JULY 2011, VOL2, NO 4 by Value-Based Cancer Care

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JULY 2011 VOL 2 NO 4

www.ValueBasedCancerCare.com

INTRODUCTION

AVBCC First Stakeholder Integration Conference Cancer care in 2011—the perfect storm By Burt Zweigenhaft, BS, and Gary M. Owens, MD, Cochairs Mr Zweigenhaft is President and Chief Executive Officer, OncoMed, and Dr Owens is President, Gary Owens Associates

n 2011 we find ourselves in the midst of a “perfect storm” as it relates to cancer care in the United States. More people are being diagnosed with cancer, more patients are living longer with cancer, and the cost of caring for cancer is rising dramatically.

The Perfect Storm Rising cancer cases. According to the American Cancer Society, in 2010 >1.5 million new cases of cancer (excluding carcinoma in situ and basalcell skin cancers) and nearly 570,000 deaths occurred from cancer.1 Cancer is responsible for 1 in 4 deaths in the United States and is the leading cause of death for individuals age <85 years. The sheer number of cancer cases in the United States represents the first arm of the perfect storm.

Value-Based Insurance Design in Oncology Incentivize high-value rather than low-value services to curb costs By Wayne Kuznar Philadelphia, PA—The “one-size-fitsall” approach to current benefit designs does not recognize that health services have different levels of value; such an approach, therefore, lacks incentives for patients to adhere to diagnostic tests and treatments with proven effectiveness that may help to contain costs to various healthcare stakeholders.

This was the message delivered by A. Mark Fendrick, MD, Professor, Department of Internal Medicine, Department of Health Management and Policy, and Founder and CoDirector, University of Michigan Center for Value-Based Insurance Design, Ann Arbor. Continued on page 7

Payer Trends in Oncology: Challenges and Solutions Rising cancer costs. Advances in our understanding of the molecular and genetic mechanisms of tumor growth are expanding the treatment horizons, but these advances come at a rising cost, and this cost represents the second arm of the perfect storm. In a June 2011 article published in the New York Times, the author notes that the cost of treating metastatic castrationresistant prostate cancer has increased

Reducing care variability will enhance value By Wayne Kuznar

Continued on page 5

The First Annual Conference of AVBCC

n March 29-30, 2011, approximately 200 oncologists, payers, employers, managed care executives, drug manufacturers, and cancer patient advocates gathered in Philadelphia for the First Annual Conference of the Association for Value-Based Cancer Care (AVBCC), which focused on stakeholder integration toward the enhancement of patient care and care delivery. Reflecting on the conference after the meeting, Al B. Benson III, MD, said, “This type of communication has great potential for each of these groups to understand where each component is coming from and understand each other’s issues.” This issue of VBCC is dedicated to coverage of the conference, providing summaries of all the major presentations and interviews, highlighting the yearning for a strong spirit of cooperation exhibited by the various stakeholders involved in cancer care. Plan to attend future meetings. The “best of” this meeting will be coming to your area soon. See page 55 for more details.

From left: Maria Lopes, Scott Breidbart, Mona Chitre, Nick Calla.

Philadelphia, PA—As the cost of cancer care continues to rise, payers are struggling with solutions to curtail the cost trend while maintaining value. This was the topic of the preconference session, which opened the 2-day First Annual Conference of the Association for Value-Based Cancer Care on March 29, 2011. The cost of cancer care is on everyone’s front burner, said moderator Burt Zweigenhaft, BS, President and Chief Executive Officer at OncoMed,

Great Neck, NY. “We’ve seen the average cost per cancer patient go from $53,000 [in 2005] to $115,000 [in 2010],” he said. “That’s unsustainable. That’s why it’s on everyone’s radar.” Employers Looking for Value Employers are increasingly asking about the value received for their money spent on cancer care, said Mona Chitre, PharmD, CGP, Director of Clinical Services, Strategy and Policy, Continued on page 8

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THE FIGHT IS CHANGING. It’s more personal than ever. Now, genetic biomarker tests may help deliver the right cancer treatment to the right patient. Bio-specific medicine is changing the way we treat cancer. In many instances, doctors can now test a tumor’s distinct profile with the goal of providing more targeted, more effective treatments with fewer side effects. The battle is being redefined. And it starts by testing. See how at www.canceritspersonal.com

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IN THIS ISSUE

Publisher Nicholas Englezos nick@engagehc.com 732-992-1884 Associate Publisher Maurice Nogueira maurice@engagehc.com 732-992-1895 Editorial Director Dalia Buffery dalia@engagehc.com 732-992-1889 Associate Editors Brett Kaplan brett@engagehc.com Lara Reiman lara@engagehc.com 732-992-1892 Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896 Senior Production Manager Robyn Jacobs Quality Control Director Barbara Marino Business Manager Blanche Marchitto

Mission Statement Value-Based Cancer Care provides a forum for payers, providers, and the entire oncology team to consider the cost-value issues particular to cancer treatments. This unique focus is achieved through news coverage from major hematology/oncology meetings and the cancer literature, supplemented with commentaries and perspectives from those involved in evaluating therapies, treating patients, and paying for care. BPA Worldwide membership applied for August 2010. Contact Information: For subscription information please contact: circulation@valuebasedcancercare.com Telephone: 732-992-1538 Fax: 732-992-1881 Permission requests to reprint all or part of any article published in this magazine should be addressed to editorial@valuebasedcancercare.com Address all editorial queries to: editorial@valuebasedcancercare.com Telephone: 732-992-1889 Fax: 732-992-1881 Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 7 times a year by Engage Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Copyright © 2011 by Engage Healthcare Communications, LLC. All rights reserved. Value-Based Cancer Care is a registered trademark of Engage Healthcare Communications, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America. The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication. Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 241 Forsgate Drive, Suite 205A, Monroe Township, NJ 08831. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

DIAGNOSTICS

REIMBURSEMENT IN ONCOLOGY

Role of Molecular Diagnostics in Cancer Care

Drug Reimbursement and Administration Benchmarks More….

ONCOLOGY BENEFIT DESIGN Benefit Design Trends in Oncology More….

HEALTH POLICY

NCCN GUIDELINES

Global Fees, ACOs, and Medicare Trends More….

NCCN Guidelines Inform Decisions Across the Care Continuum More….

Medical and Pharmacy Directors’ Strategies

CARE MANAGEMENT MODELS

PERSONALIZED MEDICINE

SPECIALTY PHARMACY

Personalized Oncology Medicine: Value Implications

Clinical Fragmentation More….

COMMUNITY ONCOLOGY

CONTINUING EDUCATION

Oncology Clinics under Increasing Financial Pressure Oncologists Face Economic Challenges More….

Evolving Role of Outcomes and End Points in Evaluating Therapy for Hematologic Malignancies

PATIENT NAVIGATION Patient Assistance Programs

VBCC Editorial Board Al B. Benson III, MD, FACP Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University Chicago, IL Immediate Past President, ACCC Past Chair, NCCN Board of Directors Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, NY Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA Craig Deligdish, MD Florida Comprehensive Cancer Network, Melbourne, FL Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers Pittsburgh, PA Arlene A. Forastiere, MD ITA Partners Philadelphia, PA Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

VALUE-BASED CANCER CARE

July 2011

Section Editor

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT David Hom, MBA Solucia Farmington, CT Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL Ira Klein, MD, MBA Aetna Hartford, CT Crystal Kuntz, MPA Astellas Pharma US Washington, DC Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN Lynn Nishida, RPh Regence BlueCross BlueShield of Oregon Portland, OR

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Ted Okon, BS, MBA Executive Director Community Oncology Alliance

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA

Naimish Pandya, MD University of Maryland Baltimore, MD

Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY

Ed Pezalla, MD, MPH Aetna Pharmacy Management Hartford, CT

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INTRODUCTION

AVBCC First Conference... Continued from cover dramatically in the past year. In the past 15 months, 3 new drugs that extended the lives of patients with prostate cancer in clinical trials have been approved by the US Food and Drug Administration, and several other promising medicines are in clinical trials. However, “the price of these drugs has already stirred concerns about the costs of care among patients, providers, and insurers.”2 With many pricey drugs in the pipeline, said Joel Sendek, an analyst at Lazard, “We could be talking easily $500,000 per patient or more over the course of therapy, which I don’t think the system can afford, especially since 80% of the patients are on Medicare.”2 This concern is not unique to this author. In a 2009 article, Peter Bach noted that in 1994, only 1 cancer drug— paclitaxel—cost >$2500 per month.3 As in the case of prostate cancer, new cancer drugs now routinely cost many times more. Mr Bach further notes that policymakers at the Centers for Medicare & Medicaid Services must be concerned about how to pay for these new and expensive treatments without bankrupting the system.3 Aging population. In a January 2011 article published in the Journal of the National Cancer Institute, the authors estimated that the total cost of cancer care in the United States would be $158 billion by 2020, assuming that the most recent trends of incidence, survival, and cost remain the same.4 This estimate represents a 27% increase from 2010, reflecting only the projected aging and growth of the US population. This demographic change is yet the third aspect of cancer’s perfect storm.4 AVBCC Conference Accomplishments These statistics highlight only a few of the issues that provided the backdrop for the First Conference of the Association for Value-Based Cancer Care, which convened on March 29-30, 2011, in Philadelphia. The meeting was among the first of its kind to provide a forum for the multiple stakeholders involved in all aspects of cancer care. The goal was to foster an open dialogue between providers, payers, patients, and other members of the oncology team to gain a better understanding of the issues regarding cost, quality, and access in cancer care. The participants had the opportunity to: • Identify challenges and potential solutions regarding access to affordable oncology therapies • Determine the value proposition of cost, quality, and access when evaluating the overall management

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The meeting was among the first of its kind to provide a forum for the multiple stakeholders involved in all aspects of cancer care.

of patients with cancer • Define appropriate clinical pathways to be used as tools to evaluate the current recommendations for patient management Continued on page 6

Help reduce the risk of infection in patients receiving moderate-risk* chemotherapy regimens

Act before febrile neutropenia strikes Potential consequences of febrile neutropenia may be serious and can impact patient care First- and every-cycle Neulasta® achieved: Q 94% reduction in febrile neutropenia (17% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 93% reduction in febrile neutropenia– related hospitalization (14% placebo vs 1% Neulasta®; P < 0.001).1,2 Q 80% reduction in febrile neutropenia– related IV anti-infective use (10% placebo vs 2% Neulasta®; P < 0.001).1,2

Neulasta® (pegfilgrastim) is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anti-cancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta® is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation.

Important Safety Information Do not administer Neulasta® to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Splenic rupture, including fatal cases, can occur following the administration of Neulasta®. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta®. Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta®. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta® for ARDS. Discontinue Neulasta® in patients with ARDS. Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta®. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta® in patients with serious allergic reactions. Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta®. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. The granulocyte colony-stimulating factor (G-CSF) receptor, through which pegfilgrastim and filgrastim act, has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded. Bone pain and pain in extremity occurred at a higher incidence in Neulasta®-treated patients as compared with placebotreated patients. Please see brief summary of Neulasta® Prescribing Information on the adjacent page. *Regimens associated with ≥ 17% risk of febrile neutropenia. References: 1. Vogel C, et al. J Clin Oncol. 2005;23:1178-1184. 2. Neulasta® (pegfilgrastim) Prescribing Information. Thousand Oaks, Calif: Amgen. © 2010 Amgen. All rights reserved.

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INTRODUCTION

AVBCC First Conference...

Continued from page 5

• Analyze trends in the delivery of care for patients with cancer. Some of the many timely topics presented in this issue are: • Community Oncology Clinics under Increasing Financial Pressure

• Payer Trends in Oncology: Challenges and Solutions • Value-Based Insurance Design in Oncology • The Role of Molecular Diagnostics in Cancer Treatment.

BRIEF SUMMARY OF PRESCRIBING INFORMATION Neulasta® (pegﬁlgrastim) injection, for subcutaneous use

randomized, double-blind, placebo-controlled study in patients with metastatic or non-metastatic breast cancer receiving docetaxel 100 mg/m2 every 21 days. (Study 3). A total of 928 patients were randomized to receive either 6 mg Neulasta (n = 467) or placebo (n = 461). The patients were 21 to 88 years of age and 99% female. The ethnicity was 66% Caucasian, 31% Hispanic, 2% Black, and < 1% Asian, Native American or other. Bone pain and pain in extremity occurred at a higher incidence in Neulasta-treated patients as compared with placebo-treated patients. Table 1. Adverse Reactions With ≥ 5% Higher Incidence in Neulasta Patients Compared to Placebo in Study 3

INDICATIONS AND USAGE Neulasta is indicated to decrease the incidence of infection, as manifested by febrile neutropenia, in patients with nonmyeloid malignancies receiving myelosuppressive anticancer drugs associated with a clinically significant incidence of febrile neutropenia. Neulasta is not indicated for the mobilization of peripheral blood progenitor cells for hematopoietic stem cell transplantation. CONTRAINDICATIONS Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. WARNINGS AND PRECAUTIONS Splenic Rupture Splenic rupture, including fatal cases, can occur following the administration of Neulasta. Evaluate for an enlarged spleen or splenic rupture in patients who report left upper abdominal or shoulder pain after receiving Neulasta. Acute Respiratory Distress Syndrome Acute respiratory distress syndrome (ARDS) can occur in patients receiving Neulasta. Evaluate patients who develop fever and lung infiltrates or respiratory distress after receiving Neulasta, for ARDS. Discontinue Neulasta in patients with ARDS. Serious Allergic Reactions Serious allergic reactions, including anaphylaxis, can occur in patients receiving Neulasta. The majority of reported events occurred upon initial exposure. Allergic reactions, including anaphylaxis, can recur within days after the discontinuation of initial anti-allergic treatment. Permanently discontinue Neulasta in patients with serious allergic reactions. Do not administer Neulasta to patients with a history of serious allergic reactions to pegfilgrastim or filgrastim. Use in Patients With Sickle Cell Disorders Severe sickle cell crises can occur in patients with sickle cell disorders receiving Neulasta. Severe and sometimes fatal sickle cell crises can occur in patients with sickle cell disorders receiving filgrastim, the parent compound of pegfilgrastim. Potential for Tumor Growth Stimulatory Effects on Malignant Cells The granulocyte-colony stimulating factor (G-CSF) receptor through which pegfilgrastim and filgrastim act has been found on tumor cell lines. The possibility that pegfilgrastim acts as a growth factor for any tumor type, including myeloid malignancies and myelodysplasia, diseases for which pegfilgrastim is not approved, cannot be excluded.

System Organ Class Preferred Term

Placebo (N = 461)

Neulasta 6 mg SC on Day 2 (N = 467)

Musculoskeletal and connective tissue disorders Bone pain 26% 31% Pain in extremity 4% 9%

Leukocytosis In clinical studies, leukocytosis (WBC counts > 100 x 109/L) was observed in less than 1% of 932 patients with nonmyeloid malignancies receiving Neulasta. No complications attributable to leukocytosis were reported in clinical studies. Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. Binding antibodies to pegfilgrastim were detected using a BIAcore assay. The approximate limit of detection for this assay is 500 ng/mL. Pre-existing binding antibodies were detected in approximately 6% (51/849) of patients with metastatic breast cancer. Four of 521 pegfilgrastim-treated subjects who were negative at baseline developed binding antibodies to pegfilgrastim following treatment. None of these 4 patients had evidence of neutralizing antibodies detected using a cell-based bioassay. The detection of antibody formation is highly dependent on the sensitivity and specificity of the assay, and the observed incidence of antibody positivity in an assay may be influenced by several factors, including assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Neulasta with the incidence of antibodies to other products may be misleading. Postmarketing Experience The following adverse reactions have been identified during post approval use of Neulasta. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal ADVERSE REACTIONS The following serious adverse reactions are discussed in greater relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following detail in other sections of the Brief Summary: factors: (1) seriousness of the reaction, (2) reported frequency • Splenic Rupture [See Warnings and Precautions] of the reaction, or (3) strength of causal relationship to Neulasta. • Acute Respiratory Distress Syndrome [See Warnings Gastro-intestinal disorders: Splenic rupture [see Warnings and Precautions] and Precautions] • Serious Allergic Reactions [See Warnings and Precautions] Blood and lymphatic system disorder: Sickle cell crisis • Use in Patients with Sickle Cell Disorders [See Warnings [see Warnings and Precautions] and Precautions] Hypersensitivity reactions: Allergic reactions/hypersensitivity, • Potential for Tumor Growth Stimulatory Effects on Malignant including anaphylaxis, skin rash, and urticaria, Sweet’s Cells [See Warnings and Precautions] syndrome, generalized erythema and flushing [see Warnings The most common adverse reactions occurring in ≥ 5% of and Precautions] patients and with a between-group difference of ≥ 5% higher Respiratory, thoracic, and mediastinal disorder: ARDS in the pegfilgrastim arm in placebo controlled clinical trials [see Warnings and Precautions] are bone pain and pain in extremity. General disorders and administration site conditions: Clinical Trials Experience Injection site reactions Because clinical trials are conducted under widely varying Skin and subcutaneous tissue disorders: Cutaneous vasculitis conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical DRUG INTERACTIONS trials of another drug and may not reflect the rates observed in No formal drug interaction studies between Neulasta and other drugs have been performed. Increased hematopoietic activity clinical practice. Neulasta clinical trials safety data are based upon 932 patients of the bone marrow in response to growth factor therapy may result in transiently positive bone-imaging changes. Consider receiving Neulasta in seven randomized clinical trials. The these findings when interpreting bone-imaging results. population was 21 to 88 years of age and 92% female. The ethnicity was 75% Caucasian, 18% Hispanic, 5% Black, and USE IN SPECIFIC POPULATIONS 1% Asian. Patients with breast (n = 823), lung and thoracic Pregnancy tumors (n = 53) and lymphoma (n = 56) received Neulasta Pregnancy Category C after nonmyeloablative cytotoxic chemotherapy. Most patients There are no adequate and well-controlled studies in pregnant received a single 100 mcg/kg (n = 259) or a single 6 mg women. Pegfilgrastim was embryotoxic and increased pregnancy (n = 546) dose per chemotherapy cycle over 4 cycles. loss in pregnant rabbits that received cumulative doses approximately 4 times the recommended human dose (based on The following adverse reaction data in Table 1 are from a

VALUE-BASED CANCER CARE

July 2011

These proceedings represent a firstin-class effort to open the lines of communication among all stakeholders in cancer care. This meeting was unique in bringing together different viewpoints from many oncology stakeholders,

body surface area). Signs of maternal toxicity occurred at these doses. Neulasta should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. In animal reproduction studies, when pregnant rabbits received pegfilgrastim at cumulative doses approximately 4 times the recommended human dose (based on body surface area), increased embryolethality and spontaneous abortions occurred. Signs of maternal toxicity (reductions in body weight gain/food consumption) and decreased fetal weights occurred at maternal doses approximately equivalent to the recommended human dose (based on body surface area). There were no structural anomalies observed in rabbit offspring at any dose tested. No evidence of reproductive/developmental toxicity occurred in the offspring of pregnant rats that received cumulative doses of pegfilgrastim approximately 10 times the recommended human dose (based on body surface area). Women who become pregnant during Neulasta treatment are encouraged to enroll in Amgen’s Pregnancy Surveillance Program. Patients or their physicians should call 1-800-77-AMGEN (1-800-772-6436) to enroll. Nursing Mothers It is not known whether pegfilgrastim is secreted in human milk. Other recombinant G-CSF products are poorly secreted in breast milk and G-CSF is not orally absorbed by neonates. Caution should be exercised when administered to a nursing woman. Pediatric Use Safety and effectiveness of Neulasta in pediatric patients have not been established. The adverse reaction profile and pharmacokinetics of pegfilgrastim were studied in 37 pediatric patients with sarcoma. The mean (± standard deviation [SD]) systemic exposure (AUC0-inf) of pegfilgrastim after subcutaneous administration at 100 mcg/kg was 22.0 (± 13.1) mcg·hr/mL in the 6 to 11 years age group (n = 10), 29.3 (± 23.2) mcg·hr/mL in the 12 to 21 years age group (n = 13), and 47.9 (± 22.5) mcg·hr/mL in the youngest age group (0 to 5 years, n = 11). The terminal elimination half-lives of the corresponding age groups were 20.2 (± 11.3) hours, 21.2 (± 16.0) hours, and 30.1 (± 38.2) hours, respectively. The most common adverse reaction was bone pain. Geriatric Use Of the 932 patients with cancer who received Neulasta in clinical studies, 139 (15%) were age 65 and over, and 18 (2%) were age 75 and over. No overall differences in safety or effectiveness were observed between patients age 65 and older and younger patients. Renal Impairment In a study of 30 subjects with varying degrees of renal dysfunction, including end stage renal disease, renal dysfunction had no effect on the pharmacokinetics of pegfilgrastim.Therefore, pegfilgrastim dose adjustment in patients with renal dysfunction is not necessary. DOSAGE AND ADMINISTRATION The recommended dosage of Neulasta is a single subcutaneous injection of 6 mg administered once per chemotherapy cycle in adults. Do not administer Neulasta between 14 days before and 24 hours after administration of cytotoxic chemotherapy. Visually inspect parenteral drug products for particulate matter and discoloration prior to administration, whenever solution and container permit. Do not administer Neulasta if discoloration or particulates are observed. NOTE: The needle cover on the single-use prefilled syringe contains dry natural rubber (latex); persons with latex allergies should not administer this product. This product, its production, and/or its use may be covered by one or more US Patents, including US Patent Nos. 5,824,784; 5,582,823; 5,580,755, as well as other patents or patents pending.

Neulasta® (pegfilgrastim) Manufactured by: Amgen Inc. One Amgen Center Drive Thousand Oaks, California 91320-1799 © 2011 Amgen Inc. All rights reserved. www.neulasta.com 1-800-77-AMGEN (1-800-772-6436) v 12.0

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such as health plans, pharmacy benefit managers, providers, patients, government, manufacturers, and caregivers. Ultimately, the conference enabled stakeholders to share their own views of the world of oncology care and gain an understanding of the views of other stakeholders who also have a part in cancer care. Opening the lines of communication among stakeholders with differing viewpoints in oncology was a major accomplishment of the conference. This allowed for sharing of issues that are critical to facilitating the best care possible for patients with cancer. Ultimately, all stakeholders shared the common goal of finding solutions to the growing concerns in cancer care, while understanding the need to optimize the clinical and economic value of the resources expended. ■ References 1. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 2. Pollack A. New drugs fight prostate cancer, but at high cost. New York Times. June 28, 2011. www.nytimes. com/2011/06/28/health/28prostate.html?_r=2&hp. Accessed June 28, 2011. 3. Bach PB. Limitations on Medicare’s ability to control rising spending on cancer drugs. N Engl J Med. 2009;360:626-633. 4. Mariotto AB, Yabroff KR, Shao Y, et al. Projections of the cost of cancer care in the United States: 2010-2020. J Natl Cancer Inst. 2011;103:117-128.

