these same patients continue to have high expectations for therapeutic benefit.

Some researchers interpret this optimism as ethically benign. They say that we shouldn’t worry about it because patients are just being hopeful and what’s wrong with that? But my colleagues and I thought that maybe there was something more going on. Maybe these patients were under the sway of an optimistic bias. No one had studied that before.”

While patients may understand the purpose of early-phase oncology trials, the optimistic bias they exhibit, said Dr. Jansen, is problematic because it may adversely affect the informed consent process. “When we talk about op-

NY State Law Mandates Discussion on End-of-life Care

E

arlier this year, the New York State legislature passed a law requiring physicians and nurse practitioners to talk to patients with an expected survival of less than 6 months about their options, including hospice care and aggressive vs palliative treatment, although patients can refuse to discuss end-of-life care if they choose. “The hope is that we would introduce the idea of palliative care and hospice care a little more routinely… [with] more emphasis on symptom control and on keeping a person comfortable,” said Jimmie C. Holland, MD, of Memorial Sloan-Kettering Cancer Center, New York.

■

timistic bias, we’re not suggesting that the understanding element has been impaired, but that the bias may compromise other elements of informed consent. It’s either affecting the way in which a person appreciates how the risks and benefits involved in a clinical trial affect him or, because the bias is distorting his judgment in some way, he is not fully voluntarily entering into the trial. That’s a bit more controversial,” said Dr. Jansen.

from a population frequency standpoint.

Dr. Jansen agrees. “When a person is asked, compared to other people participating in the same clinical trial, how likely are you to benefit, he should not be saying ‘above average.’ Or, with respect to experiencing health problems, he should not say ‘below average,’ be-

Improving Informed Consent The study results are prompting some physicians to consider improving the informed consent process, even though patients seem to understand both the purpose of the early oncology trials and the low likelihood of personal benefit to ensure that there are no bioethical lapses.

“Through more than a decade of heightened sensitivity and education around the ethical issues in phase I clinical trials, there has definitely been an improvement in the informed consent process, [but] I think that these findings highlight the need to develop better ways to affect the quality of informed consent,” said Neal J. Meropol, MD, the Lester E. Coleman, Jr. Professor of Cancer Research and Therapeutics and Chief, Division of Hematology and Oncology, University Hospitals Case Medical Center and Case Western Reserve University in Cleveland. “Merely asking patients what they think the potential benefit will be may not be an adequate measure of the quality of the informed consent process.” At a minimum, said Dr. Meropol, physicians need to ensure that patients understand the potential benefit—or harm—of early-phase trials

Neal J. Meropol, MD

cause… he shouldn’t think that there’s anything about himself that’s special. He should be saying, ‘I’m average. I should expect to experience all of these things as much as any other person in the trial.’

That’s the issue,” said Dr. Jansen.

Is Too Much Hope a Bad Thing?

The difference between being dispositionally optimistic (or having a general optimistic outlook) and being unrealistically optimistic, said Dr. Jansen, is that dispositionally optimistic patients are just hoping for the best, whereas unrealistically optimistic patients tend to distort risk and benefit information and how it applies to them. That distortion is potentially raising an ethical dilemma for physicians.

“From the standpoint of informed consent, the key feature is that the patient understands the facts. What we continued on page 36

The ASCO Post | SEPTEMBER 1, 2011

PAGE 36

Clinical Trials

‘Unrealistic Optimism’ Poses Ethical Challenges continued from page 35

don’t know at this point is the true meaning of an expression of optimism.

In other words, we still don’t know whether it’s a bad thing for patients to be optimistic. Also, what is the role of hope and optimism in the health of people facing life-threatening illnesses, and at what point, if any, is hope and optimism detrimental?” said Dr. Meropol.

odds, such reactions are not unusual at all,” said Dr. Holland. “People have a way of changing the information they’re hearing in a way to maintain hope. I

Coping Mechanism Jimmie C. Holland, MD, Wayne E. Chapman Chair in Psychiatric Oncology and Attending Psychiatrist at Memorial Sloan-Kettering Cancer Center in New York, says being hopeful when facing a critical illness like cancer is a positive coping mechanism, even if patients distort the facts of their treatment and potential outcome.