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VALUE-BASED INSURANCE

Value-Based Insurance Design... With current benefit designs, argued Dr Fendrick, copayments, premiums, and deductibles are similar no matter the value of the service rendered. This misalignment of incentives fails to encourage utilization of high-value treatments and discourage utilization of low-value treatments. By properly aligning incentives, patient outcomes can be improved at any level of healthcare expenditure, Dr Fendrick says. “If you move from current benefit design systems to one that is value-based, I could give you first class for the price of coach.” With cost remaining the principal focus of healthcare deliberations, the “health” portion of the healthcare cost debate seems to have been forgotten, he says. “Too many are trying to drive down cost, without any consideration of the product—the health of our patients, clients, and family members,” Dr Fendrick emphasizes. When oncologists or physician extenders are asked which health services are underutilized, they mention high-value screenings, diagnostic tests, therapies, and monitoring/follow-up tests. The probability of receiving such high-value services is no better than a coin flip for most Americans, says Dr Fendrick. These quality gaps are costing payers: an extra $500 million is spent on healthcare because evidence-based practices are not followed. He implores all stakeholders to encourage widespread implementation of evidence-based clinical practices and to look beyond the initial cost of implementing such services. A redistribution of $2.5 trillion spent annually on healthcare in this country could catapult the United States to number one in healthcare metrics among industrialized countries, he argues, as opposed to last—the position it now occupies. The Rationale for VBID “There are meaningful ways to redistribute money we have in the system to bring about more health at the price we are paying now—the motivation behind value-based health insurance design [VBID],” says Dr Fendrick. Many previous strategies to lower costs have not lived up to their hype, he insists. Managed care and information technology have not produced the cost-savings promised, and although patient-centered medical homes are likely to improve quality of care and value, they are not likely to lower costs. Cost-sharing—how much patients pay at the point of service for various

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interventions—in most health plans, public and private, has been implemented in a one-size-fits-all way, meaning that every physician visit costs the same. “Whether you see the top oncologist for a treatable cancer costs the same as seeing a dermatologist for mild acne that I could barely see,” he says. “Every diagnostic test costs the same, whether it is a US Preventive Services Task Force Grade A recommended service or ‘D,’ as in dangerous.”

“This misalignment of incentives fails to encourage utilization of high-value treatments and discourage utilization of low-value treatments.” —A. Mark Fendrick, MD

The same is true for drug tiers; patients pay the same out-of-pocket (OOP) amount for drugs in the same tier, regardless of their value. In some plans, all generic drugs may cost as little as $4. “There are some generic drugs I would pay my patients to take,” given the extraordinary benefit they provide, notes Dr Fendrick, whereas others in the same generic tier may have little value. One problem with this practice is that most patients have no way to distinguish a drug that is potentially lifesaving from one that has no benefit or, in some rare circumstances, may actually be harmful. Oncologists cite similar coinsurance for drugs of different value as a major inefficiency. For example, the coinsurance for a drug that can cure a cancer is the same as for one used in a late

round of chemotherapy with practically no chance for a cure. Removing Barriers to High-Value Services Financial hurdles to proven cancerscreening tests also create disincentives for patients. One example is the woman with multiple family members with breast cancer having to pay a high cost for a mammogram. Another is the patient with familial polyposis being asked to pay 20% of the cost of a colonoscopy. In both instances, the copayment discourages use of the screening test in populations that payers want to screen. Consumer-directed high-deductible health plans were considered to be the answer to cost-sharing, but asking consumers to make wise choices with their healthcare options is unrealistic. “Colleagues who are physicians make terrible choices with their money regarding healthcare,” he says. As cost-sharing goes up, “people stop buying the things you don’t want them to buy, which is exactly why you should cost-share, but people also stop buying the things I beg them to do: immunizations, screening, prescription drugs, specialist visits, and necessary treatments.” In some cases, patients are asked to share in the cost of procedures for which doctors receive bonuses, resulting in a misalignment of incentives in the system. Charging copayments for ambulatory doctor visits had the intended effect of limiting visits, along with the unintended consequence of increasing the number of hospitalizations, thereby eating up any savings generated from fewer visits. “Consumers are not the appropriate decision maker, particularly in a clinical area as stressful as cancer,” advises Dr Fendrick. Where the evidence is hard and equivocal, barriers to services (through lower costs to patients) should be removed, and physicians and other providers should be awarded for the increased uptake of those services. VBID: Incentives for EvidenceBased Services The VBID concept is one in which value trumps cost alone. The challenge with the approach is in determining which patients derive high value from a particular intervention and which do not. “We can use VBID across the whole continuum of oncology care,” Dr Fendrick said. “If you’re a first-degree relative of a colon cancer sufferer, you should be

paid to get colon cancer screening. That’s because the evidence is strong that screening first-degree relatives not only improves health enormously, it actually lowers medical spending,” he said. “I have argued that people at age 50 should get colonoscopy for free,” because of the substantial underutilization of this test in this population. High-cost chemotherapy is another treatment for which incentives for use are misaligned. Most health plans require the same OOP expenditure for a chemotherapy agent with multiple indications, even though its use for one of the indications can cure cancer 50% of the time, whereas its use in another indication is dubious on outcomes. Some health plans are now recognizing the value of positive incentives and pay their doctors to perform evidence-based screening and may even pay their patients in the form of cash or lower premiums to obtain these evidence-based services. In diagnostic testing, the use of genetic markers in some instances can lead to better targeting of therapies, while lessening the risk for potential harm by avoiding the use of an agent in patients not likely to benefit. “Why not set the patient’s copay on the likelihood of significant benefit?” he asks.

“If you move from current benefit design systems to one that is value-based, I could give you first class for the price of coach….Too many are trying to drive down cost, without any consideration of the product—the health of our patients.” —A. Mark Fendrick, MD

The VBID concept was included in the Patient Protection and Affordable Care Act. In December 2010, the Departments of Labor, Health, and Human Services and the Treasury issued a Request for Information on VBID and preventive care. This request sought detailed information on VBID programs in relation to the current health reform legislation to address VBID and preventive care. “We hope to see this beyond preventive services into cancer care,” Dr Fendrick concluded. ■

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PAYER PANEL DISCUSSION

Payer Trends in Oncology... Excellus Health Plan, FLRx Pharmacy Management, Rochester, NY. “They are asking, ‘Are my patients living longer, am I reducing medical costs? What am I getting for $30,000 a dose?’ That’s difficult for us to articulate,” Dr Chitre pointed out. In western New York, considerable cost-shifting to the member is taking place, and payers are increasingly favoring generics.

“We often sell hope and not science. A great example is resource utilization in the last 30 days of life, and how much cancer care we provide in the last 10 days of life.” —Maria Lopes, MD “The decisions that are occurring with small, medium, and large employers are impactful to our patient population because of cost and our inability to articulate value,” she said. Oncology Coverage Decisions Actuarial predictions have long been the basis for adjusting premiums, said Scott Breidbart, MD, Chief Medical Officer at Empire BlueCross BlueShield, NY, but limits to premium increases are directed by government regulations. “So we’re not in a position where we can match our prediction. We know this is our only shot, because we’re all worried about what’s going to happen if we can’t keep costs down and how much government intervention there will be.” Everyone is feeling the pressure to control costs, including employers, patients, providers, and the health plans. “The bottom line is that even members are concerned about the cost,” noted Maria Lopes, MD, Chief Medical Officer at AMC Health, Cresskill, NJ. “A great example that a provider shared with me recently is Provenge [sipuleucel-T vaccine for the treatment of advanced hormone therapy–resistant prostate cancer]. Members are actually concerned about the cost, outcome, and value. We’re in a world where overall survival and treatment options are at the forefront.” A major dilemma for payers is that cancer therapy cost remains at their risk. Cancer therapy risk or control is

Continued from cover

100% covered under medical or Medicare Part B benefits. Chemother apy drugs remain in the medical coverage based on coverage rules if a drug is “incident to physician visit/service under Medicare Part B or in a commercial payer world under medical benefit designs,” said Mr Zweigenhaft. “Increasingly, all of the control and spending for cancer is on the medical side,” he said. “Does anyone have good data? When it’s in the medical side, it’s buried under J codes and nondescriptive codes. How do you manage something as a payer when you don’t have good data?” “Even when we have the data, we don’t have staging data that’s so critical from an actuary perspective,” responded Dr Lopes. “For new drugs, we have trained people who look at J codes. From 5 years ago to today, we’ve made tremendous progress. Our oncologists are on board, and it’s actually become a very collaborative environment in that they want to make sure that they get paid and they follow the rules of the health plan.”

“From the insurance perspective, we can’t make our decisions based on value. We have to make our decisions based on evidence.” —Mona Chitre, PharmD, CGP Coverage: Cost versus Evidence One criticism of coverage decisions regarding cancer care is that such decisions do not seem to adhere to the evidence base. In some cases, it becomes futility care. “From the pharmacy perspective, we’re seeing payers pay more attention to cancer care and what products are being used,” said Nick Calla, RPh, Vice President, Trade Relations, Specialty Pharmacy at Walgreens, Carnegie, PA. “We’re starting to see a trend toward more visibility and more management in this space.” Mr Calla noted that, “The use of clinical pathways in oncology is increasing. With that said, cancer does receive special treatment to some degree, but we’re trending away from it.” The challenge to payers is that “we’re seen as all about saving money.

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July 2011

“From the pharmacy perspective, we’re seeing payers pay more attention to cancer care and what products are being used.” —Nick Calla, RPh It’s not about evidence,” said Dr Lopes. “I think we often do sell hope and not science. A great example is resource utilization in the last 30 days of life, and how much cancer care we provide in the last 10 days of life. Maybe we should think about palliative care, which some evidence suggests may have additional benefit in terms of survival.” More successful partnerships with physicians, who are in a position to have critical discussions around “end of life” with the patient, would help, she said. Such discussions should occur much earlier in the continuum of care and should take the direction of informed consent regarding treatment options and risk versus benefit to allow patients to make better decisions. Cancer Drugs Price Spurs Debate The price of drugs continues to spur cost debates. In the case of metastatic melanoma, the newly approved drug ipilimumab (Yervoy) costs $120,000 for a complete course of therapy, or $1 billion in new costs to payers. One randomized clinical trial showed that patients treated with ipilimumab had a median of 10 months overall survival compared with 6.4 months overall survival for those in the placebo-treated group, an almost 4-month advantage with this drug; furthermore, 20% of the ipilimumab-treated patients had 2 years of overall survival. Unfortunately, “we don’t have a genetic marker to predict who benefits,” said Dr Chitre. “From the insurance perspective, we can’t make our decisions based on value. We have to make our decisions based on evidence. The concern becomes how we are going to determine our premiums based on drugs like that, and the potential population, when we don’t know staging from our own medical claims.” Ipilimumab will be a “buy and bill” product for the next several years, which is managed through the medical

benefit at the doctor’s discretion, with a slow evolution toward a more tightly managed product, advised Mr Calla. Is Risk Sharing a Viable Option? In Europe, 54% of oncology drugs are under risk-based contracting, said Mr Zweigenhaft. Dr Lopes said that although such a contract might work in a single-payer system, it is not practical in the United States, where members move from one carrier to another. In addition, “we don’t always agree what constitutes success, much less what constitutes failure. How are we going to align agendas if we can’t define what outcomes look like?” “I don’t think that risk sharing will work in the United States,” said Dr Breidbart. “If we have to look at every claim and ask if it’s medically necessary, that’s where you get disagreement, controversy, and contention.” The amount of time, effort, and expertise involved would make risksharing rebates prohibitive, and “by the time we get the money back, if we do, who does it go to: the patient’s current employer, the last employer? Right now, there’s a lot of pressure on payers not to spend money on administrative costs, and this would be an administrative cost…to determine if the drug worked,” Dr Breidbart added. Rebates and shared differentials may be practical in instances of competition, where multiple oral options exist for treating a certain cancer, said Dr Chitre. Clinical Guidelines Mr Zweigenhaft returned to the theme of futile care and the opportunity it presents to reduce variation in care and control costs through better adherence to clinical pathways. During salvage therapy, “we throw everything at them [the patients],” he said. “We seem to bombard them at the end of life. The final dose can be 3 times the cost of the first-line therapy, yet we have no outcomes.” Dr Breidbart cited evidence that institution of hospice care prolongs life, although care may become less aggressive. “It does not surprise me that one can extend life by reducing unnecessary or unproven care,” he said. “The difficulty is that we as physicians like to help our patients, and the feeling is that what we’re doing is beneficial, even if there isn’t science. We need to come up with a system so that oncologists are more comfortable delivering care appropriately,” said Dr Continued on page 9

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PAYER PANEL DISCUSSION Breidbart. “We need to have difficult conversations with the patients before they go on first-line therapy, not after they fail it, so the care can continue.” Some large employers are initiating discussions about living wills and endof-life care with wellness programs and their members, said Dr Lopes. She added that physicians’ offices or medical homes rarely have the infrastructure in place to assist members and their families in this way. Variability in Care Pharmacy is attempting to reduce variation in care and divergence from pathways by becoming more involved with the management of oral oncology products and moving slowly into the infused products, Mr Calla pointed out. “We’re working with the health plans and doctors to ensure that doctors are adhering to the pathway at least initially, or if they are deviating from them, [to see if] there is a documented reason,” he said. Perhaps rewarding physicians for practicing better medicine could im prove care by reducing variation, but how best to accomplish this goal is open to debate. “In many instances we don’t pay certain doctors enough to deliver the kind of care we want for our members and our families,” Dr Breidbart acknowledged. “In addition, it is best to pay in a way that aligns incentives. If we pay somebody for piecework, we’re going to get a whole lot of pieces,” he said. “If we want the doctor to spend his or her time thinking, then we should pay the doctor for thinking. Sometimes paying the doctor for thinking makes it look like we’re paying the doctor to reduce care, so we have to be careful about the way we pay,” observed Dr Breidbart. “In cancer care, variability is the

at a glance ➤ The pressure to control cancer costs is affecting employers, patients, providers, and health plans ➤ Oncologists must have difficult conversations with their patients regarding treatment options and risks versus benefits before the administration of first-line therapy, not after it fails ➤ In cancer care, variability is the norm; the challenge is how to stop paying for care that has no value and pay for care with value, such as preventive readmissions

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“The difficulty is that we as physicians like to help our patients, and the feeling is that what we’re doing is beneficial, even if there isn’t science.” —Scott Breidbart, MD

norm. At the heart is how we reduce variability,” Dr Chitre explained. “How do we stop paying for things that don’t have value, or pay for things that have value, like paying for preventing readmissions? We must change the landscape as far as how we define outcomes and aligning incentives.” ■

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DIAGNOSTICS

The Role of Molecular Diagnostics in Cancer Treatment A pharmacy benefit manager’s perspective By Wayne Kuznar

Molecular diagnostics cost, $ billions

Figure 1 Double-Digit Growth in Molecular Diagnostics

= Rate wth o r lG nua

35%

➤ $1.6

$1.1 $0.8 $3.2

2008

$6.4 $4.4

2009

2010, estimate

Note: Inappropriate tests = 20% of total costs. Source: Washington G-2 Reports Advisory Services’ 2008 Molecular Diagnostics Survey, health plan data.

Figure 2 Range of Oncology Tests on the Market Evidence of utility

Colon cancer screening Breast cancer Pancreatic cancer Breast cancer risk

Oncotype DX Genome-wide arrays Whole genome sequencing

Colon cancer All cancers All cancers

Evidence still being developed AML indicates acute myelogenous leukemia; GIST, gastrointestinal stromal tumor.

VALUE-BASED CANCER CARE

July 2011

Figure 3 Driving to Value-Based Diagnostics in Cancer Care

Ed uc

y lic

Oncology Molecular Testing

ge me

ion at

Stool DNA testing MammaPrint BRCA OncoVue

What It Means for Health Plans Adding value to diagnostics in oncology requires the alignment of various aspects of care (Figure 3). At Medco, there is a specialty treatment management protocol, which is soft coverage management or support.

Leukemias Inherited breast cancer Breast cancer AML and GIST

line, an estimated 12% to 50% of drugs are considered to be “personalized medicine.” A whopping 80% of companies have strategic partnerships related to personalized medicine, she said. It is expected that by 2025, 10% to 20% of all new drugs will be labeled with a companion test, in particular cancer drugs, according to April 2010 data from Kalorama Information. Dr Barlow discussed 9 pipeline drugs that have partnerships to develop companion diagnostics. The US Food and Drug Administration (FDA) is helping drive the push, she said. “Last year for the first time, the FDA didn’t approve a leukemia drug for which, during the clinical trials, the pharma company had not performed companion testing to identify those who would benefit from the drug. When the company brought the drug to approval, the companion test or diagnostics hadn’t been developed for commercial use. FDA sent it back and said get the testing developed so that when the drug is approved it can be used in the appropriate people,” she said. “This is the first time that this occurred at FDA. It really heralds where we’re headed in the future with diagnostics.”

Chromosome analysis BRCA Oncotype DX C-kit

—Jane F. Barlow, MD, MPH, MBA

es s

Drug Companion Tests on the Rise There are more drugs in development for cancer than for any other clinical area, according to Dr Barlow, who points to 900 drugs in some stage of development, many of which are oral oncolytics. Many pharmaceutical companies are using diagnostics as part of their regimen for evaluating the drugs. In the current oncology drug pipe-

“What was surprising even to us—98% of providers recognized that diagnostics plays a role in choosing the drug and dose of drug. But only 10% said that they knew enough to put it to use.”

huge compared with other types of diagnostics, which are experiencing single-digit growth. Yet about 20% of the molecular-based tests are believed to be inappropriate, said Dr Barlow. “With the range of oncology tests on the market, we’re measuring clinical utility—evidence of utility (eg, BRCA for inherited breast cancer) versus evidence still being developed (eg, Oncotype DX for colon cancer),” she says (Figure 2).

Philadelphia, PA—The field of oncology stands to benefit greatly from molecular diagnostic trends, according to Jane F. Barlow, MD, MPH, MBA, Vice President, Clinical Innovation, Medco Health Solutions, who offered a pharmacy benefit manager’s (PBM) perspective of the role of diagnostics, including the use of companion tests in drug development. These companion tests will represent another potential expenditure and coverage decision for PBM companies. Currently, more than 800 tests are available for tumor profiling on solid tumors, Dr Barlow said, and another 100 tests are available for hematologic malignancies. In addition, 22 inherited cancer syndromes can now be tested for, and an additional 10 risk profiling and cancer screening tests are available. The entire molecular diagnostics area is boasting double-digit growth at a rate of 35% yearly (Figure 1). This is

c Ac

“When we see drugs that come to play being dispensed through Medco or elsewhere, we have questions we ask to be sure testing is being done. We work with patients and with providers to ensure that the right person is getting the right drug; if testing is indicated, then testing is done. We’ve merged from our client population into one umbrella focus. It’s one oncology focus so we can pull orals, injectables, everything together,” she said. Medco also works to facilitate discussions with providers so that providers make the call regarding testing. Yet, there is inherent difficulty in managing these tests, whether on the health plan side or pharmacy side, because it’s hard to know whether people have had tests. Education’s Influence “When we think about driving value-based diagnostics in cancer care, we recognize that it’s a multifaceted program,” Dr Barlow said. “It’s not just about access to testing. We do realize there’s also a huge role for education.” She notes that in 2008, Medco, along with the American Medical Association (AMA), sent a fax survey to all AMA physicians on pharmacogenomics and received about 10,000 responses. “What was surprising even to us— 98% of providers recognized that diagnostics plays a role in choosing the drug and dose of drug. But only 10% said that they knew enough to put it to use in practice. There’s a huge gap,” she said. “With rapid development of new tests, that education gap likely will remain. There’s a role for policy and how plans think about what they’re going to cover and not cover. Then there’s a role for management, whether through a prior authorization process or friendlier management.” Dr Barlow points to a “tremendous” role for diagnostics in disease treatment, especially via the new companion tests. Yet, there must be recognition that every new test is something additional to cover. “We have to figure out if we’re going to spend the same amount or more for this type of testing. We have to use that money wisely,” she added. ■

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ONCOLOGY BENEFIT DESIGN

Benefit Design Trends in Oncology Management A large payer’s perspective By Wayne Kuznar Philadelphia, PA—Third-party oncology benefits management, tiered networks, and accountable care organizations (ACOs) are some of the trends gaining traction in the health insurance industry, according to Donald Liss, MD, Senior Medical Director, Independence Blue Cross of Philadelphia, who described cancer care from a large insurer’s perspective. Health plans, viewed as moderately simple entities, carry a 3-fold set of responsibilities, said Dr Liss. The first responsibility of a health plan is to offer a benefits plan, typically on behalf of a purchaser (eg, employer, governmental entity, labor union) that

Table Industry Trends • Most cost-effective setting • Tiered networks –Cost –Combination of outcomes and cost • Moving self-injectable medications to pharmacy/pharmacy benefits management • More onerous utilization review and claims review –Dosage and frequency as well as coverage for drugs • Oncology benefits management by third parties –Based on experience in diagnostic imaging and other focused service lines

will cover medically necessary, nonexperimental services. The second responsibility is to contract with a network of providers, negotiating for price, trading volume for discount, and ultimately offering availability of access to membership. The third responsibility of health plans is to adjudicate and pay claims. “The goals are to figure out whether someone is at high risk, and whether a benefit is useless or wasteful,” said Dr Liss, Senior Medical Director of Clinical Programs and Policy at Independence Blue Cross. Shifting Makeup of Benefits In benefit design, there’s a growing trend among payers toward shifting the cost burden more toward the patient by increasing the out-of-pocket costs, including premiums, copayments, deductibles, and coinsurance at point of sale. “These are blunt instruments applicable to categories of services—office visits, outpatient procedures, and diagnostic imaging—but they do not distinguish value of service,” Dr Liss said. “Those increased costs for the consumer clearly have the intended effect of reducing costs for the insurer, but whether they are differentiating highvalue services and low value is not so clear,” he said. Transparency is another challenge in benefit design. It concerns issues of where the service is being performed—“Is it part of a physician’s

“Those increased costs for the consumer clearly have the intended effect of reducing costs for the insurer, but whether they are differentiating highvalue services and low value is not so clear.” —Donald Liss, MD

office, an infusion center, or a hospital outpatient department?” Trends to Watch Among the recent trends in the industry (Table), tiered networks, regarded as high-quality networks, are gaining a foothold among providers. As recently as 2003 or 2004, nobody could show significant benefits of

REGIONAL MEETINGS September 24 • Chicago, IL October 1 • San Francisco, CA November 19 • Tampa, FL

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What Attendees of the First Conference Said: Great discussion and networking • Better understanding of issues • New approaches to old problems • Nice balance of multiple perspectives • I got a clearer understanding of issues facing payers and clinicians • Really liked the aspect of addressing “state of the state” in addition to future-looking opinions and ideas • Would like to see more clinician participation •

these trends for health outcomes, according to Dr Liss, but the ability to show significant outcomes with these strategies has improved. Self-injectable medications are moving away from medical benefits to pharmacy and pharmacy benefits management. Of significance is the move toward more careful review of the high cost of cancer treatments. Health plans are increasingly more sensitive to issues surrounding dosage and frequency, ensuring that claims they are paying are for drugs and treatments that were actually given. A move toward oncology benefits management by third parties has arrived, based on experience in diagnostic imaging and other focused service lines, Dr Liss observes. In addition, there is an effort to collaborate with organized oncology groups. Dr Liss points to a macro industry of oncology benefit management firms that are in existence today. The ACO is yet another noteworthy trend to monitor, according to Dr Liss. “How ACOs organize themselves— and cancer care is a fascinating window to view this—is significant, because treatment of cancer is an intense expense for a small group of people,” he says. “If the population for an ACO that is both clinically and financially accountable simply has bad luck with a couple of people with very high-cost cancer therapy, they’re screwed. The whole concept of health insurance is to spread risk across huge populations. An ACO has got to be big enough to balance those risks—the law of large numbers.” Expect molecular diagnostics to present a huge opportunity and challenge in managing the expense of technology. With regard to the Patient Protection and Affordable Care Act (ACA), the elimination of lifetime limits and preexisting conditions is “a huge deal” in oncology, especially as the cost of cancer therapeutics increases, according to Dr Liss. The ACA helped with the establishment of essential benefits, which are loosely recognized as services that will be covered in the insurance plan, and with the determination of how each plan will distribute those benefits to individual cases. One final trend to watch in the financing of healthcare involves comparative effectiveness research, which is an investment in the analysis of which therapies work. ■

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NCCN GUIDELINES

NCCN Guidelines Inform Decisions Across the Continuum of Cancer Care By Wayne Kuznar Philadelphia, PA—The National Comprehensive Cancer Network (NCCN) is an alliance of academic cancer centers in the United States that seeks to optimize decision-making and policies for improving the delivery of appropriate and effective cancer care, said Al B. Benson III, MD, FACP, Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center and Northwestern University, Chicago, immediate Past Presi dent of the Association of Community Cancer Centers, and Past Chair of the Board of Directors of NCCN. The 21-member NCCN represents clinical communities across the United States. As one of its main missions, the NCCN evaluates scientific information to inform and improve the decisionmaking between patients and physicians. The major way it achieves this mission is through the development of evidence-based guidelines. One type of guideline is a process map of integrated interventions over time (Figure). The map addresses coordination of care and the continuum of care, offering references for each decision pathway. For example, there are more than 1500 decision pathways in the guideline for management of breast cancer. “The intent is to deal with reallife clinical situations” that are applicable to most patients, said Dr Benson. “We do follow a 5% rule; if there’s a situation that occurs less than 5% of the time, it becomes very difficult to create a guideline. For much of what affects patients on a routine basis, we try to incorporate guidance in terms of decision-making.”

The second type of guidance is a systematic review of a single issue. The systematic review is a comprehensive review and analysis of the literature that can address a single decision point. “These aren’t mutually exclusive; systematic reviews are considered strongly in the NCCN guideline development,” said Dr Benson. Evidence-Based Clinical Decision-Making The various NCCN clinical guidelines are created by multidisciplinary panels for cancer screening, diagnosis, treatment, and supportive care. Each recommendation is supported by 1 of 4 categories of evidence ranging from category 1 (based on high level of evidence and uniform consensus) to category 3 (any level of evidence but major disagreement that the recommendation is appropriate). Most of the recommendations are supported by category 2A evidence (based on a lower level of evidence and uniform consensus that it constitutes appropriate care), usually data from clinical trials. “The guidelines are not prescriptive” and are not meant to dictate decision-making but, rather, to inform decision-making. “We contend that something is wrong if a center is 100% concordant with guidelines. It’s impossible with the variability of clinical situations seen on a daily basis. However, they are applicable in cancer medicine to the majority of our patients,” Dr Benson said. Each guidelines panel has on average 25 members. The evidence is reviewed continuously and guidelines

Figure NCCN Guidelines Update Process Clinical Practice Guidelines in Oncology – v.1.2010 ➤

➤

•

➤ Panel meeting/

teleconference

NCCN staff ➤ review and

update

➤

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Institutional review Literature review Outside submissions

•

Panel chair review

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FDA approval Significant scientific publication or presentation ➤

Publication

➤

Monitoring and review of literature

Concurrent development and production of discussion, compendium, and chemotherapy order templates FDA indicates US Food and Drug Administration; NCCN, National Comprehensive Cancer Network. Courtesy of Al B. Benson III, MD.

VALUE-BASED CANCER CARE

Panel review

➤

•

➤

•

July 2011

“We do follow a 5% rule; if there’s a situation that occurs less than 5% of the time, it becomes very difficult to create a guideline. For much of what affects patients on a routine basis, we try to incorporate guidance in terms of decision-making.” —Al B. Benson III, MD, FACP are updated accordingly; new studies change the standard of care over time. The entire process is transparent. “We spend a great deal of effort to minimize bias,” he said. About 900 clinicians serve on the review panels, which represent different geographical areas and specialties. No industry or other interest group funds are used to support panel meetings, and no industry representatives are allowed at the meetings. Potential conflicts of interest are declared formally (verbal and written), and members can be removed from a panel permanently if their association with industry is too pervasive. Financial conflicts of interest for individuals are published on nccn.org. The NCCN Compendium™ supports decision-making on appropriate use of drugs and biologics and is used for coverage policy by the Centers for Medicare & Medicaid Services and many private health plans. “Our precertification folks use the compendium, because virtually all our chemotherapy regimens are precertified, even oral regimens,” Dr Benson said. “This process is a continuum, so if the guidelines are revised and it affects the compendium, the compendium is revised at the same time to reflect the guideline changes.”

Benchmarking Concordance with Guidelines Another critical component of NCCN is the creation of an outcomes database in 1997. The initial purpose was to monitor and benchmark concordance of practice in NCCN institutions to the guidelines and to describe the patterns and outcomes of care in the member institutions. All clinical interventions are collected, including specific regimens, lines of therapy, and oral agents. More than 270 separate data elements are collected. The database also establishes a major research repository of data relevant to patient situations. As oncology moves to personalized medicine, data that reflect subsets of patients based on tumor biology will be important. “When there are biological profiles such as predictive or prognostic markers available, they get integrated into the database and are integrated into the guidelines,” said Dr Benson. The reports from the database inform discussion of individual recommendations at NCCN guidelines panel meetings. If a recommendation is not being followed, it can be for one of several reasons: • The recommendation is unclear, perhaps because of the variability of evidence • The recommendation is wrong • Doctors are practicing in advance of guidelines. “When we send concordance data to our institutions, we expect a response,” he said. “We need to understand when there is a nonconcordance. So if you have a category 1 level of evidence, you would expect concordance to be around the 90% mark. If it’s not, we need to know why.” The NCCN is interested in developing a compendium of predictive and prognostic testing. Molecular testing has the potential to identify: • Patients with more aggressive variants of disease • Those whose disease may (or may not) respond to specific interventions • Select systemic therapies based on the individual patient and the molecular profile. “We are looking for better ways to utilize guidelines and decision-making,” said Dr Benson. “We’re calling it at this moment a therapeutic index. We would like to look at each recommendation in light of both safety and efficacy. In a potentially curative situation, more toxicity may be tolerated for good efficacy, whereas in a palliative situation, less toxicity is acceptable.” ■

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EVIDENCE-BASED PRACTICE

Evidence-Based Practice Should Drive Patient Care Interview with Al B. Benson III, MD, FACP Professor of Medicine and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine, Chicago, IL Q: Are you concerned about the growing trend of payers demanding increased concordance with the National Comprehensive Cancer Network (NCCN) guidelines? Dr Benson: There is certainly a trend that emphasizes expectations that clinicians will practice evidence-based medicine. Providers should try to hone in on more appropriate use of drugs for an indication and not use agents when there is evidence that a regimen is no longer effective. Because imaging can be a very critical expense, and with the growing use of diagnostics, payers will likely be very interested in how people are using imaging and diagnostic tests in the context of cancer treatment guidelines. It makes sense that we talk about utilization of healthcare dollars most effectively and try to avoid use when there is no projected added benefit. It is equally important that we recognize that guidelines are not prescriptive but offer a medical decision tool for specific medical situations. The appropriate use of guidelines also is very critical in the discussions about measuring concordance to a specific guideline. For example, there may be an indication that for most people would be considered effective therapy, but for a patient with comorbid conditions may not be appropriate. We know therefore that 100% concordance to guidelines cannot be viewed as appropriate care given the variable of clinical situations. We always have to take the individual patient’s circumstances into account. If a patient adheres more to guidelines where appropriate, that should result in better healthcare delivery and more efficient care, and also in appropriate care in terms of resource utilization.

Q: As an oncologist, do you have any concern about where patients are getting their information on the internet about care? Dr Benson: Absolutely, and it is one of the reasons the NCCN is working on offering patient guidelines as a resource. For example, guidelines created for the layperson but mirror the clinical guidelines will enable patients to discuss treatment pathways with their clinicians. Patients will have a document to review with the clinician to see where they fall in a given guideline and what the rationale is for a decision in a particular situation. It is vital that people have reliable

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information, and it is often difficult for individuals to know what sites are indeed reliable. There are good resources, such as the American Society of Clinical Oncology, the National Cancer Institute, the Oncology Nursing Society, the Association of Community Cancer Centers, and the NCCN. But in terms of actual treatment algorithms, the NCCN guidelines are actually able to direct an individual to the appropriate section that applies to that person as a component of the continuum of care. If patients are newly diagnosed, in the middle of treatment, under surveillance, or need to make a treatment decision, they can at least see what experts and any available evidence suggest they do. We hope that the public begins to embrace utilization of evidence to help guide decisions.

“If more clinicians followed evidence-based practice, and patients began to accept that evidence-based practice is the most appropriate way to care for people, in general, we not only would have the most optimal healthcare outcomes but also more effective use of our resources.”

“Providers should try to hone in on more appro priate use of drugs for an indication and not use agents when there is evidence that a regimen is no longer effective.”

with epithelial ovarian cancer, advanced or not, were not being treated according to NCCN guidelines? Dr Benson: As I have said, if more clinicians followed evidence-based practice, and more patients began to accept that evidence-based practice is the most appropriate way to care for people, in general, we not only would have the most optimal healthcare outcomes but also more effective use of our resources. This is something that people should explore to see why individuals are not treated according to guidelines and to come up with some solutions.

Q: When developing guidelines, are there any cost considerations taken into account?

Q: Are drug shortages interfering with the ability of clinicians to follow the guidelines?

Dr Benson: Generally not, because the purpose of the guidelines is to look at what should be best practice based on the evidence. The introduction of an NCCN therapeutic index, which is currently under development, is an attempt to fine-tune therapeutic selection when there may be multiple options—for example, taking into account goals of therapy and toxicity, which is perhaps an even better way to guide selection of a treatment.

Dr Benson: In general, yes. The drug shortage issue is of enormous concern, because there is a potential that people will not be receiving the component of a regimen that leads to maximum benefit. These regimens are in the guidelines, so the ability to deliver appropriate medical care is affected. It is a particular concern when no adequate alternative therapy is available, or if a less effective therapy is the only remaining choice. This is a very serious problem that must be addressed by the US Food and Drug Administration, the pharmaceutical companies, and the oncology community at large. ■

Q: Does it surprise you that a recent study showed a majority of women

Q: What if a patient insists on a certain treatment because a study showed positive benefits for a drug that is not in the guidelines? Dr Benson: That would be a point of discussion. The clinician would need to see that study and discuss how it is relative to that individual. The clinician would also need to see if the drug is available and if it applies to that individual patient. With experimental therapy, the drug may simply not be available, or there may be another clinical trial for which the person would qualify, which would be great. However, if the data are not robust enough to integrate into routine practice, then the reality is that the patient may be denied reimbursement, which is another component in the equation. An increasing number of insurance carriers are going to link reimbursement with evidence, and if a treatment indication does not have a place in current guidelines, the carrier will deny that coverage.

October 1 San Francisco, CA

November 19 Tampa, FL

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in su 3 y pr rviv ea M evi al r o ul ou ad ve tip s v ra le ly u an ll M nt tag y e re e lo at m ed a

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If You Define Value as an Overall Survival Advantage:

In Previously Untreated Multiple Myeloma IMPORTANT IMPOR TANT 3-YEAR UPDATEUPDA ATETE- SUSTAINED SUSTTAINED AINE BENEFIT AINED UPDATED VIST UPDATED VISTA* TA* A* OVERALL OVERALLL SURVIV SURVIVAL VAL AL (OS) ANALYSIS: ANALLY YS SIS: VcM VcMP P† vs MP (36.7-month median follow-up) 100

MEDIAN OS NOT REACHED FOR VcMP

% Pa Patients tients Without Event

80 70 60 50 40 30 20 10

VELCADE+MP (n=344) MP (n=338)

HR 0.65 (95% CI, 0.51-0.84); P=0.00084

0 0

Months Kaplan-Meier estimate.

If You Define Value as Medication Cost:

VELCADE Warnings, Precautions, and Adverse Events

Please see Brief Summary for VELCADE on the next page of this advertisement. www.VELCADE.com

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Brief Summary INDICATIONS: VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with multiple myeloma. VELCADE® (bortezomib) for Injection is indicated for the treatment of patients with mantle cell lymphoma who have received at least 1 prior therapy. CONTRAINDICATIONS:

VELCADE is contraindicated in patients with hypersensitivity to bortezomib, boron, or mannitol. WARNINGS AND PRECAUTIONS:

VELCADE should be administered under the supervision of a physician experienced in the use of antineoplastic therapy. Complete blood counts (CBC) should be monitored frequently during treatment with VELCADE. Pregnancy Category D: Women of childbearing potential should avoid becoming pregnant while being treated with VELCADE. Bortezomib administered to rabbits during organogenesis at a dose approximately 0.5 times the clinical dose of 1.3 mg/m2 based on body surface area caused post-implantation loss and a decreased number of live fetuses. Peripheral Neuropathy: VELCADE treatment causes a peripheral neuropathy that is predominantly sensory. However, cases of severe sensory and motor peripheral neuropathy have been reported. Patients with pre-existing symptoms (numbness, pain or a burning feeling in the feet or hands) and/or signs of peripheral neuropathy may experience worsening peripheral neuropathy (including ≥Grade 3) during treatment with VELCADE. Patients should be monitored for symptoms of neuropathy, such as a burning sensation, hyperesthesia, hypoesthesia, paresthesia, discomfort, neuropathic pain or weakness. Patients experiencing new or worsening peripheral neuropathy may require change in the dose and schedule of VELCADE. Following dose adjustments, improvement in or resolution of peripheral neuropathy was reported in 51% of patients with ≥Grade 2 peripheral neuropathy in the relapsed multiple myeloma study. Improvement in or resolution of peripheral neuropathy was reported in 73% of patients who discontinued due to Grade 2 neuropathy or who had ≥Grade 3 peripheral neuropathy in the phase 2 multiple myeloma studies. The long-term outcome of peripheral neuropathy has not been studied in mantle cell lymphoma. Hypotension: The incidence of hypotension (postural, orthostatic, and hypotension NOS) was 13%. These events are observed throughout therapy. Caution should be used when treating patients with a history of syncope, patients receiving medications known to be associated with hypotension, and patients who are dehydrated. Management of orthostatic/postural hypotension may include adjustment of antihypertensive medications, hydration, and administration of mineralocorticoids and/or sympathomimetics. Cardiac Disorders: Acute development or exacerbation of congestive heart failure and new onset of decreased left ventricular ejection fraction have been reported, including reports in patients with no risk factors for decreased left ventricular ejection fraction. Patients with risk factors for, or existing heart disease should be closely monitored. In the relapsed multiple myeloma study, the incidence of any treatmentemergent cardiac disorder was 15% and 13% in the VELCADE and dexamethasone groups, respectively. The incidence of heart failure events (acute pulmonary edema, cardiac failure, congestive cardiac failure, cardiogenic shock, pulmonary edema) was similar in the VELCADE and dexamethasone groups, 5% and 4%, respectively. There have been isolated cases of QT-interval prolongation in clinical studies; causality has not been established. Pulmonary Disorders: There have been reports of acute diffuse infiltrative pulmonary disease of unknown etiology such as pneumonitis, interstitial pneumonia, lung infiltration and Acute Respiratory Distress Syndrome (ARDS) in patients receiving VELCADE. Some of these events have been fatal. In a clinical trial, the first two patients given high-dose cytarabine (2 g/m2 per day) by continuous infusion with daunorubicin and VELCADE for relapsed acute myelogenous leukemia died of ARDS early in the course of therapy. There have been reports of pulmonary hypertension associated with VELCADE administration in the absence of left heart failure or significant pulmonary disease. In the event of new or worsening cardiopulmonary symptoms, a prompt comprehensive diagnostic evaluation should be conducted. Reversible Posterior Leukoencephalopathy Syndrome (RPLS): There have been reports of RPLS in patients receiving VELCADE. RPLS is a rare, reversible, neurological disorder which can present with seizure, hypertension, headache, lethargy, confusion, blindness, and other visual and neurological disturbances. Brain imaging, preferably MRI (Magnetic Resonance Imaging), is used to confirm the diagnosis. In patients developing RPLS, discontinue VELCADE. The safety of reinitiating VELCADE therapy in patients previously experiencing RPLS is not known. Gastrointestinal Adverse Events: VELCADE treatment can cause nausea, diarrhea, constipation, and vomiting sometimes requiring use of antiemetic and antidiarrheal medications. Ileus can occur. Fluid and electrolyte replacement should be administered to prevent dehydration. Thrombocytopenia/Neutropenia: VELCADE is associated with thrombocytopenia and neutropenia that follow a cyclical pattern with nadirs occurring following the last dose of each cycle and typically recovering prior to initiation of the subsequent cycle. The cyclical pattern of platelet and neutrophil decreases and recovery remained consistent over the 8 cycles of twice weekly dosing, and there was no evidence of cumulative thrombocytopenia or neutropenia. The mean platelet count nadir measured was approximately 40% of baseline. The severity of thrombocytopenia was related to pretreatment platelet count. In the relapsed multiple myeloma study, the incidence of significant bleeding events (≥Grade 3) was similar on both the VELCADE (4%) and dexamethasone (5%) arms. Platelet counts should be monitored prior to each dose of VELCADE. Patients experiencing thrombocytopenia may require change in the dose and schedule of VELCADE. There have been reports of gastrointestinal and intracerebral hemorrhage in association with VELCADE. Transfusions may be considered. The incidence of febrile neutropenia was <1%.

Patients with Hepatic Impairment: VELCADE is metabolized by liver enzymes. VELCADE exposure is increased in patients with moderate or severe hepatic impairment. These patients should be treated with VELCADE at reduced starting doses and closely monitored for toxicities. ADVERSE EVENT DATA:

Safety data from phase 2 and 3 studies of single-agent VELCADE 1.3 mg/m2/dose twice weekly for 2 weeks followed by a 10-day rest period in 1163 patients with previously treated multiple myeloma (N=1008, not including the phase 3, VELCADE plus DOXIL® [doxorubicin HCI liposome injection] study) and previously treated mantle cell lymphoma (N=155) were integrated and tabulated. In these studies, the safety profile of VELCADE was similar in patients with multiple myeloma and mantle cell lymphoma. In the integrated analysis, the most commonly reported adverse events were asthenic conditions (including fatigue, malaise, and weakness); (64%), nausea (55%), diarrhea (52%), constipation (41%), peripheral neuropathy NEC (including peripheral sensory neuropathy and peripheral neuropathy aggravated); (39%), thrombocytopenia and appetite decreased (including anorexia); (each 36%), pyrexia (34%), vomiting (33%), anemia (29%), edema (23%), headache, paresthesia and dysesthesia (each 22%), dyspnea (21%), cough and insomnia (each 20%), rash (18%), arthralgia (17%), neutropenia and dizziness (excluding vertigo); (each 17%), pain in limb and abdominal pain (each 15%), bone pain (14%), back pain and hypotension (each 13%), herpes zoster, nasopharyngitis, upper respiratory tract infection, myalgia and pneumonia (each 12%), muscle cramps (11%), and dehydration and anxiety (each 10%). Twenty percent (20%) of patients experienced at least 1 episode of ≥Grade 4 toxicity, most commonly thrombocytopenia (5%) and neutropenia (3%). A total of 50% of patients experienced serious adverse events (SAEs) during the studies. The most commonly reported SAEs included pneumonia (7%), pyrexia (6%), diarrhea (5%), vomiting (4%), and nausea, dehydration, dyspnea and thrombocytopenia (each 3%). In the phase 3 VELCADE + melphalan and prednisone study, the safety profile of VELCADE in combination with melphalan/prednisone is consistent with the known safety profiles of both VELCADE and melphalan/prednisone. The most commonly reported adverse events in this study (VELCADE+melphalan/prednisone vs melphalan/prednisone) were thrombocytopenia (52% vs 47%), neutropenia (49% vs 46%), nausea (48% vs 28%), peripheral neuropathy (47% vs 5%), diarrhea (46% vs 17%), anemia (43% vs 55%), constipation (37% vs 16%), neuralgia (36% vs 1%), leukopenia (33% vs 30%), vomiting (33% vs 16%), pyrexia (29% vs 19%), fatigue (29% vs 26%), lymphopenia (24% vs 17%), anorexia (23% vs 10%), asthenia (21% vs 18%), cough (21% vs 13%), insomnia (20% vs 13%), edema peripheral (20% vs 10%), rash (19% vs 7%), back pain (17% vs 18%), pneumonia (16% vs 11%), dizziness (16% vs 11%), dyspnea (15% vs 13%), headache (14% vs 10%), pain in extremity (14% vs 9%), abdominal pain (14% vs 7%), paresthesia (13% vs 4%), herpes zoster (13% vs 4%), bronchitis (13% vs 8%), hypokalemia (13% vs 7%), hypertension (13% vs 7%), abdominal pain upper (12% vs 9%), hypotension (12% vs 3%), dyspepsia (11% vs 7%), nasopharyngitis (11% vs 8%), bone pain (11% vs 10%), arthralgia (11% vs 15%) and pruritus (10% vs 5%). DRUG INTERACTIONS:

Co-administration of ketoconazole, a potent CYP3A inhibitor, increased the exposure of bortezomib. Therefore, patients should be closely monitored when given bortezomib in combination with potent CYP3A4 inhibitors (e.g. ketoconazole, ritonavir). Co-administration of melphalan-prednisone increased the exposure of bortezomib. However, this increase is unlikely to be clinically relevant. Co-administration of omeprazole, a potent inhibitor of CYP2C19, had no effect on the exposure of bortezomib. Patients who are concomitantly receiving VELCADE and drugs that are inhibitors or inducers of cytochrome P450 3A4 should be closely monitored for either toxicities or reduced efficacy. USE IN SPECIFIC POPULATIONS: Nursing Mothers: It is not known whether bortezomib 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 VELCADE, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. Pediatric Use: The safety and effectiveness of VELCADE in children has not been established. Geriatric Use: No overall differences in safety or effectiveness were observed between patients ≥age 65 and younger patients receiving VELCADE; but greater sensitivity of some older individuals cannot be ruled out. Patients with Renal Impairment: The pharmacokinetics of VELCADE are not influenced by the degree of renal impairment. Therefore, dosing adjustments of VELCADE are not necessary for patients with renal insufficiency. Since dialysis may reduce VELCADE concentrations, the drug should be administered after the dialysis procedure. For information concerning dosing of melphalan in patients with renal impairment, see manufacturer's prescribing information. Patients with Hepatic Impairment: The exposure of VELCADE is increased in patients with moderate and severe hepatic impairment. Starting dose should be reduced in those patients. Patients with Diabetes: During clinical trials, hypoglycemia and hyperglycemia were reported in diabetic patients receiving oral hypoglycemics. Patients on oral antidiabetic agents receiving VELCADE treatment may require close monitoring of their blood glucose levels and adjustment of the dose of their antidiabetic medication.