“I think that this discrimination between ‘optimism’ and ‘unrealistic optimism’ is not very healthy because it implies that unrealistic optimism is an aberration of normal emotions. But in situations when you’re SEE PAGE 39 facing tremendous

Brachytherapy Shows Quality-of-life Advantages continued from page 31

could explain the poor SPIRIT accrual rate, Dr. Crook replied, “It wasn’t just that they didn’t want to be randomly assigned to prostatectomy—they just didn’t want to be randomly assigned.

They talked to their friends. They talked to their family doctor. They talked to their urologist. They have preconceived notions of what is best for them, and a lot of that is based on anecdotes,” she said, such as hearing about men who had radical prostatectomy and were still wearing pads years later. “They take that as evidence they shouldn’t have surgery,

Jimmie C. Holland, MD

don’t think that people live well without some hope.”

According to Dr. Jansen, her optimism study helps researchers clarify the nature of hope. “Hope is not just one thing,” she commented. “When we talk about taking away hope, we first have to step back and ask ourselves, what kind of hope are we talking about? Some optimism, like dispositional optimism, is ethically benign, but other kinds of optimism may be ethically troubling. So when we talk about hope we probably do better to shift our attention to these different types of optimism and think about and it is hard to sway those opinions, no matter how much balanced information you give them,” she added. “But we were relatively successful in getting rid of the biases, as one in six eligible men who attended the educational sessions was actually randomized, and if people across North America had had the same success rate, we would have completed the trial.”

Consistent Results Although the number of patients who were randomly assigned was small (19%), the results among this group were consistent with those of the men who had selected their preferred treatment. “I think it shows that the people

what motivates people and the ways in which optimism can undermine the processing of risk-benefit information.”

Dr. Meropol also wonders whether patients with high levels of optimism suffer greater psychological problems when they do receive bad news than patients with a more balanced assessment of their situation. To find out, in collaboration with Kevin P. Weinfurt, PhD, Associate Professor in Psychiatry and Behavioral Sciences at Duke University School of Medicine, Dr. Meropol is co-leading a study of patients enrolled in phase I clinical trials to examine their expectations and the impact that initial optimism might have on their psychological well-being when they don’t have a positive treatment outcome.

Balancing Act Providing patients with the most accurate information about their cancer diagnosis while helping them maintain hope has always been a delicate balancing act for oncologists. And that challenge increases, said Dr. Meropol, when the patient’s disease worsens.

“There comes a point in the care of many patients when the goals of therapy change, and with that change who were randomly assigned to treatment were representative of the total population and lends credence to the results,” Dr. Crook said.

The median age of the men was 60 years (range, 45–73 years), with patients in the brachytherapy cohort being an average of 2 years older. No differences in the comorbidities assessed, including diabetes, heart disease, and hypertension, were seen between the men treated with brachytherapy and radical prostatectomy. Mean baseline PSA was similar (5.5 ng/mL for brachytherapy and 5.3 ng/mL for radical prostatectomy, P = .38), although mean baseline International Prostate Symptom Score (IPSS) was lower in the brachytherapy cohort (5.8 vs 8.6, P = .02). The median post-intervention PSA for both the radical prostatectomy and brachytherapy cohorts at the time of the report was < 0.5 ng/mL.

in goals, the targets of hope also have to be adjusted,” said Dr. Meropol.

“Oncologists need to be aware that patients will latch on to language that provides hope. We need to be especially balanced in our presentation of the facts in situations where the best possible outcome includes only a small potential magnitude of benefit and perhaps a higher likelihood of side effects. The key is to be aware of the patient’s decision-making calculus on the one hand, and on the other, of how the choice of language affects that patient.”

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Disclosure: Drs. Holland, Jansen, and Meropol reported no potential conflicts of interest.

Reference 1. Jansen LA, Appelbaum PS, Klein WMP, et al: Unrealistic optimism in earlyphase oncology trials. IRB 33:1-8, 2011.

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“One of the advantages of having a clinical trial and these education sessions is that patients basically had a personal navigator to get them through the system,” Dr. Crook explained. “Kris Wallace, the research assistant who is a coauthor on the paper, talked to these men on the phone to book them into the sessions, and talked to them afterwards. So they knew that whenever they had a problem or a question, they could call Kris and she would return their call and give them the information,” she said.

“That continuing relationship obviously helped with the response rate,” Dr. Crook continued. “When she contacted them again and said, ‘Would you be interested in answering this questionnaire? I know it has been 5 years, but we want to see how things are going,’ they were happy to do it.”