Tumor Lysis Syndrome: Because VELCADE is a cytotoxic agent and can rapidly kill malignant cells, the complications of tumor lysis syndrome may occur. Patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken. Hepatic Events: Cases of acute liver failure have been reported in patients receiving multiple concomitant medications and with serious underlying medical conditions. Other reported hepatic events include increases in liver enzymes, hyperbilirubinemia, and hepatitis. Such changes may be reversible upon discontinuation of VELCADE. There is limited re-challenge information in these patients.

VELCADE, MILLENNIUM and are registered trademarks of Millennium Pharmaceuticals, Inc. Other trademarks are property of their respective owners. MA 02139Company. Cambridge, MA 02139 Millennium Pharmaceuticals, Inc., Cambridge, The Takeda Oncology 10 Millennium Pharmaceuticals, Inc. Copyright ©2009, V-10-0204 10 All rights reserved. Printed in USA V1215 12/09

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PERSONALIZED MEDICINE

The Age of Personalized Oncology Therapies Value implications for payers, researchers, and manufacturers By Wayne Kuznar Philadelphia, PA—The age of personalized cancer therapies is upon us. In oncology, personalized medicine encompasses the use of tests to determine the genes and gene interactions that can reliably predict an individual’s response to therapy or the chance of disease recurrence. The use of molecular diagnostic testing that provides the genomic profile of an individual’s tumor facilitates an understanding of some specific tumors that allows the selection of a treatment most likely to induce a response in that patient. A session devoted to personalized oncology therapy examined its current and future role in cancer care and its impact on all oncology stakeholders. A Broader Perspective Needed Personalized oncology should be considered in a broader sense, incorporating not just genetic testing but also comorbidities and pharmacokinetic characteristics of patients, among other things, according to Gene Morse, PharmD, Professor and Associate Director, University at Buffalo, New York State Center of Excellence in Bioinformatics and Life Sciences. Guidelines have attempted to introduce best practices into cancer care, but comorbidities can complicate guidelines implementation, Dr Morse said. Another level of personalization is individualized drug dosing based on pharmacokinetic considerations (ie, renal and hepatic sufficiency), which is often omitted from personalized medicine approaches. “The use of therapeutic drug monitoring to individualize dosing...all of these technologies exist but are not really brought together in many therapeutic areas,” Dr Morse said. The Human Genome Project has sequenced the full set of genes in the human body, but applying this information to personalized medicine has been difficult, because the genes’ rela-

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tive expressions and their impact on disease recurrence must first be known before the tests can be useful. Genetic Testing: A “Wild West” Situation? About 1800 genetic tests are currently available and more are in development. Although genetic testing has generated a lot of enthusiasm, “I would consider it very experimental,” said Dr Morse. Some of these tests have solid evidence, but results from others vary from laboratory to laboratory. Similarly, gene-expression profiling is relatively new and unproven. The concept of molecular tests, genomics, and proteomics is still mainly a research area, “yet, there are

“The payers may or may not want to have anything to do with these tests because the data are not there to support this.” —Gene Morse, PharmD patients right now walking in for care, and these tests are being requested,” he said. “The payers may or may not want to have anything to do with these tests because the data are not there to support this.” “It is a Wild West situation, where

“It is a Wild West situation, where these tests are being developed with little regulatory oversight and have questionable clinical utility and a very uncertain impact on physician treatment choice.” —Gary L. Johnson, MD, MS, MBA

these tests are being developed with little regulatory oversight and have questionable clinical utility and a very uncertain impact on physician treatment choice. In other words, does the test influence what the physician is going to do? If the test isn’t going to change your treatment approach, why do the test?” said Gary L. Johnson, MD, MS, MBA, Medical Director, Humana, Clinical Leadership and Policy Development. The economic value of many genetic tests is another area of uncertainty, said Dr Johnson, and incorporating these tests into clinical guidelines is in early stages. Finding the best method to manage testing with these uncertainties is a challenge, he said. The options for managed care are to observe and eventually react, rely on external guidelines (that take a long time to develop), or develop in-house expertise. Another option is to look externally to organizations that act similarly to how a pharmaceutical benefits management company acts for pharmaceuticals. “Our organization has chosen this last approach,” he said. “We partnered with a genomic testing management company that provides the evidencebased policy development, in collaboration with our medical directors, both for the pharmaceuticals that we use

and for the tests that are provided.” Pretest counseling and test interpretation counseling services are offered. In the future, Dr Johnson envisions “preferred” genomic tests similar to the preferred pharmaceuticals that are on many drug formularies. The approach to oncology services at Premier Source Diagnostics is a patient-centric approach, said Perry Dimas, Vice President of Business Development, Premier Source Diagnostics, Orlando, FL. “If the ordering physician finds that the test is medically necessary and he or she wants to order it, the patient should get it,” Mr Dimas said. Premier Source Diagnostics has mimicked the traditional specialty pharmacy model and applied it to molecular diagnostic tests. Physicians are offered no incentives (ie, reimbursement) to order a molecular test. Molecular Testing Will Revolutionize Care Molecular testing has the potential to revolutionize the way care is provided, said Richard Bender, MD, Clinical Professor of Medicine, UCLA School of Medicine, and Senior Vice President for Medical Affairs, Oncology, Caris Life Sciences (formerly Chief Medical Officer at Agendia). Continued on page 18

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PERSONALIZED MEDICINE

The Age of Personalized Oncology...

—Perry Dimas “We now can detect tiny transcripts of the translocations and the genomic abnormalities…so we can monitor small numbers of residual tumor cells and determine very quickly whether our patient has responded to Gleevec

at a glance

—Richard Bender, MD caid Services (CMS) is starting a demonstration project in June 2011, lasting 24 months, in which it will investigate paying for certain complex diagnostic laboratory tests (ie, gene protein expression, genotyping, cancer chemotherapy sensitivity assay) outside the 14-day rule. Under the demonstration, independent and hospital-based laboratories may bill separately for demonstration tests that are ordered within a 14-day period after a hospital discharge. “It will be up to us to demonstrate that this rule, within the CMS and other healthcare codes, needs to be changed,” said Dr Bender.

Barrier to Molecular Testing: Medicare 14-Day Rule A barrier to molecular testing is the Medicare 14-day rule. The rule states that any service rendered within 14 days of a hospital inpatient or outpatient admission must be billed directly to the hospital as part of the Inter na tional Classification of Diseases, 9th Revision (ICD-9)-coded service. Therefore, a laboratory test must be performed outside the 14-day window for it to be paid as an outpatient test. The rule causes delays in test ordering, which is not in the best interest of the patient. The Centers for Medicare & Medi-

Changing the Translational Research Structure Many companies are challenged by limited resources for research, preventing them from bringing their ideas

Figure Healthcare Informatics Facilitate a Translational Research Model

VALUE-BASED CANCER CARE

➤ Drug development

Drug interactions

Healthcare informatics

Translational science research

➤

➤ Personalized oncology should consider each patient’s comorbidities, pharmacokinetic characteristics, and drug use ➤ Payers many not cover genetic testing for lack of sufficient evidence for their value ➤ The management of genetic testing is a challenge without established guidelines ➤ Molecular testing can poten tially revolutionize cancer care and provide more uniform selection of systemic therapies ➤ Medicare’s 14-day rule is a barrier to molecular testing ➤ Healthcare informatics can link drug development, clinical research, and nanopharma cology to translational science

“We now can…monitor small numbers of residual tumor cells and determine very quickly...how the mutations have developed. This has changed dramatically the way we practice healthcare.”

➤

“If the ordering physician finds that the test is medically necessary and he or she wants to order it, the patient should get it.”

or has responded to newer-class agents, how the mutations have developed, what the mutations are, and what drugs might be appropriate,” he said. “This has changed dramatically the way we practice healthcare.” The evolution to molecular testing will allow for more uniform selection of systemic therapies. “I was delighted to hear that the National Comprehensive Cancer Network was going to be organizing a way to develop standards for how these kinds of tests are moved into the marketplace,” Dr Bender said. “You would be dismayed to know that organizations such as the College of American Pathology, which looks at all of our laboratories and sets standards for all of the tasks we do…have no standards for molecular testing.” The reason for the absence of standards for molecular testing is that no method for developing proficiency exists, he said. Organizations that perform gene-expression profiling, for example, use their own tissues to set laboratory proficiencies. Therefore, it is “difficult for the industry to develop a standard. One of the things as an industry that we absolutely have to do is to have proficiency standards,” said Dr Bender.

➤

In the case of chronic myelogenous leukemia, for example, treatment decisions depended on the absence or presence of Philadelphia chromosome–positive disease based on cytogenetic testing, which was costly and time-consuming, and it detected only large numbers of cells and not smallvolume disease.

Continued from page 17

Clinical research

Nanopharmacology

July 2011

Biomedical informatics

Postapproval safety research

to the level of approval, said Dr Morse. “We think the system should work with those companies and move those drugs and technologies forward,” he said. “There are a lot of good ideas, but the system doesn’t work well for people who can’t get the support from the venture capitalist.” Establishing a translational practice–research–payer center interface can facilitate drug development and outcomes research programs. The introduction of healthcare informatics can help bridge drug development, clinical research, and nanopharmacology with translational science research and postapproval safety research (Figure), believes Dr Morse. “In Buffalo, for example, we’ve bridged our bioinformatics center, which is one of the largest computing clusters, with what will now be one of the largest HIPAA [Health Insurance Portability and Accountability Act]compliant data centers, through a partnership with Dell,” he said. Although the goal of healthcare informatics is to permit health and economics outcomes evaluations to guide clinical use and reimbursement policies, “the reality is that state by state, and region by region, the information technologies are at different stages of implementation,” said Dr Morse. “Even though we’d like to do that and that’s our vision, I think there’s a long way to go.” Wise Resource Utilization Needed In the process of extending the lives of cancer patients, more healthcare resources are being devoted to oncology care. “We need to use those resources wisely, and that’s the concept of value,” said Dr Johnson. “Our job in managed care is to be stewards of these generous but somewhat limited resources. We have a lot of treatment variability and we have a lot of outcome variability. It’s our job as the stewards of those resources to try to limit that treatment variability.” The premise of marketing a test or drug to every patient is no longer valid, said Dimas. “We want the right patient to get the right drug or right test. It increases the value of that service,” he said. Health plan reimbursement for personalized oncology therapies is currently unpredictable and variable. As new molecular or genotyping tests and personalized drugs come to market, affordability cannot be underestimated, said Dr Morse. Therefore, methods for applying them cost-effectively must be devised. ■

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BREAST CANCER

A New Option for Metastatic Breast Cancer By Wayne Kuznar Philadelphia, PA—The new biologic therapy eribulin (Halaven) was recently approved by the US Food and Drug Administration for the treatment of patients with metastatic breast cancer. Stephen C. Malamud, MD, Attending Physician, Beth Israel Medical Center, New York City, discussed the benefits and risks associated with this new treatment option at a special session during the meeting. Eribulin is a nontaxane microtubule dynamics inhibitor indicated for the treatment of metastatic breast cancer in patients who have previously received treatment with at least 2 chemotherapeutic medications that include a taxane and an anthracycline in the adjuvant or metastatic setting. According to Dr Malamud, the mechanism of action of eribulin is “slightly different from that of the other microtubules, in that eribulin inhibits the growth phase rather than shortening the phase of the microtubules.” In an open-label, phase 3, randomized, multicenter clinical trial investigating the safety and efficacy of eribulin, the drug extended overall survival (OS) by 2.5 months: median OS was 13.1 months with eribulin (N = 508) compared with 10.6 months in the control group (N = 254), a significant difference (P = .041).

“If I don’t ask them, they don’t tell me. The incentive for patients to stay on [chemotherapy] is usually so great that they are usually willing to forgo some symptomatology.” —Stephen C. Malamud, MD

Adverse Events The most common adverse events in clinical trials have been neutropenia and peripheral neuropathy. Of 503 participants in one trial, severe neu-

tropenia lasting >1 week occurred in 12% of patients, leading to discontinuation of eribulin in <1% of patients. Grade 3 peripheral neuropathy occurred in 8% of the patients and

grade 4 in 0.4%. Peripheral neuropathy was the most common cause for therapy discontinuation in phase 1 and phase 3 clinical trials. Embryo-fetal toxicity has not been well studied with eribulin; however, it is expected to cause harm to the fetus when used during pregnancy. ■

With a unique focus on supporting the patient throughout their care continuum, Innovent Oncology offers health plans and oncology practices a comprehensive solution that enhances the quality and consistency of patient care. With evidence-based medicine as the foundation of the program, we

Ongoing Patient Monitoring As with all chemotherapeutic agents, patients must be monitored on an ongoing basis and must be asked directly for any potential adverse events. “If I don’t ask them, they don’t tell me,” said Dr Malamud. Indeed, he added, “the incentive for patients to stay on [chemotherapy] is usually so great that they are usually willing to forgo some symptomatology, so you have to push them to find out what’s going on.” When adverse events occur, Dr Malamud cautioned, “adjust dosing, hold dosing to maintain functionality.”

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further help patients by providing direct, personalized support and education between office visits as well as advance care planning regarding future treatment and care preferences. Through this patient-centric approach, we help health plans and oncology practices collaborate by aligning incentives to drive better patient outcomes as well as encourage the efficient use of healthcare resources. After all, isn’t cancer a disease we should manage together? To learn more about how Innovent Oncology is transforming cancer care, visit us at innoventoncology.com or call 866-214-2194.

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COMMUNITY ONCOLOGY

Community Oncology Clinics under Increasing Financial Pressure By Wayne Kuznar Philadelphia, PA—Changes in oncology reimbursement have driven the consolidation of community oncology practices, as more of these practices are being squeezed financially, according to Ted Okon, BS, MBA, Executive Director, Community Oncology Alliance. Consolidation decreases alternatives, and that means reduced competition, as many oncologists lose their practices. The transformation of cancer care from the inpatient setting to the outpatient community setting over the past 3 decades resulted in an improvement in the quality of care and overall costsavings, even as the treatment cost per case has increased substantially. The total cost of inpatient cancer care has fallen from 64.5% in 1987 to 27.5% this decade, for an overall costsavings of $5.5 billion. At the same time, Americans live longer with a cancer diagnosis than patients with cancer in Europe, he said. Today, 4 of every 5 patients with cancer are treated in community oncology clinics. “Many of these are fairly integrated clinics, with comprehensive facilities that provide a broad scope of patient care,” said Mr Okon, referring to clinics that perform computed tomography and positron emission tomography imaging in

health insurance may have greater out-of-pocket responsibilities over time, warned Mr Okon. “The problem with cancer care is not going to be ‘no insurance’; it’s going to be ‘underinsurance,’” he said.

“If we don’t come together, there’s going to be less quality, higher cost, and inefficiencies all over the map.” —Ted Okon, BS, MBA addition to laboratory work and chemotherapy and radiation administration. Reimbursement Pressure However, community oncology practices have been under increasing pressure since the Centers for Medicare & Medicaid Services (CMS) changed its oncology reimbursement in 2004/2005 and have made subsequent payment cuts. Since 2004, Medicare reimbursement has fallen by 35%. A study by Avalere Health showed

Figure Impact of Financial Pressure on Private Oncology Practices, March 31, 2011

that Medicare covered only 57% of the cost of drug administration in 2008, and it covers even less now. As a result, community oncology clinics are closing at an accelerating pace, and more private practices are being sold or absorbed by hospitals (Figure). The Medicare payment system that is based on the flawed sustainable growth rate (SGR) has created additional pressures on cash flow (when claims are held) and business planning. The healthcare reform law will mean more Americans aged <65 years covered by insurance, but 50% will come under Medicaid, at a time when more states are under pressure to cut Medicaid coverage and provider reimbursement. Eliminating cost-sharing for certain diagnostic tests is expected to increase the number of cancer cases detected. Patients with cancer who have private

at a glance

Acquired by hospital Clinics closed Merged/acquired by another entity Practices sending patients elsewhere Practices struggling financially

1042 clinics/practices have been affected in the past 3.5 years, as of March 31, 2011: 199 clinics closed 369 practices struggling financially 48 practices sending ALL patients elsewhere for treatment 315 practices acquired by a hospital 111 practices merged/acquired by another entity

Source: Community Oncology Association Practice Impact Tracking database as of March 31, 2011. Courtesy of Ted Okon.

➤ Changes in reimbursement have driven the consolidation of community oncology practices ➤ Since 2004, Medicare reimbursement has fallen by 35% ➤ In 2008, Medicare covered only 57% of the cost of drug adminis tration; it covers even less now ➤ By 2020, 1 in every 4 patients with cancer will be short an oncologist ➤ If the flawed Medicare/SGR payment system is not fixed, oncology practices may not survive

Affordable Care Act: Pros, Cons The Patient Protection and Affordable Care Act of 2010 contains some positive changes for oncology—breaking down barriers to cancer care, such as the elimination of annual and lifetime caps, removing preexisting conditions as a reason for coverage exclusion, and the prohibition of rescinding insurance policies retroactively, said Mr Okon. In addition, the Medicare doughnut hole will be closed fully by 2020. Elimination of individual cost-sharing will lower the barrier to certain preventive care services. New safeguards in the use of comparative effectiveness research are provided through the creation of the Patient-Centered Outcomes Research Institute, to offer objective data to providers.

“The problem with cancer care is not going to be ‘no insurance’; it’s going to be ‘underinsurance.’” —Ted Okon, BS, MBA

The healthcare reform bill, however, has also created uncertainties for oncology. It includes no fix for the Medicare/SGR payment system. If the system is not fixed, oncology practices may not be able to survive, Mr Okon warned. Under reform, Medicare will transition physicians to a value-based purchasing reimbursement system using quality and cost measures. Reimbursement will be tied to CMS reporting on physicians’ relative patterns of use, but it is unclear how this will be implemented for oncology. The creation of the Independent Payment Advisory Board “is a disaster to me, like SGR on steroids,” said Mr Okon. Any recommendations from the board will be fast-tracked into law, as they will be difficult for Congress to override. The Physician Quality Reporting Initiative changes from an incentive to a penalty program for nonparticipants. Continued on page 26

VALUE-BASED CANCER CARE

July 2011

VOL. 2

NO. 4

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In advanced RCC:

Afinitor doubled median PFS after progression on sunitinib*1 Progression-free survival (PFS) after progression on sunitinib or sorafenib1 100

Hazard Ratio=0.33 95% CI [0.25, 0.43] Kaplan-Meier medians Afinitor: (n=277) 4.9 months (95% CI, 4.0-5.5) Placebo: (n=139) 1.9 months (95% CI, 1.8-1.9) Log rank P value=<0.0001

Probability (%)

1.9

4.9

months

Placebo 40

Afinitor 20

Time (months)

4.9 months median PFS with Afinitor + BSCâ&#x20AC; (vs 1.9 months with placebo + BSC; P<0.0001)1 HR 0.33=67% reduction in risk of progression Effective for patients with all prognostic scores1 For more information about Afinitor, call 1-888-4Afinitor (1-888-423-4648) or visit www.AFINITOR.com For reimbursement questions, call 1-888-5AfiniTRAC (1-888-523-4648). *In the RECORD-1 trial, Afinitor extended PFS after progression on sunitinib or sorafenib.1,2 â&#x20AC; BSC=best supportive care.

Important Safety Information There have been reports of non-infectious pneumonitis and infections, some with fatal outcomes. Oral ulceration has been reported. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes, neutrophils, and platelets have been reported. Please see Important Safety Information on right side of page. Please see Brief Summary of full Prescribing Information on the following pages.

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Afinitor is indicated for the treatment of patients with advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib. Important Safety Information Afinitor is contraindicated in patients with hypersensitivity to everolimus, to other rapamycin derivatives, or to any of the excipients. Non-infectious pneumonitis is a class effect of rapamycin derivatives, including Afinitor. Fatal outcomes have been observed. If symptoms are moderate or severe, patients should be managed with dose interruption until symptoms improve or discontinuation, respectively. Corticosteroids may be indicated. Afinitor may be reintroduced at 5 mg daily depending on the individual clinical circumstances. Afinitor has immunosuppressive properties and may predispose patients to bacterial, fungal, viral or protozoan infections, including infections with opportunistic pathogens. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, and viral infections including reactivation of hepatitis B virus have occurred. Some of these infections have been severe (e.g. leading to respiratory or hepatic failure) or fatal. Complete treatment of pre-existing invasive fungal infections prior to starting treatment. While taking Afinitor be vigilant for signs and symptoms of infection; if a diagnosis of infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of Afinitor. If a diagnosis of invasive systemic fungal infection is made, discontinue Afinitor and treat with appropriate antifungal therapy. Oral ulcerations (i.e. mouth ulcers, stomatitis, and oral mucositis) have occurred in patients treated with Afinitor. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided. Antifungal agents should not be used unless fungal infection has been diagnosed. Elevations of serum creatinine, glucose, lipids, and triglycerides and reductions of hemoglobin, lymphocytes,

neutrophils, and platelets have been reported in clinical trials. Renal function, hematological parameters, blood glucose, and lipids should be evaluated prior to treatment and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on Afinitor. Avoid concomitant use with strong CYP3A4 or PgP inhibitors. If co-administration with moderate CYP3A4 or PgP inhibitors is required, use caution and reduce dose of Afinitor to 2.5 mg daily. Increase the Afinitor dose if co-administered with a strong CYP3A4 inducer. Afinitor should not be used in patients with severe hepatic impairment. Afinitor dose should be reduced to 5 mg daily for patients with moderate hepatic impairment. The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with Afinitor. Fetal harm can occur if Afinitor is administered to a pregnant woman. The most common adverse reactions (incidence ≥30%) were stomatitis (44%), infections (37%), asthenia (33%), fatigue (31%), cough (30%), and diarrhea (30%). The most common grade 3/4 adverse reactions (incidence ≥3%) were infections (9%), dyspnea (8%), fatigue (5%), stomatitis (4%), dehydration (4%), pneumonitis (4%), abdominal pain (3%), and asthenia (3%). The most common laboratory abnormalities (incidence ≥50%) were anemia (92%), hypercholesterolemia (77%), hypertriglyceridemia (73%), hyperglycemia (57%), lymphopenia (51%), and increased creatinine (50%). The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia (18%), hyperglycemia (16%), anemia (13%), hypophosphatemia (6%), and hypercholesterolemia (4%). Deaths due to acute respiratory failure (0.7%), infection (0.7%), and acute renal failure (0.4%) were observed on the Afinitor arm.

References: 1. Afinitor [prescribing information]. East Hanover, NJ: Novartis Pharmaceuticals Corporation; 2010. 2. Motzer RJ, Escudier B, Oudard S, et al; for the RECORD-1 Study Group. Efficacy of everolimus in advanced renal cell carcinoma: a double-blind, randomised, placebo-controlled phase III trial. Lancet. 2008;372:449-456. 2.5 mg 5 mg 10 mg

Printed in U.S.A.