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Disclosure: Dr. Crook reported no potential conflicts of interest.

‘Relationship of Trust’ Among the 190 men treated, 168 responded to quality-of-life questionnaires—a response rate of 88.5%. Dr. Crook attributed the high response rate to the “relationship of trust” built between the investigators and patients.

Reference 1. Crook JM, Gomez-Iturriaga A, Wallace K, et al: Comparison of health-related quality of life 5 years after SPIRIT: Surgical Prostatectomy Versus Interstitial Radiation Intervention Trial. J Clin Oncol 29:362-368, 2010.

ASCOPost.com | SEPTEMBER 1, 2011

PAGE 37

In the Literature

Emerging Clinical Data on Cancer Management LUNG CANCER Identifying Genetic Factors That Predict Response to Chemotherapy in NSCLC A genetic variation in the chemokine-like receptor 1 (CMKLR1) gene was statistically significantly associated with poor overall survival in patients with non–small cell lung cancer (NSCLC) who were treated with platinum-based chemotherapy with or without radiation. The variation was identified by a genome-wide scan performed to identify genetic variants associated with decreased overall survival in these patients and was validated in patient populations of more than 300 each at The University of Texas MD Anderson Cancer Center in Houston and the Mayo Clinic. The patients had stage III or IV NSCLC, had smoked, and had not had surgery.

“This study provides additional biomarkers that can be integrated with known epidemiological, clinical, and genetic risk factors to potentially identify patients who are more likely to respond to chemotherapy, thereby helping the physician develop individualized treatment regimens,” the investigators concluded in a report in the Journal of the National Cancer Institute. They noted that response to platinum-based chemotherapy, the main treatment for NSCLC, varies among patients, but the 1-year survival rate is just 29%.

The potential biomarker is a germline genetic variation known as single-nucleotide polymorphism (SNP) rs1878022. “Germline SNPs are stable markers that do not vary with disease severity and can be screened for using DNA isolated from a blood sample before treatment,” the investigators noted. In contrast, somatic alterations, which can also help select targeted therapy, require tumor specimens.

Wu X, et al: J Natl Cancer Inst 103:817825, 2011.

PROSTATE CANCER Androgen Deprivation Therapy plus Radiotherapy Increases Survival in Men with Localized Prostate Cancer The addition of short-term androgen deprivation therapy to radiotherapy for men with stage T1b, T1c, T2a, or T2b prostate adenocarcinoma and

a prostate-specific antigen (PSA) level of 20 ng/mL or less “conferred a modest but significant increase in the 10-year rate of overall survival, from 57 to 62%,” investigators reported.

“This increase was accompanied by a significant reduction in 10-year dis-

ease-specific mortality from 8% to 4% as well as reductions in the secondary endpoints of biochemical failure, distant metastases, and the rate of positive findings on repeat prostate biopsy at 2 years,” they added.

Radiation Therapy Oncology

Group (RTOG) trial 94-08, summarized in an article in The New England Journal of Medicine, randomly assigned 992 patients to radiotherapy alone and 987 patients to radiotherapy with 4 months of total androgen continued on page 38

The ASCO Post | SEPTEMBER 1, 2011

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In the Literature

Emerging Clinical Data continued from page 37

suppression starting 2 months before radiotherapy. The total radiation dose was 66.6 Gy to the isocenter. Androgen deprivation therapy consisted of flutamide at 250 mg orally three times a day and either monthly subcutaneous goserelin (Zoladex) at 3.6 mg or intramuscular leuprolide at 7.5 mg for 4 months. Flutamide was discontinued if alanine aminotransferase increased to more than twice the upper limit of the normal range.

Risk-Benefit Considerations “The efficacy gains were achieved with minimal temporary acute hepatic toxic effects and some decreased erectile function at 1 year, but with no increased risk of death from intercurrent disease, serious cardiovascular toxic effects, or acute or long-term gastrointestinal or genitourinary complications of radiotherapy. The rate of erectile dysfunction observed in this study is similar to that reported in previous studies that involved the use of similar doses of radiotherapy,” the authors noted.

“Reanalysis of the data according to risk subgroups showed that the gains in overall survival and reductions in disease-specific mortality were mainly limited to men in the intermediate-risk subgroup,” they added.