10/10

AFI-1002330

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

while using AFINITOR and for up to 8 weeks after ending treatment [see Use in Specific Populations (8.1)]. 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in another section of the label:

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

• Non-infectious pneumonitis [see Warnings and Precautions (5.1)].

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

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

5 WARNINGS AND PRECAUTIONS 5.1 Non-infectious Pneumonitis Non-infectious pneumonitis is a class effect of rapamycin derivatives, including AFINITOR. In the randomized study, non-infectious pneumonitis was reported in 14% of patients treated with AFINITOR. The incidence of Common Toxicity Criteria (CTC) grade 3 and 4 non-infectious pneumonitis was 4% and 0%, respectively [see Adverse Reactions (6.1)]. Fatal outcomes have been observed. Consider a diagnosis of non-infectious pneumonitis in patients presenting with non-specific respiratory signs and symptoms such as hypoxia, pleural effusion, cough, or dyspnea, and in whom infectious, neoplastic, and other causes have been excluded by means of appropriate investigations. Advise patients to report promptly any new or worsening respiratory symptoms. Patients who develop radiological changes suggestive of non-infectious pneumonitis and have few or no symptoms may continue AFINITOR therapy without dose alteration. If symptoms are moderate, consider interrupting therapy until symptoms improve. The use of corticosteroids may be indicated. AFINITOR may be reintroduced at 5 mg daily. For cases where symptoms of non-infectious pneumonitis are severe, discontinue AFINITOR therapy and the use of corticosteroids may be indicated until clinical symptoms resolve. Therapy with AFINITOR may be re-initiated at a reduced dose of 5 mg daily depending on the individual clinical circumstances. 5.2 Infections AFINITOR has immunosuppressive properties and may predispose patients to bacterial, fungal, viral, or protozoan infections, including infections with opportunistic pathogens [see Adverse Reactions (6.1)]. Localized and systemic infections, including pneumonia, other bacterial infections, invasive fungal infections, such as aspergillosis or candidiasis, and viral infections including reactivation of hepatitis B virus have occurred in patients taking AFINITOR. Some of these infections have been severe (e.g., leading to respiratory or hepatic failure) or fatal. Physicians and patients should be aware of the increased risk of infection with AFINITOR. Complete treatment of pre-existing invasive fungal infections prior to starting treatment with AFINITOR. While taking AFINITOR be vigilant for signs and symptoms of infection; if a diagnosis of an infection is made, institute appropriate treatment promptly and consider interruption or discontinuation of AFINITOR. If a diagnosis of invasive systemic fungal infection is made, discontinue AFINITOR and treat with appropriate antifungal therapy. 5.3 Oral Ulceration Mouth ulcers, stomatitis, and oral mucositis have occurred in patients treated with AFINITOR. In the randomized study, approximately 44% of AFINITOR-treated patients developed mouth ulcers, stomatitis, or oral mucositis, which were mostly CTC grade 1 and 2 [see Adverse Reactions (6.1)]. In such cases, topical treatments are recommended, but alcohol- or peroxide-containing mouthwashes should be avoided as they may exacerbate the condition. Antifungal agents should not be used unless fungal infection has been diagnosed [see Drug Interactions (7.1)]. 5.4 Laboratory Tests and Monitoring Renal Function Elevations of serum creatinine, usually mild, have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of renal function, including measurement of blood urea nitrogen (BUN) or serum creatinine, is recommended prior to the start of AFINITOR therapy and periodically thereafter. Blood Glucose and Lipids Hyperglycemia, hyperlipidemia, and hypertriglyceridemia have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of fasting serum glucose and lipid profile is recommended prior to the start of AFINITOR therapy and periodically thereafter. When possible, optimal glucose and lipid control should be achieved before starting a patient on AFINITOR. Hematological Parameters Decreased hemoglobin, lymphocytes, neutrophils, and platelets have been reported in clinical trials [see Adverse Reactions (6.1)]. Monitoring of complete blood count is recommended prior to the start of AFINITOR therapy and periodically thereafter. 5.5 Drug-drug Interactions Due to significant increases in exposure of everolimus, co-administration with strong inhibitors of CYP3A4 (e.g., ketoconazole, itraconazole, clarithromycin, atazanavir, nefazodone, saquinavir, telithromycin, ritonavir, indinavir, nelfinavir, voriconazole) or P-glycoprotein (PgP) should be avoided. Grapefruit, grapefruit juice and other foods that are known to affect cytochrome P450 and PgP activity should also be avoided during treatment [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. A reduction of the AFINITOR dose is recommended when co-administered with a moderate CYP3A4 inhibitor (e.g., amprenavir, fosamprenavir, aprepitant, erythromycin, fluconazole, verapamil, diltiazem) or PgP inhibitor [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.1)]. An increase in the AFINITOR dose is recommended when co-administered with a strong CYP3A4 inducer (e.g., St. John’s Wort (Hypericum perforatum), dexamethasone, prednisone, prednisolone, phenytoin, carbamazepine, rifampin, rifabutin, rifapentine, phenobarbital) [see Dosage and Administration (2.2) in the full prescribing information and Drug Interactions (7.2)]. 5.6 Hepatic Impairment The safety and pharmacokinetics of AFINITOR were evaluated in a study in eight patients with moderate hepatic impairment (Child-Pugh class B) and eight subjects with normal hepatic function. Exposure was increased in patients with moderate hepatic impairment, therefore a dose reduction is recommended. AFINITOR has not been studied in patients with severe hepatic impairment (Child-Pugh class C) and should not be used in this population [see Dosage and Administration (2.2) in the full prescribing information and Use in Specific Populations (8.7)]. 5.7 Vaccinations The use of live vaccines and close contact with those who have received live vaccines should be avoided during treatment with AFINITOR. Examples of live vaccines are: intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines. 5.8 Use in Pregnancy Pregnancy Category D There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception

• Infections [see Warnings and Precautions (5.2)].

The data described below reflect exposure to AFINITOR (n=274) and placebo (n=137) in a randomized, controlled trial in patients with metastatic renal cell carcinoma who received prior treatment with sunitinib and/or sorafenib. The median age of patients was 61 years (range 27-85), 88% were Caucasian, and 78% were male. The median duration of blinded study treatment was 141 days (range 19-451) for patients receiving AFINITOR and 60 days (range 21-295) for those receiving placebo. The most common adverse reactions (incidence ≥30%) were stomatitis, infections, asthenia, fatigue, cough, and diarrhea. The most common grade 3/4 adverse reactions (incidence ≥3%) were infections, dyspnea, fatigue, stomatitis, dehydration, pneumonitis, abdominal pain, and asthenia. The most common laboratory abnormalities (incidence ≥50%) were anemia, hypercholesterolemia, hypertriglyceridemia, hyperglycemia, lymphopenia, and increased creatinine. The most common grade 3/4 laboratory abnormalities (incidence ≥3%) were lymphopenia, hyperglycemia, anemia, hypophosphatemia, and hypercholesterolemia. Deaths due to acute respiratory failure (0.7%), infection (0.7%) and acute renal failure (0.4%) were observed on the AFINITOR arm but none on the placebo arm. The rates of treatment-emergent adverse events (irrespective of causality) resulting in permanent discontinuation were 14% and 3% for the AFINITOR and placebo treatment groups, respectively. The most common adverse reactions (irrespective of causality) leading to treatment discontinuation were pneumonitis and dyspnea. Infections, stomatitis, and pneumonitis were the most common reasons for treatment delay or dose reduction. The most common medical interventions required during AFINITOR treatment were for infections, anemia, and stomatitis. Table 1 compares the incidence of treatment-emergent adverse reactions reported with an incidence of ≥10% for patients receiving AFINITOR 10 mg daily versus placebo. Within each MedDRA system organ class, the adverse reactions are presented in order of decreasing frequency. Table 1 Adverse Reactions Reported in at least 10% of Patients and at a Higher Rate in the AFINITOR Arm than in the Placebo Arm AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

Any Adverse Reaction

Gastrointestinal Disorders Stomatitisa Diarrhea Nausea Vomiting

44 30 26 20

4 1 1 2

<1 0 0 0

8 7 19 12

0 0 0 0

Infections and Infestationsb

<1 0 0 0 0

23 27 8 9 1

4 3 <1 0 0

0 <1 0 0 0

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

0 1 0 0

16 15 0 0

0 3 0 0

0 0 0 0

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

1 <1 <1

0 0 0

7 7 5

0 0 0

<1 0

9 2

<1 0

0 0

Musculoskeletal and Connective Tissue Disorders Pain in extremity 10 1

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

Metabolism and Nutrition Disorders Anorexia 25 Nervous System Disorders Headache Dysgeusia

19 10

Median Duration of Treatment (d)

141

CTCAE Version 3.0 a Stomatitis (including aphthous stomatitis), and mouth and tongue ulceration. b Includes all preferred terms within the ‘infections and infestations’ system organ class, the most common being nasopharyngitis (6%), pneumonia (6%), urinary tract infection (5%), bronchitis (4%), and sinusitis (3%), and also including aspergillosis (<1%), candidiasis (<1%), and sepsis (<1%). c Includes pneumonitis, interstitial lung disease, lung infiltration, pulmonary alveolar hemorrhage, pulmonary toxicity, and alveolitis. Other notable adverse reactions occurring more frequently with AFINITOR than with placebo, but with an incidence of <10% include: Gastrointestinal disorders: Abdominal pain (9%), dry mouth (8%), hemorrhoids (5%), dysphagia (4%) General disorders and administration site conditions: Weight decreased (9%), chest pain (5%), chills (4%), impaired wound healing (<1%) Respiratory, thoracic and mediastinal disorders: Pleural effusion (7%), pharyngolaryngeal pain (4%), rhinorrhea (3%) Skin and subcutaneous tissue disorders: Hand-foot syndrome (reported as palmar-plantar erythrodysesthesia syndrome) (5%), nail disorder (5%), erythema (4%), onychoclasis (4%), skin lesion (4%), acneiform dermatitis (3%) Metabolism and nutrition disorders: Exacerbation of pre-existing diabetes mellitus (2%), new onset of diabetes mellitus (<1%) Psychiatric disorders: Insomnia (9%) Nervous system disorders: Dizziness (7%), paresthesia (5%) Eye disorders: Eyelid edema (4%), conjunctivitis (2%)

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Vascular disorders: Hypertension (4%)

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

Renal and urinary disorders: Renal failure (3%) Cardiac disorders: Tachycardia (3%), congestive cardiac failure (1%) Musculoskeletal and connective tissue disorders: Jaw pain (3%) Hematologic disorders: Hemorrhage (3%) Key treatment-emergent laboratory abnormalities are presented in Table 2. Table 2 Key Laboratory Abnormalities Reported at a Higher Rate in the AFINITOR Arm than the Placebo Arm Laboratory Parameter

AFINITOR 10 mg/day N=274

Placebo N=137

All grades %

Grade 3 %

Grade 4 %

All grades %

Grade 3 %

Grade 4 %

92 51 23 14

12 16 1 0

1 2 0 <1

79 28 2 4

5 5 0 0

<1 0 <1 0

77 73 57 50 37

4 <1 15 1 6

0 0 <1 0 0

35 34 25 34 8

0 0 1 0 0

0 0 0 0 0

21 3

1 <1

0 <1

4 2

0 0

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

CTCAE Version 3.0 a Includes reports of anemia, leukopenia, lymphopenia, neutropenia, pancytopenia, thrombocytopenia. Information from further clinical trials In clinical trials, everolimus has been associated with serious cases of hepatitis B reactivation, including fatal outcomes. 7 DRUG INTERACTIONS Everolimus is a substrate of CYP3A4, and also a substrate and moderate inhibitor of the multidrug efflux pump PgP. In vitro, everolimus is a competitive inhibitor of CYP3A4 and a mixed inhibitor of CYP2D6.

In a pre- and post-natal development study in rats, animals were dosed from implantation through lactation. At approximately 10% of the recommended human dose based on body surface area, there were no adverse effects on delivery and lactation and there were no signs of maternal toxicity. However, there was reduced body weight (up to 9% reduction from the control) and slight reduction in survival in offspring (~5% died or missing). There were no drug-related effects on the developmental parameters (morphological development, motor activity, learning, or fertility assessment) in the offspring. Doses that resulted in embryo-fetal toxicities in rats and rabbits were ≥0.1 mg/kg (0.6 mg/m2) and 0.8 mg/kg (9.6 mg/m2), respectively. The dose in the pre- and post-natal development study in rats that caused reduction in body weights and survival of offspring was 0.1 mg/kg (0.6 mg/m2). 8.3 Nursing Mothers It is not known whether everolimus is excreted in human milk. Everolimus and/or its metabolites passed into the milk of lactating rats at a concentration 3.5 times higher than in maternal serum. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants from everolimus, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric Use The safety and effectiveness in pediatric patients have not been established. 8.5 Geriatric Use In the randomized study, 41% of AFINITOR-treated patients were ≥65 years in age, while 7% percent were 75 and over. No overall differences in safety or effectiveness were observed between these subjects and younger subjects, and other reported clinical experience has not identified differences in responses between the elderly and younger patients, but greater sensitivity of some older individuals cannot be ruled out [see Clinical Pharmacology (12.3) in the full prescribing information]. No dosage adjustment is required in elderly patients [see Clinical Pharmacology (12.3) in the full prescribing information]. 8.6 Renal Impairment No clinical studies were conducted with AFINITOR in patients with decreased renal function. Renal impairment is not expected to influence drug exposure and no dosage adjustment of everolimus is recommended in patients with renal impairment [see Clinical Pharmacology (12.3) in the full prescribing information].

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

8.7 Hepatic Impairment For patients with moderate hepatic impairment (Child-Pugh class B), the dose should be reduced to 5 mg daily [see Dosage and Administration (2.2) in the full prescribing information, Warnings and Precautions (5.6) and Clinical Pharmacology (12.3) in the full prescribing information].

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

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

• erythromycin (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.0- and 4.4-fold, respectively. • verapamil (a moderate CYP3A4 inhibitor and a PgP inhibitor) - Cmax and AUC increased by 2.3- and 3.5-fold, respectively. Concomitant strong inhibitors of CYP3A4 and PgP should not be used [see Warnings and Precautions (5.5)]. Use caution when AFINITOR is used in combination with moderate CYP3A4 or PgP inhibitors. If alternative treatment cannot be administered reduce the AFINITOR dose. [See Dosage and Administration (2.2) in the full prescribing information] 7.2 Agents that may Decrease Everolimus Blood Concentrations CYP3A4 Inducers: In healthy subjects, co-administration of AFINITOR with rifampin, a strong inducer of CYP3A4, decreased everolimus AUC and Cmax by 64% and 58% respectively, compared to everolimus treatment alone. Consider a dose increase of AFINITOR when co-administered with strong inducers of CYP3A4 (e.g., dexamethasone, phenytoin, carbamazepine, rifampin, rifabutin, phenobarbital) or PgP if alternative treatment cannot be administered. St. John’s Wort may decrease everolimus exposure unpredictably and should be avoided [see Dosage and Administration (2.2) in the full prescribing information].

10 OVERDOSAGE In animal studies, everolimus showed a low acute toxic potential. No lethality or severe toxicity were observed in either mice or rats given single oral doses of 2000 mg/kg (limit test). Reported experience with overdose in humans is very limited. Single doses of up to 70 mg have been administered. The acute toxicity profile observed with the 70 mg dose was consistent with that for the 10 mg dose. 16 STORAGE Store AFINITOR (everolimus) tablets at 25°C (77°F); excursions permitted between 15°-30°C (59°-86°F). [See USP Controlled Room Temperature.] Store in the original container, protect from light and moisture. Keep this and all drugs out of the reach of children. Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published. AFINITOR tablets should not be crushed. Do not take tablets which are crushed or broken.

7.3 Agents whose Plasma Concentrations may be Altered by Everolimus Studies in healthy subjects indicate that there are no clinically significant pharmacokinetic interactions between AFINITOR and the HMG-CoA reductase inhibitors atorvastatin (a CYP3A4 substrate) and pravastatin (a non-CYP3A4 substrate) and population pharmacokinetic analyses also detected no influence of simvastatin (a CYP3A4 substrate) on the clearance of AFINITOR. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category D [see Warnings and Precautions (5.8)] There are no adequate and well-controlled studies of AFINITOR in pregnant women. However, based on mechanism of action, AFINITOR may cause fetal harm when administered to a pregnant woman. Everolimus caused embryo-fetal toxicities in animals at maternal exposures that were lower than human exposures at the recommended dose of 10 mg daily. If this drug is used during pregnancy or if the patient becomes pregnant while taking the drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to use an effective method of contraception while receiving AFINITOR and for up to 8 weeks after ending treatment.

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

T2010-56

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COMMUNITY ONCOLOGY

The Crisis in Cancer Care Interview with Ted Okon, BS, MBA Executive Director, Community Oncology Alliance, Washington, DC Q: In your presentation, you said that oncology is in crisis—what did you mean by that? Mr Okon: When I say cancer care is in crisis, I mean that we have a perfect storm brewing. First, we have the graying of America, so we are going to have an increasing incidence of cancer. Second, we have a growing unhealthy population that is going to result in increased cases of cancer. Third, we have an oncologist population that is flat or declining in the face of increasing demand for cancer care. We have a situation that is going to produce a crisis, and we are not going to see when we hit it. Congress won’t be able to stimulate its way out of that. Delivering cancer care is very complex: we are not going to be able to create oncologists overnight. So we have a real crisis brewing.

the MMA, the effective decline of reimbursement has been 47%. We cannot operate a business where we are seeing such steep declines. We need to look at the reimbursement system differently. We should be paying oncologists for one of the most important things they do: treatment plans. We should be paying oncolo-

Q: Do you have suggestions for solving this crisis? Mr Okon: The suggestions right now are unrealistic. What the government is doing reflects the reimbursement system changes for cancer care that were introduced in the 2003 Medicare Modernization Act (MMA). Medicare is 50% cancer care, which is the 800-pound gorilla in the room. Medicare influences everything on the private pay side as well. The reimbursement is just not realistic. If we look at the increasing expenses of running a practice as measured by

“We have a perfect storm brewing. We have the graying of America…a growing unhealthy population…[and] an oncologist population that is flat or declining in the face of increasing demand for cancer care.”

Community Oncology... Continued from page 20 “The oncology measures are weak at best,” said Mr Okon. A Physician Compare database will be implemented, similar to the Hospital Compare database, but how oncologists are going to be compared has not been elucidated. Grim Outlook for Oncology Healthcare reform “will likely pressure a cancer care delivery system already under pressure,” as reimbursement is decreased in numerous ways, said Mr Okon. Costs for payers are likely going to increase as competition is reduced through the consolidation of community clinics. In addition, demand for cancer care may outstrip the supply of oncologists. It has been estimated that by 2020, the equivalent of “1 in every 4 patients with cancer will be short an oncologist,” he said.

Payer-Provider Collaboration Oncology payers and providers need to come together to preserve and enhance the delivery system. “If we don’t come together, there’s going to be less quality, higher cost, and inefficiencies all over the map,” Mr Okon noted. Working together to use evidencebased clinical pathways can enhance treatment quality and efficiencies, he said, but just as important is the inclusion of a feedback loop to gauge how clinical pathways are working and how they can be improved. In addition, appropriate payment should be considered for key cognitive services, such as treatment planning and follow-up care planning. “Treatment planning is the key thing you want your oncologists to do when you have cancer,” he concluded. ■

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July 2011

gists for cognitive services, such as treatment plans. Oncologists are reimbursed in 3 ways. First, they are reimbursed for their evaluation and management, like all physicians. Second, they are reimbursed for administering chemotherapy drugs in the office, including for related services. Third, they are reimbursed for the drugs. All the other cognitive services, such as planning for treatment, follow-up care, and survivorship, are not reimbursed. The reimbursement system flies in the face of value-based insurance design. If we want to create value in the system, that is where we have to focus the reimbursement, and it is not. If some things are not done now, and we let some aspects of healthcare reform go into play—for example, the Independent Payment Advisory Board, where there is just going to be wholesale and immediate cuts to Medicare when spending targets are exceeded—it will hit providers, and we are going to put a knife in cancer care.

Q: Why are so many cancer sites closing? Mr Okon: We have had roughly 200 individual sites that have closed since 2008. In some cases, entire practices have closed. It has hit some rural and underserved areas hard, because it becomes extremely expensive to operate clinics in the face of this declining reimbursement. We are seeing a big escalation in practices that are being acquired on the hospital side. I do not mean to be disrespectful to hospitals, but we are going to end up decreasing competition. We are going to create mega-entities, and it is going to cost payers and patients more.

“Medicare is 50% cancer care, which is the 800-pound gorilla in the room. If we want to create value in the

system, that is where we have to focus the reimbursement, and it is not.”

Many hospitals now have good outpatient centers. When that gets consolidated—and there are lots of hospitals that are in trouble—many hospitals are going to close. When the market consolidates down that far, it reduces alternatives. Therefore competition in the market is never healthy in terms of quality and value.

Q: Several states are talking about cutting Medicaid. Will it have a large impact on oncology practices? Mr Okon: Typically an oncology practice will not have a large Medicaid population, but it is going to get bigger. There are going to be an additional 32 million to 34 million Americans covered by insurance in 2014, if the law is not declared unconstitutional by then, and that is going to increase the Medicaid population by 16 million individuals. As a result, there is going to be even more strain, because states are cutting Medicaid benefits for the individual. This is unrealistic, because fewer states are going to be able to afford to cover cancer care. And the issue of dual-eligible persons with both Medicare and Medicaid is going to be a huge problem.

Q: Does sustainable growth rate (SGR) still have a negative effect on oncology practices? Mr Okon: Yes, it has an inordinate adverse impact on oncology practices every time there is an SGR patch that results in held claims. SGR affects only the services, not the drugs. But when a service claim is held up, that service claim is tied to a drug. If we decouple those, we are going to run the risk of never getting paid for the drug. On average, an oncologist is responsible for $2.2 million to $2.5 million annually in terms of drugs administered, so they are essentially subsidizing Medi care when claims are held. The problem is that a medical practice has to operate as a business, or it will die. This involves business and strategic planning, but that planning cycle has been thrown out the window. The federal government is not held to the same laws. A practice has to worry about its cash flow and planning. Medical practices that experience patch after patch on the SGR cannot efficiently operate and plan. We do not know what future reimbursement will look like. When we have a potential 29.4% Medicare cut by the end of the year, how do practices plan and staff? It makes providers think of closing facilities. So, the SGR is a huge problem for all providers, but it inordinately impacts oncology, because of the magnitude of the capital outlay that oncology practices have to make in drug purchases and facilities.

Q: Does failure to sustain the growth rate ultimately drive up costs for everyone? Mr Okon: Absolutely. It could have been fixed 5 to 6 years ago at approxiContinued on page 27

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ONCOLOGY PRACTICES

Oncologists Face Economic Challenges while Improving Patient Care Stakeholder partnership can enhance clinical practice By Wayne Kuznar Philadelphia, PA—The estimated cost for physician practices to interact with health insurance plans is $23 billion to $31 billion annually, according to a 2009 national survey conducted by Casalino and colleagues (Health Aff. 2009;28:w533-w543). In the survey, physicians reported spending 3 hours weekly interacting with health plans; nursing and clerical staff spent much larger amounts of time. “This describes the cost to practices over and above the costs of care for the uninsured and the cost to manage preauthorization and prior approval,” said Craig Deligdish, MD, Chief Medical Officer, Florida Comprehensive Care Network, Melbourne. “This is something that patients don’t see. It is something in an oncologist’s office that requires a great deal of time and effort. And it is one of the major reasons I suspect that certain practices do not buy and bill anymore, because administering treatments that, in 1 session, can cost $30,000 is potentially challenging when your reimbursement is only 2% greater than the cost of that treatment in a given day.” Today, an average encounter in an oncologist’s office could result in a $10,000 or $20,000 bill, which is problematic when a denial comes, because

the practice did not obtain proper preauthorization. A recent survey conducted by the American Medical Association (www. ama-assn.org/ama/pub/news/news/ survey-insurer-preauthorization.page) reveals that policies requiring physicians to ask permission from a patient’s insurance company before performing a treatment have a negative impact on patient care. The survey results suggest that: • 37% of physicians face a 20% rejection rate from insurers on first-time preauthorization requests for tests and procedures • 57% of physicians face a 20% rejection rate from insurers on first-time preauthorization requests for drugs • 46% of physicians have difficulty obtaining approval from insurers on ≥25% of preauthorization requests for tests and procedures • 63% of physicians typically wait several days to receive preauthorization from an insurer for tests and procedures; 13% wait >1 week • 64% of physicians have difficulty determining which tests and procedures require preauthorization by insurers. Assisting the Uninsured “To my recollection, one of the rea-

The Crisis in Cancer... mately $50 billion. Now it is well over $300 billion.

Q: Do oncologists get reimbursed for counseling patients on adherence? Mr Okon: No, oncologists do not get reimbursed for counseling patients on the details, which can be extensive, associated with prescribing oral cancer drugs. Some payers mistakenly believe that they can deal with all of the details by contracting with a specialty pharmacy or other outside provider, but we have seen disaster in some cases. We have seen cases where an outside nurse will call a patient and ask why the patient is not taking his/her drug, when the reason is the oncologist just stopped the drug because of side effects. This disjointed communication is very confusing to the patient and can lead to inefficiencies and, at worse, bad patient outcomes. A major problem is that with oral

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“We believe the community setting is one of the best places to receive cancer treatment, so we are working with practices and health plans to hopefully provide the most cost-effective treatment in the most cost-effective setting.” —Craig Deligdish, MD

sons for healthcare reform initially was to cover the uninsured,” Dr Deligdish said. “Today, I don’t think that has occurred.” According to the US government, 50.3 million Americans are uninsured this year; by 2020, as many as 61.1 million will be uninsured. “And as oncologists in practice, whether in a hospital or a private setting, we are faced with taking care of these people. I do not know too many practices anywhere in the country that turn away patients who have cancer. It takes a great deal of time and effort to provide care to these patients,” Dr Deligdish said. In response to these challenges, some practices have stopped buying

Continued from page 26

oncolytics practices receive absolutely no reimbursement for patient management and counseling. Rather than provide appropriate reimbursement and optimize the coordination of care, using an outside provider often leads to disjointed, inefficient care. This will be a growing problem with oral oncolytics because the drug pipeline is huge. We have 100% adherence with intravenous drugs, because oncologists know if the patient came in and received chemotherapy treatment on site. Unless there was a mistake in giving the drug, we know the exact dose and when the patient received it. In contrast, we have major issues with oral medications. There is the possibility of side effects, and we don’t even know if the patient is taking the drug. The oncologist does not know whether the drug did not work, or if the drug was not taken. The drug could have been so expensive that the

patient cut it in half, as many patients do with their heart medications, or may not have even filled it in the first place. A practice trying to manage such a patient is not reimbursed for that.

Q: Do you support healthcare reform that can give nurses more responsibility in patient care? Mr Okon: Absolutely, I support it. I think that oncology nurses are the real glue in any clinic. I think we should support practices using mid-level providers and physician assistants, because they are so critical. Nurse practitioners add a lot of value. I support increasing not only the population but also the education incentives of physician assistants, nurse practitioners, and oncology nurses. They are part of the oncology team, especially when we see the number of oncologists decreasing relative to demand. It is great to see practices that truly work as an integrated team. ■

and billing chemotherapy, some have merged with hospitals, and some have closed their doors. The remaining practices that seek to remain independent have hired financial counselors to control costs. There is a true need to reduce the administrative burden. “Your 2 largest expenses in an oncology practice are the drugs and your payroll, and you have to manage both of them well in order to survive,” said Leonard H. Natelson, Chief Executive Officer, Hematology/Oncology Associates of Rockland, NY. “Keeping your doors open is good for the patient, and you may have to reinvent your business model. “I don’t have to do the patient assistance, because I use a specialty pharmacy,” Mr Natelson continued. “Every drug company has a patient assistance program. Most therapies are multidrug, multicompany therapies. It costs you money to have somebody sit on the phone and go back and forth with companies to get all this money. You take it out of your practice, so you don’t have to cover the payroll for the person doing it.” Specialty pharmacies also reach out to private foundations, which community oncology practices generally do not have. This is another avenue to help patients with significant copays. If there is considerable financial hardship, a patient can go through an assistance program instead of the physician’s office. “Generally, patients do not like to discuss blockades to getting patient care, and they certainly do not want to discuss it with their physician or anyone in the practice. The program gives them someone completely separate, and it’s just a telephone call, unrelated to our practice. I have a number of patients on those proContinued on page 28

www.ValueBasedCancerCare.com

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ONCOLOGY PRACTICES

Oncologists Face Economic Challenges... grams....It keeps them on their treatment schedule, which is very important,” Mr Natelson said. Mr Natelson added that specialty pharmacies have an advantage over oncology practice offices, because they get immediate adjudication. “They know that the claim blew up right then and there,” he said. “On the other hand, an oncology office will give a drug, file a claim, and 2 weeks later, it blows up. Now what do I do? I didn’t have a chance to change the therapy or say, ‘Is there another therapy that’s clinically close that I can get approved for the patient?’”

“Your 2 largest expenses in an oncology practice are the drugs and your payroll, and you have to manage both of them well in order to survive.” –Leonard H. Natelson

Working with Payers, Patients One of Dr Deligdish’s solutions to economic hardships is his collaboration with physicians in Florida. As a member of the Florida Comprehensive Care Network, he is in a partnership of physicians through a clinically integrated network working with technology solutions, advanced care, palliative care programs, and oncology benefit management programs working with payers who also face challenges from their self-insured clients to try to reduce the cost of cancer treatment. “It provides physicians and health plans with the tools to manage pathway and guideline adherence, create physician guidelines, and realign in centives around buy and bill,” Dr Deligdish said. “But more important, it

provides patients with the tools they need to determine appropriate care, the appropriate time to stop treatment, and the appropriate time to enter hospice.” Although many people have been critical of some components of their care delivery system, Dr Deligdish said they have put together what they believe to be an integrated comprehensive approach to managing the cost and the care that patients receive. The goals of the network include sustaining community oncology. “We believe the community setting is one of the best places to receive cancer treatment, so we are working with practices and health plans to hopefully provide the most cost-effective treatment in the most cost-effective setting,” Dr Deligdish said. The network also aims to provide technology for consistent delivery of quality care that allow both practices and health plans to measure outcomes and monitor adherence to pathways, and decrease the administrative burden by simplifying and obviating the prior authorization process and using technology. “We focus to a large degree as a clinically integrated network,” Dr Deligdish added. “What does that mean? Clinical integration is necessary for accountable care organizations to be a reality. It’s an active and ongoing program to evaluate and modify practice patterns by the network’s physician participants to create a high degree of interdependence and cooperation to control costs and ensure quality. “The Federal Trade Commission needs to formulate additional rules such that physicians and hospitals will be able to deliver care in a clinically integrated setting,” he continued. “But it requires a tremendous amount of effort, both financial capital and human capital, by physicians to come together and put together guidelines and pathways that work, and to work with health plans to achieve those goals,” he said. Value-Based Personalized Medicine The concept of personalized medicine should result in the greatest value for patients and payers by providing best clinical outcomes and most effective use of resources, according to YuNing Wong, MD, MSCE, a medical oncologist and health services researcher at Fox Chase Cancer Center, Philadelphia, PA. As a physician in academic practice, Dr Wong is working toward increasing the value of new treatments in development.

VALUE-BASED CANCER CARE

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Continued from page 27

“We need payers to eliminate the barriers to coverage for clinical trials. Only about 5% of American patients enter clinical trials, and it is very difficult to get them on.” —Yu-Ning Wong, MD, MSCE

“I think of this as an attempt to help physicians like me identify the best, most effective, and least toxic treatment for the individual patient,” she said. Personalized medicine “should result in the best clinical outcomes for patients, and it should result in the most effective use of resources for payers, because we won’t be treating patients with expensive therapies that

at a glance ➤ An average encounter in an oncologist’s office could result in a $10,000 or $20,000 bill ➤ The estimated annual cost for physician practices to interact with health insurance plans is $23 billion to $31 billion ➤ There is a need to reduce the administrative burden for oncology practices ➤ By 2020, 61.1 million Americans will be uninsured ➤ Payers need to eliminate the barriers to coverage for clinical trials to encourage greater patient participation in the development of improved therapies

have a low likelihood of helping them.” Breast cancer may be the furthest along in terms of personalized medicine, according to Dr Wong. The vast majority of patients with estrogenreceptive–positive breast cancer undergo surgery and receive hormonal therapy alone, but until very recently, identifying the patients who were most likely to have a recurrence was difficult, and physicians were overtreating with chemotherapy. Clinical trials and the introduction of the Oncotype DX assay are helping physicians in clinical practice to identify patients who are likely to benefit from chemotherapy and those who could be spared the toxicity because they are unlikely to benefit. “We need payers to eliminate the barriers to coverage for clinical trials,” Dr Wong said. “Only about 5% of American patients enter clinical trials, and it is very difficult to get them on. The irony of this is that, in most cases, the standard of care we’re asking payers to cover is very similar, if not identical, to what we would be treating these patients with off study. But when we treat them off study, the data do not help to benefit future patients. It’s important for practices to discuss and support clinical trials early on.” In her practice, Dr Wong focuses mainly on kidney cancer, and treatment has changed dramatically in the past 5 to 6 years, with the approval of 6 new agents that have more than doubled overall survival. “Because there have been so many trials in recent years, this is actually a disease site that has the most National Comprehensive Care Network category 1 evidence. And one would assume that it’s now easy to treat kidney cancer because we have a lot of guidelines. But unfortunately it’s really not,” she noted. There are 3 regimens for kidney cancer often used in the frontline setting, Dr Wong said, but at this point, there are no published data to demonstrate the most effective drug. Ongoing clinical trials will help with sequencing patients in the first, second, and subsequent lines of therapy. “Personalized medicine for kidney cancer comes down to some seemingly simple, but actually complicated, discussions that we have at the bedside,” she explained. “We don’t know what the best treatment is for the individual patient. We need to decide if a treatment is working, or if oral or intravenous treatment is better. Will side effects keep a patient from working, and what will the treatment cost be to the practice and to the patient?” ■

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For your patients receiving or about to start treatment with DOXIL® for recurrent ovarian cancer or relapsed/refractory multiple myeloma…

DOXIL® C.A.R.E.S. Provides Help and Support DOXIL® C.A.R.E.S. Complements the Efforts of the Healthcare Team With: ◗ Treatment follow-up — Regularly scheduled telephone calls from oncology nurses to review lifestyle tips to help manage potential side effects of DOXIL® therapy such as hand-foot syndrome and stomatitis ◗ Patient education materials Invite your patients to enroll in DOXIL® C.A.R.E.S.: 1-877-CARES-49 (1-877-227-3749) Monday to Friday, 9:30 AM to 10:00 PM (ET). To learn more, visit www.doxil.com.

INDICATIONS ◗ DOXIL® is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy ◗ DOXIL® in combination with VELCADE® (bortezomib) is indicated for the treatment of patients with multiple myeloma who have not previously received VELCADE and have received at least one prior therapy

IMPORTANT SAFETY INFORMATION BOXED WARNINGS Cardiotoxicity, infusion reaction, myelosuppression, liver impairment, substitution ◗ The use of DOXIL® may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2 — Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dose — Cardiac toxicity may also occur at lower cumulative doses (400 mg/m2) in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy ◗ Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL®. In most patients, these reactions have resolved within several hours to a day once the infusion is terminated. In some patients, reactions resolved with slowing of the infusion rate — Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have occurred. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use — The initial rate of infusion should be 1 mg/min to minimize the risk of infusion reactions ◗ Severe myelosuppression may occur ◗ DOXIL® dosage should be reduced in patients with impaired hepatic function ◗ Accidental substitution has resulted in severe side effects. Do not substitute for doxorubicin HCl on a mg per mg basis CONTRAINDICATIONS ◗ Patients with a history of hypersensitivity reactions to a conventional doxorubicin formulation or the components of DOXIL® ◗ Nursing mothers

ADDITIONAL SAFETY INFORMATION ◗ Cardiac function should be carefully monitored — Congestive heart failure or cardiomyopathy may occur after discontinuation of anthracycline therapy — For patients with a history of cardiovascular disease, or if the results of cardiac monitoring indicate possible cardiac injury, the benefit of therapy must be weighed against the risk of myocardial injury — In the randomized multiple myeloma study, 25 patients (8%) in the VELCADE arm and 42 patients (13%) in the DOXIL® plus VELCADE arm experienced left ventricular ejection fraction decrease (defined as absolute decrease 15% over baseline or a 5% decrease below institutional lower limit of normal)

◗ Myelosuppression may occur; frequently monitor complete blood count (including platelet count), at least prior to each dose of DOXIL® — In patients with recurrent ovarian cancer, hematologic toxicity (based on platelet count or absolute neutrophil count) may require dose reduction or delay in administration of DOXIL® — In patients with multiple myeloma, hematologic toxicity (based on platelet count, absolute neutrophil count, hemoglobin level, or neutropenia with fever) may require dose reduction, delay in administration, or suspension of DOXIL® and/or VELCADE — Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage — Sepsis occurring during neutropenia has resulted in discontinuation of treatment and in rare cases of death ◗ DOXIL® may potentiate the toxicity of other anticancer therapies, especially hematologic toxicities, when used in combination with other therapies that suppress bone marrow ◗ Hand-foot syndrome (HFS) may occur during therapy with DOXIL® — Based on HFS toxicity grade, dose reduction, delay in administration, or discontinuation of DOXIL® may be required — HFS was generally observed after 2 to 3 cycles of treatment, but may occur earlier • The reaction was mild in most patients, resolving in 1 to 2 weeks • The reaction can be severe and debilitating in some patients, resulting in discontinuation of therapy ◗ DOXIL® is an irritant, not a vesicant; use precautions to avoid extravasation ◗ DOXIL® can cause fetal harm when used during pregnancy ◗ Recall reaction has occurred with DOXIL® administration after radiotherapy ◗ DOXIL® may interact with drugs known to interact with the conventional formulation of doxorubicin HCl ◗ In patients with recurrent ovarian cancer, the most common all-grade adverse reactions (ARs) 20% (DOXIL® vs topotecan, respectively) included: asthenia (40% vs 51%), fever (21% vs 31%), nausea (46% vs 63%), stomatitis (41% vs 15%), vomiting (33% vs 44%), diarrhea (21% vs 35%), anorexia (20% vs 22%), dyspnea (15% vs 23%), HFS (51% vs 1%), and rash (29% vs 12%) — In addition, 19% vs 52.3% reported alopecia (all grades) — Grade 3/4 hematologic ARs reported in 5% (DOXIL® vs topotecan, respectively) were neutropenia (12% vs 76%) and anemia (6% vs 29%) ◗ In patients with multiple myeloma, the most common all-grade ARs 20% (DOXIL® plus VELCADE vs VELCADE, respectively) included: neutropenia (36% vs 22%), thrombocytopenia (33% vs 28%), anemia (25% vs 21%), fatigue (36% vs 28%), pyrexia (31% vs 22%), asthenia (22% vs 18%), nausea (48% vs 40%), diarrhea (46% vs 39%), vomiting (32% vs 22%), constipation (31% vs 31%), mucositis/ stomatitis (20% vs 5%), peripheral neuropathy (42% vs 45%), neuralgia (17% vs 20%), and rash (22% vs 18%) — In addition, 19% vs <1% reported HFS Please see brief summary of Prescribing Information, including Boxed WARNINGS, on adjacent pages. VELCADE is a registered trademark of Millennium Pharmaceuticals, Inc.

Distributed by: Centocor Ortho Biotech Products, L.P., Horsham, Pennsylvania 19044-3607 © Centocor Ortho Biotech Products, L.P. 2010 9/10 08D10019A

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reaction at the recommended dose of 20 mg/m2 [see Adverse Reactions]. Leukopenia is the most common adverse reaction experienced in this population; anemia and thrombocytopenia can also be expected. Sepsis occurred in 5% of patients; for 0.7% of patients the event was considered possibly or probably related to DOXIL. Eleven patients (1.6%) discontinued study because of bone marrow suppression or neutropenia. Table 10 presents data on myelosuppression in patients with multiple myeloma receiving DOXIL and bortezomib in combination [see Adverse Reactions].

DOXIL® (doxorubicin HCl liposome injection) for intravenous infusion BRIEF SUMMARY. Please see Full Prescribing Information. WARNING: INFUSION REACTIONS, MYELOSUPPRESSION, CARDIOTOXICITY, LIVER IMPAIRMENT, ACCIDENTAL SUBSTITUTION 1. The use of DOXIL (doxorubicin HCl liposome injection) may lead to cardiac toxicity. Myocardial damage may lead to congestive heart failure and may occur as the total cumulative dose of doxorubicin HCl approaches 550 mg/m2. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at a starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2 or between 500550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. Prior use of other anthracyclines or anthracenediones should be included in calculations of total cumulative dosage. Cardiac toxicity may also occur at lower cumulative doses in patients with prior mediastinal irradiation or who are receiving concurrent cyclophosphamide therapy [see Warnings and Precautions]. 2. Acute infusion-related reactions including, but not limited to, flushing, shortness of breath, facial swelling, headache, chills, back pain, tightness in the chest or throat, and/or hypotension have occurred in up to 10% of patients treated with DOXIL. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction has resolved with slowing of the infusion rate. Serious and sometimes lifethreatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. DOXIL should be administered at an initial rate of 1 mg/min to minimize the risk of infusion reactions [see Warnings and Precautions]. 3. Severe myelosuppression may occur [see Warnings and Precautions]. 4. Dosage should be reduced in patients with impaired hepatic function [see Full Prescribing Information]. 5. Accidental substitution of DOXIL for doxorubicin HCl has resulted in severe side effects. DOXIL should not be substituted for doxorubicin HCl on a mg per mg basis [see Full Prescribing Information]. INDICATIONS AND USAGE: Ovarian Cancer: DOXIL (doxorubicin HCl liposome injection) is indicated for the treatment of patients with ovarian cancer whose disease has progressed or recurred after platinum-based chemotherapy. AIDS-Related Kaposi’s Sarcoma: DOXIL is indicated for the treatment of AIDS-related Kaposi’s sarcoma in patients after failure of prior systemic chemotherapy or intolerance to such therapy. Multiple Myeloma: DOXIL in combination with bortezomib is indicated for the treatment of patients with multiple myeloma who have not previously received bortezomib and have received at least one prior therapy. CONTRAINDICATIONS: DOXIL (doxorubicin HCl liposome injection) is contraindicated in patients who have a history of hypersensitivity reactions to a conventional formulation of doxorubicin HCl or the components of DOXIL [see Warnings and Precautions]. DOXIL is contraindicated in nursing mothers [see Full Prescribing Information]. WARNINGS AND PRECAUTIONS: Cardiac Toxicity: Special attention must be given to the risk of myocardial damage from cumulative doses of doxorubicin HCl. Acute left ventricular failure may occur with doxorubicin, particularly in patients who have received a total cumulative dosage of doxorubicin exceeding the currently recommended limit of 550 mg/m2. Lower (400 mg/m2) doses appear to cause heart failure in patients who have received radiotherapy to the mediastinal area or concomitant therapy with other potentially cardiotoxic agents such as cyclophosphamide. Prior use of other anthracyclines or anthracenodiones should be included in calculations of total cumulative dosage. Congestive heart failure or cardiomyopathy may be encountered after discontinuation of anthracycline therapy. Patients with a history of cardiovascular disease should be administered DOXIL only when the potential benefit of treatment outweighs the risk. Cardiac function should be carefully monitored in patients treated with DOXIL. The most definitive test for anthracycline myocardial injury is endomyocardial biopsy. Other methods, such as echocardiography or multigated radionuclide scans, have been used to monitor cardiac function during anthracycline therapy. Any of these methods should be employed to monitor potential cardiac toxicity in patients treated with DOXIL. If these test results indicate possible cardiac injury associated with DOXIL therapy, the benefit of continued therapy must be carefully weighed against the risk of myocardial injury. In a clinical study in patients with advanced breast cancer, 250 patients received DOXIL at starting dose of 50 mg/m2 every 4 weeks. At all cumulative anthracycline doses between 450-500 mg/m2, or between 500–550 mg/m2, the risk of cardiac toxicity for patients treated with DOXIL was 11%. In this study, cardiotoxicity was defined as a decrease of >20% from baseline if the resting left ventricular ejection fraction (LVEF) remained in the normal range, or a decrease of >10% if the resting LVEF became abnormal (less than the institutional lower limit of normal). The data on left ventricular ejection fraction (LVEF) defined cardiotoxicity and congestive heart failure (CHF) are in the table below. Table 1: Number of Patients With Advanced Breast Cancer Patients who Developed Cardiotoxicity (LVEF Defined) Cardiotoxicity (With Signs & Symptoms of CHF) Cardiotoxicity (no Signs & Symptoms of CHF) Patients With Signs and Symptoms of CHF Only