“Although combined therapy appears to be indicated in men with intermediate-risk disease, whether a radiation dose of more than 66.6 Gy or longer durations of hormonal therapy can reduce mortality further is unknown,” Anthony V. D’Amico, MD, PhD, commented in an accompanying editorial. “Whether 4 or 6 months of hormonal therapy for intermediate-risk disease is best requires further study.”

Jones CU, et al: N Engl J Med 365:107118, 2011.

D’Amico AV: N Engl J Med 365:169171, 2011.

BLADDER CANCER Neoadjuvant Chemotherapy with CMV Improves Outcome for Invasive Bladder Cancer Long-term results from a phase III trial show that neoadjuvant chemotherapy with CMV (cisplatin, methotrexate, and vinblastine) improves the outcome for patients with muscle-invasive urothelial cancer of the bladder treated by cystectomy and/or radiotherapy.

“Three cycles of CMV before cystectomy or radiotherapy results in a 16% reduction in the risk of death, corresponding to an increase in 3-year survival from 50% to 56%, 10-year survival from 30% to 36%, and median survival time of 7 months (from 37 to 44 months),” the investigators reported in the Journal of Clinical Oncology. The median followup was 8.0 years. Based on these results and two other large randomized trials that confirmed a “statistically significant and clinically relevant survival benefit,” the authors concluded, “neoadjuvant chemotherapy followed by definitive local therapy should be viewed as state of the art, as compared with cystectomy or radiotherapy alone, for deeply invasive bladder cancer.”

The international multicenter trial randomly assigned 976 patients with histologically proven muscle-invasive urothelial cell carcinoma of the bladder (T2 grade 3, T3, or T4a and N0/X, M0) to three cycles of CMV (n = 491) or no chemotherapy (n = 485). “The choice of definitive treatment used in this trial was based on patient or physician choice and was not randomly assigned, and the trial was designed explicitly not to compare various definitive local treatments,” the investigators reported. “Thus, no conclusions should be drawn from the data presented concerning the relative merit of cystectomy compared with radiotherapy.”

The authors noted, “more than 70% of participating clinicians were

of the opinion that an improvement in survival of 10% would be needed to justify the use of neoadjuvant CMV in routine practice. This magnitude of benefit has not been achieved with this trial, which shows, along with the meta-analysis published in 2005 by the Advanced Bladder Cancer Collaboration, a clear benefit in overall survival of only 5% to 6% at 3 years.”

The increase in survival that was seen “will need to be balanced against the toxicity and other disadvantages of chemotherapy (eg, the cost to the patient in terms of treatment time and impact on quality of life),” the authors stated. Five patients assigned to CMV died from toxic effects during treatment in the study, a morality rate of 1%, and 26% experienced impaired renal function requiring dose decreases or delay. Grade 3 or 4 toxic effects included leukopenia in 16% of patients, neutropenic fever in 10%, and thrombocytopenia in 6.5%.

International Collaboration of Trialists: J Clin Oncol 29:2171-2177, 2011.

COLON CANCER Surgical Site Infections after Colectomy More Likely in Obese Patients Obese patients appear to have a significantly increased risk of developing a surgical site infection after segmental or total colectomy for colon cancer, diverticulitis, or inflammatory bowel disease, and the presence of infection increases the cost associated with the procedure, according to a report posted online and scheduled for publication in the September issue of Archives of Surgery.

“We chose to study colectomy as a standardized procedure because the risk of [surgical site infection] following this procedure is known to be greater than that following other abdominal procedures,” wrote Elizabeth C. Wick, MD, and colleagues, of the Johns Hop-

kins University School of Medicine and Johns Hopkins Bloomberg School of Public Health, Baltimore. They evaluated surgical site infection rates among obese and nonobese colectomy patients using claims data from 7,020 members of eight different Blue Cross Blue Shield insurance plans.

Among these patients, 1,243 were identified as obese (body mass index ≥ 30) and 5,777 were classified as nonobese. The overall rate of surgical site infection was 10.3%, with obese patients experiencing a higher rate, 14.5%, compared to 9.5% for nonobese patients. After adjusting for laparoscopy, diagnosis, gender, and age, obesity was the strongest predictor of surgical site infection, with obese patients experiencing a 60% increased risk compared to nonobese patients.

Relative Costs The mean cost of colectomy was $16,399, but approximately $295 more for obese patients. On average, developing a postoperative surgical site infection was associated with increased cost of the colectomy ($31,933 for patients with infection vs $14,608 for patients without infection), increased length of hospital stay (average of 9.5 days vs 8.1 days), and a significantly higher rate of hospital readmission (27.8% vs 6.8%).