DOXIL (n=250) 10 0 10 2

In the randomized multiple myeloma study, the incidence of heart failure events (ventricular dysfunction, cardiac failure, right ventricular failure, congestive cardiac failure, chronic cardiac failure, acute pulmonary edema and pulmonary edema) was similar in the DOXIL+bortezomib group and the bortezomib monotherapy group, 3% in each group. LVEF decrease was defined as an absolute decrease of 15% over baseline or a 5% decrease below the institutional lower limit of normal. Based on this definition, 25 patients in the bortezomib arm (8%) and 42 patients in the DOXIL+bortezomib arm (13%) experienced a reduction in LVEF. Infusion Reactions: Acute infusion-related reactions were reported in 7.1% of patients treated with DOXIL in the randomized ovarian cancer study. These reactions were characterized by one or more of the following symptoms: flushing, shortness of breath, facial swelling, headache, chills, chest pain, back pain, tightness in the chest and throat, fever, tachycardia, pruritus, rash, cyanosis, syncope, bronchospasm, asthma, apnea, and hypotension. In most patients, these reactions resolve over the course of several hours to a day once the infusion is terminated. In some patients, the reaction resolved when the rate of infusion was slowed. In this study, two patients treated with DOXIL (0.8%) discontinued due to infusion-related reactions. In clinical studies, six patients with AIDSrelated Kaposi’s sarcoma (0.9%) and 13 (1.7%) solid tumor patients discontinued DOXIL therapy because of infusion-related reactions. Serious and sometimes life-threatening or fatal allergic/anaphylactoid-like infusion reactions have been reported. Medications to treat such reactions, as well as emergency equipment, should be available for immediate use. The majority of infusion-related events occurred during the first infusion. Similar reactions have not been reported with conventional doxorubicin and they presumably represent a reaction to the DOXIL liposomes or one of its surface components. The initial rate of infusion should be 1 mg/min to help minimize the risk of infusion reactions [see Full Prescribing Information]. Myelosuppression: Because of the potential for bone marrow suppression, careful hematologic monitoring is required during use of DOXIL, including white blood cell, neutrophil, platelet counts, and Hgb/Hct. With the recommended dosage schedule, leukopenia is usually transient. Hematologic toxicity may require dose reduction or delay or suspension of DOXIL therapy. Persistent severe myelosuppression may result in superinfection, neutropenic fever, or hemorrhage. Development of sepsis in the setting of neutropenia has resulted in discontinuation of treatment and, in rare cases, death. DOXIL may potentiate the toxicity of other anticancer therapies. In particular, hematologic toxicity may be more severe when DOXIL is administered in combination with other agents that cause bone marrow suppression. In patients with relapsed ovarian cancer, myelosuppression was generally moderate and reversible. In the three single-arm studies, anemia was the most common hematologic adverse reaction (52.6%), followed by leukopenia (WBC <4,000 mm3; 42.2%), thrombocytopenia (24.2%), and neutropenia (ANC <1,000; 19.0%). In the randomized study, anemia was the most common hematologic adverse reaction (40.2%), followed by leukopenia (WBC <4,000 mm3; 36.8%), neutropenia (ANC <1,000; 35.1%), and thrombocytopenia (13.0%) [see Adverse Reactions]. In patients with relapsed ovarian cancer, 4.6% received G-CSF (or GM-CSF) to support their blood counts [see Full Prescribing Information]. For patients with AIDS-related Kaposi’s sarcoma who often present with baseline myelosuppression due to such factors as their HIV disease or concomitant medications, myelosuppression appears to be the dose-limiting adverse

Hand-Foot Syndrome (HFS): In the randomized ovarian cancer study, 50.6% of patients treated with DOXIL at 50 mg/m2 every 4 weeks experienced HFS (developed palmar-plantar skin eruptions characterized by swelling, pain, erythema and, for some patients, desquamation of the skin on the hands and the feet), with 23.8% of the patients reporting HFS Grade 3 or 4 events. Ten subjects (4.2%) discontinued treatment due to HFS or other skin toxicity. HFS toxicity grades are described in Dosage and Administration section [see Full Prescribing Information]. Among 705 patients with AIDS-related Kaposi’s sarcoma treated with DOXIL at 20 mg/m2 every 2 weeks, 24 (3.4%) developed HFS, with 3 (0.9%) discontinuing. In the randomized multiple myeloma study, 19% of patients treated with DOXIL at 30 mg/m2 every three weeks experienced HFS. HFS was generally observed after 2 or 3 cycles of treatment but may occur earlier. In most patients the reaction is mild and resolves in one to two weeks so that prolonged delay of therapy need not occur. However, dose modification may be required to manage HFS [see Full Prescribing Information]. The reaction can be severe and debilitating in some patients and may require discontinuation of treatment. Radiation Recall Reaction: Recall reaction has occurred with DOXIL administration after radiotherapy. Fetal Mortality: Pregnancy Category D: DOXIL can cause fetal harm when administered to a pregnant woman. There are no adequate and well-controlled studies in pregnant women. If DOXIL is to be used during pregnancy, or if the patient becomes pregnant during therapy, the patient should be apprised of the potential hazard to the fetus. If pregnancy occurs in the first few months following treatment with DOXIL, the prolonged half-life of the drug must be considered. Women of childbearing potential should be advised to avoid pregnancy during treatment with Doxil. [see Full Prescribing Information]. Toxicity Potentiation: The doxorubicin in DOXIL may potentiate the toxicity of other anticancer therapies. Exacerbation of cyclophosphamide-induced hemorrhagic cystitis and enhancement of the hepatotoxicity of 6-mercaptopurine have been reported with the conventional formulation of doxorubicin HCl. Radiation-induced toxicity to the myocardium, mucosae, skin, and liver have been reported to be increased by the administration of doxorubicin HCl. Monitoring: Laboratory Tests: Complete blood counts, including platelet counts, should be obtained frequently and at a minimum prior to each dose of DOXIL [see Warnings and Precautions]. ADVERSE REACTIONS: Overall Adverse Reactions Profile: The following adverse reactions are discussed in more detail in other sections of the labeling. • Cardiac Toxicity [see Warnings and Precautions] • Infusion reactions [see Warnings and Precautions] • Myelosuppression [see Warnings and Precautions] • Hand-Foot syndrome [see Warnings and Precautions] The most common adverse reactions observed with DOXIL are asthenia, fatigue, fever, nausea, stomatitis, vomiting, diarrhea, constipation, anorexia, hand-foot syndrome, rash and neutropenia, thrombocytopenia and anemia. The most common serious adverse reactions observed with DOXIL are described in Section Adverse Reactions in Clinical Trials. The safety data described below reflect exposure to DOXIL in 1310 patients including: 239 patients with ovarian cancer, 753 patients with AIDS-related Kaposi’s sarcoma and 318 patients with multiple myeloma. Adverse Reactions in Clinical Trials: Because clinical trials are conducted under widely varying conditions, the adverse reaction rates observed cannot be directly compared to rates on other clinical trials and may not reflect the rates observed in clinical practice. The following tables present adverse reactions from clinical trials of DOXIL in ovarian cancer, AIDS-Related Kaposi’s sarcoma, and multiple myeloma. Patients With Ovarian Cancer: The safety data described below are from 239 patients with ovarian cancer treated with DOXIL (doxorubicin HCl liposome injection) at 50 mg/m2 once every 4 weeks for a minimum of 4 courses in a randomized, multicenter, open-label study. In this study, patients received DOXIL for a median number of 98.0 days (range 1-785 days). The population studied was 27-87 years of age, 91% Caucasian, 6% Black and 3% Hispanic and other. Table 2 presents the hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 2: Ovarian Cancer Randomized Study Hematology Data Reported in Patients With Ovarian Cancer DOXIL Topotecan Patients Patients (n = 239) (n = 235) Neutropenia 19 (7.9%) 33 (14.0%) 500 - <1000/mm3 10 (4.2%) 146 (62.1%) <500/mm3 Anemia 6.5 - <8 g/dL 13 (5.4%) 59 (25.1%) <6.5 g/dL 1 (0.4%) 10 (4.3%) Thrombocytopenia 3 (1.3%) 40 (17.0%) 10,000 - <50,000/mm3 <10,000/mm3 0 (0.0%) 40 (17.0%) Table 3 presents a comparative profile of the non-hematologic adverse reactions from the randomized study of DOXIL compared to topotecan. Table 3: Ovarian Cancer Randomized Study Non-Hematologic Adverse Reaction 10% or Greater

Body as a Whole Asthenia Fever Mucous Membrane Disorder Back Pain Infection Headache Digestive Nausea Stomatitis Vomiting Diarrhea Anorexia Dyspepsia Nervous Dizziness Respiratory Pharyngitis Dyspnea Cough increased Skin and Appendages Hand-foot syndrome Rash Alopecia

DOXIL (%) treated (n = 239) All Grades grades 3-4

Topotecan (%) treated (n =235) All Grades grades 3-4

40.2 21.3 14.2

7.1 0.8 3.8

51.5 30.6 3.4

8.1 5.5 0

11.7 11.7 10.5

1.7 2.1 0.8

10.2 6.4 14.9

0.9 0.9 0

46.0 41.4 32.6 20.9 20.1 12.1

5.4 8.3 7.9 2.5 2.5 0.8

63.0 15.3 43.8 34.9 21.7 14.0

8.1 0.4 9.8 4.2 1.3 0

4.2

10.2

15.9 15.1 9.6

0 4.1 0

17.9 23.4 11.5

0.4 4.3 0

50.6 28.5 19.2

23.8 4.2 N/A

0.9 12.3 52.3

0 0.4 N/A

VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 6:37 PM Page 31

The following additional adverse reactions (not in table) were observed in patients with ovarian cancer with doses administered every four weeks. Incidence 1% to 10%: Cardiovascular: vasodilation, tachycardia, deep thrombophlebitis, hypotension, cardiac arrest. Digestive: oral moniliasis, mouth ulceration, esophagitis, dysphagia, rectal bleeding, ileus. Hemic and Lymphatic: ecchymosis. Metabolic and Nutritional: dehydration, weight loss, hyperbilirubinemia, hypokalemia, hypercalcemia, hyponatremia. Nervous: somnolence, dizziness, depression. Respiratory: rhinitis, pneumonia, sinusitis, epistaxis. Skin and Appendages: pruritus, skin discoloration, vesiculobullous rash, maculopapular rash, exfoliative dermatitis, herpes zoster, dry skin, herpes simplex, fungal dermatitis, furunculosis, acne. Special Senses: conjunctivitis, taste perversion, dry eyes. Urinary: urinary tract infection, hematuria, vaginal moniliasis. Patients With AIDS-Related Kaposi’s Sarcoma: The safety data below is based on the experience reported in 753 patients with AIDS-related Kaposi’s sarcoma enrolled in four studies. The median age of the population was 38.7 years (range 24-70 years), which was 99% male, 1% female, 88% Caucasian, 6% Hispanic, 4% Black, and 2% Asian/other/unknown. The majority of patients were treated with 20 mg/m2 of DOXIL every two to three weeks. The median time on study was 127 days and ranged from 1 to 811 days. The median cumulative dose was 120 mg/m 2 and ranged from 3.3 to 798.6 mg/m2. Twenty-six patients (3.0%) received cumulative doses of greater than 450 mg/m2. Of these 753 patients, 61.2% were considered poor risk for KS tumor burden, 91.5% poor for immune system, and 46.9% for systemic illness; 36.2% were poor risk for all three categories. Patients’ median CD4 count was 21.0 cells/mm3, with 50.8% of patients having less than 50 cells/mm3. The mean absolute neutrophil count at study entry was approximately 3,000 cells/mm3. Patients received a variety of potentially myelotoxic drugs in combination with DOXIL. Of the 693 patients with concomitant medication information, 58.7% were on one or more antiretroviral medications; 34.9% patients were on zidovudine (AZT), 20.8% on didanosine (ddI), 16.5% on zalcitabine (ddC), and 9.5% on stavudine (D4T). A total of 85.1% patients were on PCP prophylaxis, most (54.4%) on sulfamethoxazole/trimethoprim. Eighty-five percent of patients were receiving antifungal medications, primarily fluconazole (75.8%). Seventy-two percent of patients were receiving antivirals, 56.3% acyclovir, 29% ganciclovir, and 16% foscarnet. In addition, 47.8% patients received colony-stimulating factors (sargramostim/filgrastim) sometime during their course of treatment. Adverse reactions led to discontinuation of treatment in 5% of patients with AIDS related Kaposi’s sarcoma. Those that did so included bone marrow suppression, cardiac adverse reactions, infusion-related reactions, toxoplasmosis, HFS, pneumonia, cough/dyspnea, fatigue, optic neuritis, progression of a non-KS tumor, allergy to penicillin, and unspecified reasons. Table 4: Hematology Data Reported in Patients With AIDS-Related Kaposi’s Sarcoma Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 74) Neutropenia <1000/mm3 <500/mm3 Anemia <10 g/dL <8 g/dL Thrombocytopenia <150,000/mm3 <25,000/mm3

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 720)

34 8

(45.9%) (10.8%)

352 96

(48.9%) (13.3%)

43 12

(58.1%) (16.2%)

399 131

(55.4%) (18.2%)

45 1

(60.8%) (1.4%)

439 30

(60.9%) (4.2%)

Table 5: Probably and Possibly Drug-Related Non-Hematologic Adverse Reactions Reported in With AIDS-Related Kaposi’s Sarcoma Adverse Reactions

Nausea Asthenia Fever Alopecia Alkaline Phosphatase Increase Vomiting Diarrhea Stomatitis Oral Moniliasis

Patients With Refractory or Intolerant AIDS-Related Kaposi’s Sarcoma (n = 77) 14 5 6 7 1 6 4 4 1

(18.2%) (6.5%) (7.8%) (9.1%) (1.3%) (7.8%) (5.2%) (5.2%) (1.3%)

Infections and infestations Herpes zoster Herpes simplex Investigations Weight decreased Metabolism and Nutritional disorders Anorexia Nervous system disorders Peripheral Neuropathy* Neuralgia Paresthesia/dysesthesia Respiratory, thoracic and mediastinal disorders Cough Skin and subcutaneous tissue disorders Rash** Hand-foot syndrome

11 10

2 0

0 0

9 6

2 1

0 0

42 17 13

7 3 <1

<1 0 0

45 20 10

10 4 0

1 1 0

22 19

1 6

0 0

18 <1

1 0

0 0

*Peripheral neuropathy includes the following adverse reactions: peripheral sensory neuropathy, neuropathy peripheral, polyneuropathy, peripheral motor neuropathy, and neuropathy NOS. **Rash includes the following adverse reactions: rash, rash erythematous, rash macular, rash maculo-papular, rash pruritic, exfoliative rash, and rash generalized. Post Marketing Experience: The following additional adverse reactions have been identified during post approval use of DOXIL. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Musculoskeletal and Connective Tissue Disorders: rare cases of muscle spasms. Respiratory, Thoracic and Mediastinal Disorders: rare cases of pulmonary embolism (in some cases fatal). Hematologic disorders: Secondary acute myelogenous leukemia with and without fatal outcome has been reported in patients whose treatment included DOXIL. Skin and subcutaneous tissue disorders: rare cases of erythema multiforme, StevensJohnson syndrome and toxic epidermal necrolysis have been reported. DRUG INTERACTIONS: No formal drug interaction studies have been conducted with DOXIL. DOXIL may interact with drugs known to interact with the conventional formulation of doxorubicin HCl. USE IN SPECIFIC POPULATIONS: Pediatric Use: The safety and effectiveness of DOXIL in pediatric patients have not been established.

5% of Patients

Total Patients With AIDS-Related Kaposi’s Sarcoma (n = 705) 119 70 64 63 55 55 55 48 39

Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. (continued) Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4

(16.9%) (9.9%) (9.1%) (8.9%) (7.8%) (7.8%) (7.8%) (6.8%) (5.5%)

The following additional (not in table) adverse reactions were observed in patients with AIDS-related Kaposi’s sarcoma. Incidence 1% to 5%: Body as a Whole: headache, back pain, infection, allergic reaction, chills. Cardiovascular: chest pain, hypotension, tachycardia. Cutaneous: herpes simplex, rash, itching. Digestive: mouth ulceration, anorexia, dysphagia. Metabolic and Nutritional: SGPT increase, weight loss, hyperbilirubinemia. Other: dyspnea, pneumonia, dizziness, somnolence. Incidence Less Than 1%: Body As A Whole: sepsis, moniliasis, cryptococcosis. Cardiovascular: thrombophlebitis, cardiomyopathy, palpitation, bundle branch block, congestive heart failure, heart arrest, thrombosis, ventricular arrhythmia. Digestive: hepatitis. Metabolic and Nutritional Disorders: dehydration. Respiratory: cough increase, pharyngitis. Skin and Appendages: maculopapular rash, herpes zoster. Special Senses: taste perversion, conjunctivitis. Patients With Multiple Myeloma: The safety data below are from 318 patients treated with DOXIL (30 mg/m2 as a 1-hr i.v. infusion) administered on day 4 following bortezomib (1.3 mg/m2 i.v. bolus on days 1, 4, 8 and 11) every three weeks, in a randomized, open-label, multicenter study. In this study, patients in the DOXIL + bortezomib combination group were treated for a median number of 138 days (range 21-410 days). The population was 28-85 years of age, 58% male, 42% female, 90% Caucasian, 6% Black, and 4% Asian and other. Table 6 lists adverse reactions reported in 10% or more of patients treated with DOXIL in combination with bortezomib for multiple myeloma. Table 6: Frequency of treatment emergent adverse reactions reported in 10% patients treated for multiple myeloma with DOXIL in combination with bortezomib, by Severity, Body System, and MedDRA Terminology. Adverse DOXIL + bortezomib Bortezomib Reaction (n=318) (n=318) Any Grade Grade Any Grade Grade (%) 3 4 (%) 3 4 Blood and lymphatic system disorders Neutropenia 36 22 10 22 11 5 Thrombocytopenia 33 11 13 28 9 8 Anemia 25 7 2 21 8 2 General disorders and administration site conditions Fatigue 36 6 1 28 3 0 Pyrexia 31 1 0 22 1 0 Asthenia 22 6 0 18 4 0 Gastrointestinal disorders Nausea 48 3 0 40 1 0 Diarrhea 46 7 0 39 5 0 Vomiting 32 4 0 22 1 0 Constipation 31 1 0 31 1 0 Mucositis/Stomatitis 20 2 0 5 <1 0 Abdominal pain 11 1 0 8 1 0

Geriatric Use: Of the patients treated with DOXIL in the randomized ovarian cancer study, 34.7% (n=83) were 65 years of age or older while 7.9% (n=19) were 75 years of age or older. Of the 318 patients treated with DOXIL in combination with bortezomib for multiple myeloma, 37% were 65 years of age or older and 8% were 75 years of age or older. No overall differences in safety or efficacy were observed between these patients and younger patients. OVERDOSAGE: Acute overdosage with doxorubicin HCl causes increases in mucositis, leucopenia, and thrombocytopenia. Treatment of acute overdosage consists of treatment of the severely myelosuppressed patient with hospitalization, antibiotics, platelet and granulocyte transfusions, and symptomatic treatment of mucositis. 0016716-5B Manufactured by: Ben Venue Laboratories, Inc. Bedford, OH 44146 Distributed by: Ortho Biotech Products, LP Raritan, NJ 08869-0670

An ALZA STEALTH® Technology Product

STEALTH® and DOXIL® are registered trademarks of ALZA Corporation.

VBCC_July_11_1_Follow ASCO Tabloid 7/14/11 2:52 PM Page 32

PATIENT NAVIGATION

Patient Navigation and Patient Assistance Programs in Oncology By Wayne Kuznar Philadelphia, PA—The medically underserved population needs easier access to healthcare and tools that provide a seamless transition between all phases of the treatment process, from screening through therapy and survivorship. Payers play an important role in the future of oncology and need to be in the decision-making network. Patient assistance and patient navigation programs aim to provide

“Patient navigation is a concept that evolved in the 1990s. It was originated to access healthcare barriers, and we need to keep focusing on overcoming these barriers.” —Steven Patierno, PhD

patients with reliable education to inform their decision-making, but these programs are sometimes referred to as “add-ons,” and they cost money. “Patient navigation is a concept that evolved in the 1990s,” said Steven Patierno, PhD, Executive Director, George Washington University Cancer Institute, Washington, DC. “It was originated to access healthcare barriers, and we need to keep focusing on overcoming these barriers.” The 3 main barriers include structural, socioeconomic, and financial barriers (Table). To overcome these barriers, Dr Patierno and colleagues from 9 centers across the country took part in the National Cancer Institute (NCI) Patient Navigation Research Program, a $29 million program funded by the NCI to study patient navigation. The study focused on narrowing the window between cancer-related findings, diagnosis, and the onset of treatment. It also examined its cost-effectiveness. After 6 years of research, which is slated for publication, the team developed specific models, including the longitudinal patient navigation model. “To keep it as cost-effective as possible, patient navigation was envisioned as picking up people at suspicious finding, navigating them to the onset of treatment, and then stopping because it was obviously too expensive to do otherwise,” Dr Patierno said. “So we’ve created this idea of longitudinal navigation that dovetails with outreach. It actually helps people get into and through screening, past diagnosis, and into treatment, and

“There is not just one definition for value in patient navigation, and the criteria are not consistent. We can’t define it as a value if we don’t know what it is….Navigation programs can increase screening and adherence to diagnostic follow-up.” —Dawn Holcombe, MBA then it follows 2 or 3 years into the posttreatment survivorship period.” Defining Value in Patient Navigation Patient navigation has an impact on care and cost, and defining the concept is still a challenge. “As the concept of

Table Patient Navigation: Overcoming Access Barriers Logistic/structural barriers

Sociocultural barriers

Financial barriers

Barriers presenting a logistic challenge to engaging in care have a potential logistic action or resource available

Arising as a result of patients’ ethnic, social, and cultural beliefs and may not be easily overcome by logistic actions

Related to socioeconomic status that cannot be easily explained by patients’ cultural background and may not be overcome by simple logistic actions

Transportation

Fear

Child care

Location of facility

Perceptions about tests

Adult care

System scheduling problems

Literacy

Housing

Out of town/country

Social/practical support

Financial problems

Disability Mental/medical comorbidities

Communication concerns with medical Employment issues personnel

Language

Attitudes toward providers

Insurance

patient navigation has ‘steamrolled’ across the country, it has morphed into many different things. In some areas, patient navigation has evolved into actually little more than a ‘medical concierge service,’” Dr Patierno said. “They say, ‘Come to our center and meet with our patient navigators.’ That’s great, because it’s very hard for even intelligent people with advanced degrees to navigate their way through the labyrinth of our cancer healthcare system, but the people who are desperately in need of patient navigation are the ones who are affected by barriers.” Dr Patierno and Dawn Holcombe, MBA, President, DGH Consulting, and Executive Director, Connecticut Oncology Association, agree that definition is a clear challenge. “There is not just one definition for value in patient navigation, and the criteria are not consistent,” Ms Holcombe said. “We can’t define it as a value if we don’t know what it is.” Certain criteria should be considered in defining the value and quality of navigation systems, and these include education and training of navigators and certification programs, she added. The systems should focus on screening and outreach, barriers, and services. Additional challenges include lack of reimbursement, HIPAA access issues, care delivery models, and healthcare reform. Currently, the vast majority of patient navigation programs are supported by philanthropy and small grants from foundations, Dr Patierno said. “The most demonstrable success comes from programs that focus on screening and outreach,” said Ms Holcombe. For example, 2 hospital-based navigation programs focusing on screening and outreach saw a 30% increase in 5-year survival rates in women diagnosed with breast cancer, and another center reduced the rate of no-shows from 67% to 10%. The program also demonstrated a decreased wait time from initial visit to the procedure and increased early detection by as much as 50%. “We find that navigation programs can increase screening and adherence to diagnostic follow-up,” she said. In addition to the NCI Patient Navigation Research Program, the American Cancer Society Patient Navigation Program aims to provide Continued on page 33

VALUE-BASED CANCER CARE

July 2011

VOL. 2

NO. 4

VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 6:40 PM Page 33

PATIENT NAVIGATION reliable patient education and information to support informed decisionmaking and resources and emotional support, and the Centers for Medicare & Medicaid Services Cancer Prevention and Treatment Demonstration for Ethnic and Racial Minorities aims to help minority beneficiaries navigate the health system in a timely and informative manner. “There are also a number of homegrown models, which you can find at hospitals, cancer centers, physician offices, and through the pharmaceutical industry,” Ms Holcombe said. “But none of them have the same definition” of concept or value. Ms Holcombe said she believes there is so much variation because each program has a different agenda, a different goal, and access to different patients. “When considering a patient navigation system, one should identify the aim, figure out how the value and results will be measured, identify the target population and scope of services and resources, identify who will pay, and figure out if the patient can receive follow-up care.” Treatment in the Office Setting Leonard Natelson, Chief Executive Officer, Hematology/Oncology Associates of Rockland, NY, is 1 of 5 physicians in a community oncology practice; he said he does not fully understand why there is a big push to get patients to hospital settings for treatment. “That’s basically what is happening,” he said. “Some physicians are saying they cannot be bothered with human resources, accounting, and

at a glance ➤ Navigation programs can increase screening and adherence to diagnostic follow-up ➤ Two hospital-based navigation programs saw a 30% increase in 5-year survival rates in women with breast cancer ➤ Oncologists must inform patients and caregivers of all the facts when recommending chemotherapy treatments ➤ Oncologists should inform their patients about clinical trial opportunities ➤ When clinically appropriate, oncologists must address hospice and end-of-life issues instead of recommending another therapy

VOL. 2

NO. 4

payables. They just want to treat their patients. But you have to create that environment.” By no longer using the “buy and bill” method and by using specialty pharmacies, Mr Natelson is now able to treat his patients in the office. “That has saved our practice. I have a bigger practice, we offer more service, and my physicians can treat the way they want,” he said. “They do not have the financial impact on what’s going on with reimbursements for the drugs. And this saves our payers a ton of money.