The authors concluded that patients undergoing colorectal surgery who develop surgical site infections, many of whom are obese, tax the health-care system. “Pay-for-performance policies in surgery should account for the increased risk of infection and cost of caring for this population. Failure to consider these differences could lead to perverse incentives that may penalize surgeons who care for obese patients and may even affect obese patients’ access to colorectal surgery,” they said.

Coming in the September 15, 2011 Issue of The ASCO Post ■■ Important Oncology News from Meetings Worldwide

■■ More on the Oncology Drug Shortage

■■ Original Columns and Perspectives from Oncology Leaders ■■ Palliative Care, Quality of Life, and Cost

Plus important columns, features, and clinical departments.

Visit The ASCO Post online at ASCOPost.com.

■

Wick EC, et al: Arch Surg. May 16, 2011 (early release online).

ASCOPost.com | SEPTEMBER 1, 2011

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Opinion

Fixing the Drug Shortage continued from page 2

germ testis cancer, one could insert ifosfamide in place of bleomycin, but that introduces an added potential carcinogen, and involves meddling with a regimen that works (and works well). For acute leukemia, there are many options, although most of the available regimens are heavily compromised by the extant drug shortages.

To their credit, Senators Amy Klobuchar (D-MN) and Robert Casey (D-PA), and Representatives Diana DeGette (D-CO) and Tom Rooney (R-FL) have introduced a bill into both houses—the Preserving Access to Life-Saving Medications Act (S.296)—which begins to cover some of the issues, and requires Step Up the the pharmaceutiPace cal industry to noWhenever federal As usual, we sit tify government by, passively grumof impending elections loom, our bling, worrying shortages. As is so politicians listen just about our patients, often the case, this a bit more carefully. and concerned now has to work about the chalits way through Legislation can fix lenging decisions both houses, with this problem. we need to make a time limitation to compensate for of 1 year. How an industry that many patients will is behaving irresponsibly. Because of die of cancer in the meantime? the current legislation (or lack thereThe Challenge of Prioritizing of), this is one issue that the FDA just I work in the Carolinas HealthCare cannot fix.

System, with its 33 hospitals, and we The pharmaceutical industry has see more than 11,000 new cases of had years to find a solution to this cancer a year. This gives us negotiatproblem, and has failed. It’s time for ing power for acquisition of drugs, as ASCO, and our other professional well as the ability to move medicaorganizations, as well as the various tions around the system, to areas of patient advocacy groups, to step up greatest need. Our chief pharmacist, the pace. Whenever federal elections Steve Jarrett, and his team, have been loom, our politicians listen just a bit outstanding in riding shotgun over more carefully. Legislation can fix this this issue, watching supplies, negotiproblem. ating to get drugs, warning the oncolReferences ogy staff of impending shortages…

1. Horwich A, Sleijfer DT, Fosså SD, and hoping that someone in authoret al: Randomized trial of bleomycin, ity out there will fix the problem. He etoposide, and cisplatin compared with and I have convened a system-wide bleomycin, etoposide, and carboplatin in committee that is able to help priorigood-prognosis metastatic nonseminomatize and manage available supplies of tous germ cell cancer: A Multiinstitutional agents.

Medical Research Council/European OrHowever, how does one prioriganization for Research and Treatment of tize between a patient with Hodgkin Cancer Trial. J Clin Oncol 15:1844-1852, disease who is due to receive ABVD 1997. (doxorubicin, bleomycin, vinblas2. Levi JA, Raghavan D, Harvey V, et tine, dacarbazine) and a patient with al: The importance of bleomycin in combination chemotherapy for good-prognosis metastatic testis cancer who is due germ cell carcinoma. Australasian Germ to receive PEB (cisplatin, etoposide, Cell Trial Group. J Clin Oncol. 11:1300bleomycin) chemotherapy? Some1305, 1993. times there are other options—in

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How Is the Oncology Drug Shortage Affecting Your Practice?

To report information on how oncology drug shortages are affecting your practices, contact:

■■ ASCO at publicpolicy@asco.org or 571-483-1368.

■■ FDA at drugshortages@fda.hhs.gov.

■■ ASHP at http://www.ashp.org/DrugShortages/Report/

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