“Oncologists should research and share with their patients clinical trial opportunities that are available inside and outside of their own cancer centers. They shouldn’t let financial gain win over what is best for the patient.” —Monica Knoll

with our patients, keep their commutes down, and give them a nice setting to be treated in.”

“That has saved our practice. I have a bigger practice, we offer more service, and my physicians can treat the way they want.” —Leonard Natelson

“The biggest issue is giving your physicians an alternative,” Mr Natelson continued. “We have to be able to work

Patient Advocacy Set Up by Survivors Monica Knoll, who was diagnosed with breast cancer in 2000 and with ovarian cancer in 2006, founded CANCER101, a nonprofit organization to empower patients with cancer to manage their own care. Ms Knoll said that physicians must take responsibility for letting their patients and caregivers know all of the facts when recommending chemotherapy treatments. “Oncologists should research and share with their patients clinical trial opportunities that are available inside and outside of their own cancer centers,” she said. “They shouldn’t let financial gain win over what is best for the patient.” In addition, when a drug becomes cost-prohibitive for a patient, it is the oncologist’s responsibility to explain the pros and cons as well as to recommend another drug that will not create financial hardship to the patient and family, she added.

Monica Knoll In 2000, at age 36, Monica Knoll was diagnosed with stage II breast cancer, and in 2006 with ovarian cancer. While being treated for breast cancer, Ms Knoll founded CANCER101, designed to empower cancer patients and their caregivers to fight the disease from the moment of diagnosis. Monica died on June 20, 2011. CANCER101 is now used by thousands of patients across the country. Ms Knoll worked tirelessly to further the cause of patients with cancer. Donations to her cause can be made online at www.CANCER101.org.

“It’s important that the patient and family are aware that a treatment might offer a 10% chance of increased survival over another treatment, but it also may make the patient so sick that his or her quality of life will suffer greatly,” Ms Knoll said. “Saving lives is one thing, but ending someone’s life with dignity is another.” Ms Knoll suggested that it is irresponsible for an oncologist to continue to offer treatment recommendations when the patient is clearly dying and is no longer experiencing any quality of life. When the time comes, the oncologist needs to gently address hospice and end-of-life instead of recommending another drug and giving the patient and the family false hope. “The more conversations you have with your patients and your families, the easier it gets,” Ms Knoll said. Regretfully, Ms Knoll died on June 20, 2011, a few months after her presentation at the conference. ■

www.ValueBasedCancerCare.com

VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 6:41 PM Page 34

V E G F

I N H I B I T I O N

THE PROPOSED EFFECTS OF

AVASTIN

VEGF

Avastin VEGF Inhibition

The The VEGF ligand is one of the first pro-angiogenic factors

and is present throughout the tumor life cycle1,2,3 Avastin directly binds VEGF to inhibit angiogenesis4,5 Avastin is designed to directly bind to VEGF extracellularly to prevent interaction

with VEGF receptors (VEGFR) on the surface of endothelial cells, thereby inhibiting its biologic activity5 Cessation of anti-VEGF treatment may diminish impact on tumors6,7,8 TO CONTACT YOUR ACCOUNT MANAGER FOR MORE INFORMATION ON AVASTIN VISIT:

genentechmm.com

Indications Avastin is indicated for the treatment of metastatic renal cell carcinoma in combination with interferon alfa. 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.

The mechanism of action of anti-VEGF agents has been elucidated primarily in preclinical models. Its clinical significance is unknown.

VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 6:43 PM Page 35

Boxed WARNINGS and additional important safety information Gastrointestinal (GI) perforation: Serious and sometimes fatal GI perforation occurs at a higher incidence in Avastin-treated patients compared to controls. The incidences of GI perforation ranged from 0.3% to 2.4% across clinical studies. Discontinue Avastin in patients with GI perforation

Surgery and wound healing complications: The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue Avastin at least 28 days prior to elective surgery and in patients with wound dehiscence requiring medical intervention

Hemorrhage: Severe or fatal hemorrhage, including hemoptysis, GI bleeding, hematemesis, central nervous system hemorrhage, epistaxis, and vaginal bleeding, occurred up to 5-fold more frequently in patients receiving Avastin. Across indications, the incidence of grade *3 hemorrhagic events among patients receiving Avastin ranged from 1.2% to 4.6%. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis (*1/2 tsp of red blood). Discontinue Avastin in patients with serious hemorrhage (ie, requiring medical intervention)

Additional serious and sometimes fatal adverse events for which the incidence was increased in the Avastin-treated arm vs control included non-GI fistula formation ()0.3%), arterial thromboembolic events (grade *3, 2.4%), and proteinuria including nephrotic syndrome (<1%). Additional serious adverse events for which the incidence was increased in the Avastin-treated arm vs control included hypertension (grade 3–4, 5%–18%) and reversible posterior leukoencephalopathy syndrome (RPLS) (<0.1%). Infusion reactions with the first dose of Avastin were uncommon (<3%), and severe reactions occurred in 0.2% of patients

The most common adverse reactions observed in Avastin patients at a rate >10% and at least twice the control arm rate were epistaxis, headache, hypertension, rhinitis, proteinuria, taste alteration, dry skin, rectal hemorrhage, lacrimation disorder, back pain, and exfoliative dermatitis. Across all studies, Avastin was discontinued in 8.4% to 21% of patients because of adverse reactions

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 Please see the following brief summary of full Prescribing Information, including Boxed Warnings, for additional important safety information. References: 1. Hanrahan V, Currie MJ, Gunningham SP, et al. J Pathol. 2003;200:183-194. 2. Fontanini G, Vignati S, Boldrini L, et al. Clin Cancer Res. 1997;3:861-865. 3. Rini BI, Small EJ. J Clin Oncol. 2005;23:1028-1043. 4. Hicklin DJ, Ellis LM. J Clin Oncol. 2005;23:1011-1027. 5. Avastin Prescribing Information. Genentech, Inc. February 2011. 6. Bagri A, Berry L, Gunter B, et al. Clin Cancer Res. 2010;16:3887-3900 [and supplemental appendix]. 7. Baluk P, Hashizume H, McDonald DM. Curr Opin Genet Dev. 2005;15:102-111. 8. Inai T, Mancuso M, Hashizume H, et al. Am J Pathol. 2004;165:35-52.

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AVASTIN® (bevacizumab) Solution for intravenous infusion Initial U.S. Approval: 2004 WARNING: GASTROINTESTINAL PERFORATIONS, SURGERY AND WOUND HEALING COMPLICATIONS, and HEMORRHAGE Gastrointestinal Perforations The incidence of gastrointestinal perforation, some fatal, in Avastin-treated patients ranges from 0.3 to 2.4%. Discontinue Avastin in patients with gastrointestinal perforation. [See Dosage and Administration (2.4), Warnings and Precautions (5.1).] Surgery and Wound Healing Complications The incidence of wound healing and surgical complications, including serious and fatal complications, is increased in Avastin-treated patients. Discontinue Avastin in patients with wound dehiscence. The appropriate interval between termination of Avastin and subsequent elective surgery required to reduce the risks of impaired wound healing/wound dehiscence has not been determined. Discontinue at least 28 days prior to elective surgery. Do not initiate Avastin for at least 28 days after surgery and until the surgical wound is fully healed. [See Dosage and Administration (2.4), Warnings and Precautions (5.2), and Adverse Reactions (6.1).] Hemorrhage Severe or fatal hemorrhage, including hemoptysis, gastrointestinal bleeding, central nervous systems (CNS) hemorrhage, epistaxis, and vaginal bleeding occurred up to five-fold more frequently in patients receiving Avastin. Do not administer Avastin to patients with serious hemorrhage or recent hemoptysis. [See Dosage and Administration (2.4), Warnings and Precautions (5.3), and Adverse Reactions (6.1).]

AVASTIN® (bevacizumab) Suspend Avastin administration for ≥ 2 grams of proteinuria/24 hours and resume when proteinuria is <2 gm/24 hours. Discontinue Avastin in patients with nephrotic syndrome. Data from a postmarketing safety study showed poor correlation between UPCR (Urine Protein/ Creatinine Ratio) and 24 hour urine protein (Pearson Correlation 0.39 (95% CI 0.17, 0.57). [See Use in Specific Populations (8.5).] The safety of continued Avastin treatment in patients with moderate to severe proteinuria has not been evaluated. [See Dosage and Administration (2.4).] 5.9 Infusion Reactions Infusion reactions reported in the clinical trials and post-marketing experience include hypertension, hypertensive crises associated with neurologic signs and symptoms, wheezing, oxygen desaturation, Grade 3 hypersensitivity, chest pain, headaches, rigors, and diaphoresis. In clinical studies, infusion reactions with the first dose of Avastin were uncommon (< 3%) and severe reactions occurred in 0.2% of patients. Stop infusion if a severe infusion reaction occurs and administer appropriate medical therapy. [See Dosage and Administration (2.4).] 6 ADVERSE REACTIONS The following serious adverse reactions are discussed in greater detail in other sections of the label: L Gastrointestinal Perforations [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.1).] L Surgery and Wound Healing Complications [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.2).] L Hemorrhage [See Boxed Warning, Dosage and Administration (2.4), Warnings and Precautions (5.3).] L Non-Gastrointestinal Fistula Formation [See Dosage and Administration (2.4), Warnings and Precautions (5.4).] L Arterial Thromboembolic Events [See Dosage and Administration (2.4), Warnings and Precautions (5.5).] L Hypertensive Crisis [See Dosage and Administration (2.4), Warnings and Precautions (5.6).] L Reversible Posterior Leukoencephalopathy Syndrome [See Dosage and Administration (2.4), Warnings and Precautions (5.7).] L 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.

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REIMBURSEMENT ISSUES

Oncology Drug Reimbursement and Administration Benchmarks By Wayne Kuznar Philadelphia, PA—When preparing to tackle oncology drug reimbursement concerns, it is critical to understand the benchmarks that influence reimbursement, according to John F. Aforismo, BScPharm, RPh, FASCP, Chief Executive Officer, RJ Health Systems Inter national, Rocky Hill, CT. At a payers’ session on reimbursement issues, Mr Aforismo said that the commercial sector evaluates these benchmarks when managing oncology drug reimbursement. The benchmarks, which are part of provider contracts, include the average sales price (ASP), average wholesale price (AWP), maximum allowable cost (MAC), wholesale acquisition cost (WAC), International Classification of Diseases, Ninth Revision (ICD-9), Healthcare Common Procedure Coding System (HCPCS) versus National Drug Code (NDC), and clinical guidelines. Peyton Howell, MHA, President, Consulting Services, and Senior Vice President, Business Development, AmerisourceBergen, Frisco, TX, noted that ASP, which came about via the Medicare Modernization Act and carries a 2-month lag time in reimbursement, has “dramatically changed” the reimbursement for oncology care, because Medicare and most private payers use some form of ASP-based payment. She cited 2 key “flaws” in the current system: reimbursements for cancer care management and treatment administration are inadequate— financial “losers.” “Because of reimbursement issues involved with ASP, it makes no sense currently to do the right thing as a provider for your oncology care patients. That is why it is important to find models to incent,” she said. In addition, the actual definition and reporting of ASP have significant flaws, which create inconsistent payment. Ms Howell said that one of the biggest flaws of ASP is that it promotes high-cost products and discourages the use of low-cost products. “These are critical issues that have created inconsistencies in the adequacy of ASP reimbursement, but congressional action is needed to clarify many of these issues,” Ms Howell said. AWP, MAC, and WAC Benchmarks The AWP (the price at which a wholesaler sells a product to a provider) is determined by 4 national data sources—First DataBank, MediSpan, Red Book, and Gold Standard.

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All sources produce an AWP that providers use to bill for a product or that payers use to reimburse for a product. According to Mr Aforismo, the provider and physician community use Red Book as their guidance. The payer community uses either First DataBank or Medi-Span as a basis for their reimbursement methodology. Consequently, the sources do not match, because there is a lag time between pricing that enters Red Book and pricing that enters the payer’s system. “As a result, there is much talk as to whether AWP is going away. The term ‘AWP’ will eventually go away. Someone’s just got to come up with another name, as the methodology is still there,” he said.

to review. “The only problem in a WAC-based system is you will not receive a WAC in a generic environment, nor will you see it in a repackaged environment. WAC is only for a limited supply of drugs,” Mr Aforismo said. Guidelines and Coding The reimbursement methodology reviews the guidelines, tying them into the drug component. “It’s about how to pay for a drug adequately, as well as pay for the service. Payers are struggling with this,” Mr Aforismo noted. Controversy surrounds the HCPCS versus NDC benchmark. According to Mr Aforismo, payers are asking for the NDC in nonclassified codes. Phar-

“Because of reimbursement issues involved with ASP, it makes no sense currently to do the right thing as a provider for your oncology care patients. That is why it is important to find models to incent.” —Peyton Howell, MHA Wholesalers set the AWP by percent profit or another method—and they set it immediately, because they have to make a profit, Mr Aforismo noted. Currently, many manufacturers do not provide an AWP, but they will provide a suggested AWP combined with a WAC. Commercial payers use MAC not only on the pharmacy side but also on the medical side, according to Mr Aforismo. Controversy about MAC on the pharmacy side is abundant, yet some payers are looking at MAC as another way of reimbursing a provider. “The MAC on an HCPCS drug code level probably is a lot better than an ASP plus level. It gives incentive to providers to use a generic if a generic is available,” he said. There’s also MAC on an NDC level. Acquisition costs are used as a reference. The WAC is yet another benchmark

maceutical companies have put a new crease in this. With the ability to capture an NDC, pharmaceutical companies are able to receive data. Payers are able to be remunerated for the data they receive. Finally, Mr Aforismo addressed the ICD-9. With this benchmark, payers are using methodologies that will associate an ICD-9 code (US Food and Drug Administration– and compendia-listed) with pricing and other characteristics and adjudicate a claim financially and clinically. Future Trends One trend to look for involves payers’ adherence to clinical guidelines for appropriate use of pharmaceuticals. Another trend entails episodes of care per treatment regimen relating to how patients should be treated, and how a provider should be reimbursed.

Guideline reimbursement is “about how to pay for a drug adequately, as well as pay for the service. Payers are struggling with this.” —John F. Aforismo, BScPharm, RPh, FASCP Ms Howell elaborated on trends linked to the growth in pharmaceuticals, especially in oncology. The forecasted growth between 2009 and 2014 for specialty (6%) and nonspecialty (4%) pharmaceuticals is substantial. The growth is disproportionate in oncology (7%). “It’s a challenge, because the same healthcare providers who are focused on oncology patients have a disproportionate share of Medicare patients. Because Medicare is the primary payer for most cancers, this creates a lot of pressure on managed care contracts,” Ms Howell commented. Perhaps not surprising is the trend that oncology practices are struggling, Ms Howell said. In recent surveys by AmerisourceBergen, oncology practices answered a series of questions about their financial health over time. The vast majority of respondents (70% of the total) indicated they are in a worse situation than before. To offset lost revenue, most have diversified dramatically outside of their core oncology focus. Practices were surveyed regarding their most significant negative drivers. For 74% of respondents, the top driver was Medicare reimbursement. Private reimbursement is also an issue, and 63% ranked this in the top 3 drivers. In response to financial pressures, many practices are considering closing locations or seeking acquisition by another entity. Underserved or rural areas may find it especially difficult to reverse some of these trends, Ms Howell said. Scott Breidbart, MD, Chief Medical Officer, Empire Blue Cross/Blue Shield, NY, said that the patient must be kept at the forefront of all reimbursement issues. “Our job is to make sure treatment is based on patients’ best interest. We need to reimburse in a manner that is appropriate and does not incentivize other uses,” he said. Some options to consider when evaluating reimbursement of oncologists include offering global payment by diagnosis, monitoring use of established protocols, requiring prior authorization, and using an oncology pharmacy vendor. ■

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MEDICARE TRENDS

Global Fees, ACOs, and New Reimbursement Trends Will Influence Medicare’s Future By Wayne Kuznar Philadelphia, PA—Growth in Medicare Part B spending, increasing roles in specialty pharmacy, formation of accountable care organizations (ACOs), and bundling of payments for care are all anticipated trends in the Medicare and reimbursement arenas, according to Jayson Slotnick, JD, MPH, Partner, Health Policy Strategies, Washington, DC. In 2009, a total of 46.3 million Americans were covered by Medicare, and approximately 10,000 new people are becoming Medicare eligible every day as a result of the baby boomers coming of age. Consequently, the government is faced with the huge spending for Medicare Part B, said Mr Slotnick. “Some figures from the most recent Medicare Trustees Report note that government is looking at huge growth in Part B spending. Within Part B spending is specialty drugs—especially physician-administered drugs,” Mr Slotnick said. “Part B costs are growing rapidly, averaging 8.3% annual growth over the past 5 years,” he noted. This continuing expansion and growth evokes 3 independent issues in Medicare Part B: • How much of the cost will be reimbursed? • Will there be any payment at all? • How will it be billed? Healthcare Reform Specifics From a broader perspective, the healthcare reform, or the Patient Protection and Affordable Care Act (ACA), addresses coverage and delivery system reforms—in the form of ACOs and comparative effectiveness research—among other grand-scale initiatives. “Our federal government can create markets, change markets, and destroy markets. With the latest reiteration of health reform, we have all 3 occurring at the same time,” said Mr Slotnick, who represents innovative companies in the pharmaceutical/biotechnology device and diagnostic base, monitoring what goes on at the Centers for Medicare & Medicaid Services (CMS)

and the US Food and Drug Administration regarding commercialization of products. The ACA does nothing to change compendia policy or coverage criteria; however, it includes an expansion of the 340B drug discount program. Also, the ACA preserves current average sales price payment methodology for small molecule pharmaceuticals and for biologics administered in physicians’ offices. The ACA’s newly created CMS’s Center on Medicare and Medicaid Innovation will test new ways to improve quality and manage costs. Demonstrations of payment and delivery system reforms in Medicare, Medicaid, and both programs will be established and may require more federal money if quality is improved. Successful models may go nationwide without further congressional action. ACOs Gaining Momentum The ACA’s Medicare shared savings program creates the option for healthcare providers to form ACOs. A new nationwide ACO option in Medicare starts January 2012. Physicians, hospitals, and other providers will be responsible for quality and overall care of Medicare patients through an ACO. Medicare’s program will share savings from better quality, fewer hospitalizations, and elimination of unnecessary costs with ACO providers. Payment models will include feefor-service with shared savings, and partial capitation. The formation of multipayer ACOs is likely with participation from state Medicaid programs. Many provider groups will be able to form an ACO, including hospitals, physicians, physician groups, and other healthcare professionals via a joint venture or partnership arrangement. In addition, physicians and other healthcare professionals in group practices or a network of practices, along with integrated hospital– physician systems, will have an opportunity to establish ACOs. The ACO option further extends to hospitals, physicians, and post–acute

VALUE-BASED CANCER CARE

July 2011

provider gets to keep any savings from greater care efficiency and elimination of unnecessary services. There are many opportunities to improve quality, access, and cost-effectiveness through the use of global fees. To be effective, an adequate global fee is required, along with risk adjustment, capacity, infrastructure, new workflow, and care redesign.

“Our federal government can create markets, change markets, and destroy markets. With the latest reiteration of healthcare reform, we have all 3 occurring at the same time.” —Jayson Slotnick, JD, MPH

care providers, such as skilled nursing facilities and home healthcare agencies. Although ACOs need not include a hospital, ACOs do require physician participation. Global Fees Enhance Patient Care Continued consolidation of physicians’ offices will be seen in the near future. Mr Slotnick indicated there would be an increased migration of specialty products to the pharmacy benefit, specifically pertaining to the use of pharmacy benefit tools on specialty products and paying for adherence to clinical guidelines. The specialty pharmacy arena will also have an increased role in data collection and demonstrating value proposition. Currently, the federal government is establishing demonstrations to replace the traditional fee-for-service payment with global fees to achieve incentives for quality. With global fees, the

Bundled Payment In the new Medicare bundled payment initiative, a national Medicare pilot program is under way to investigate the single, bundled payment based on an episode of care rather than the fee-for-service payment system. This bundled payment approach would include all inpatient, physician, outpatient, and post–acute care services from 3 days before admission through 30 days after discharge. The demonstration project is set to begin by January 2013. As an option, state Medicaid programs could participate in this project or demonstrate their own bundled payment models. If the state health plans are successful, the overall Medicare bundled payment may expand nationwide in 2016. Reimbursement Trends Significant new reimbursement trends include measurement and public reporting of clinical performance; expectation for evidence-based, patientcentered clinical practice; payment methods that place physicians, hospitals, and other providers financially at risk for low-quality performance, which is in contrast to “insurance risk” experienced by health plans; and bundling of payments for an episode of care or a condition. Other increasing reimbursement trends involve using cost-effectiveness and comparative effectiveness research in making coverage decisions; payment rates and methods that are increasingly driven by budget considerations; and recognition that the fiscal outlook for Medicare is very poor, according to Mr Slotnick. ■

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ONCOLOGY PHARMACY

Oncology Pharmacy as a Specialty New distribution channels needed By Wayne Kuznar Philadelphia, PA—An expanding role for oncology pharmacy in the optimization of cancer care is likely to emerge over the next 3 to 5 years, as payers seek better outcomes for their money, said Jeff Ulanet, MBA, Vice President, Oncology, Medco, at a roundtable payers’ discussion. Oncology pharmacy is a specialty that will likely progress to mimic a medical specialty that a physician can use to optimize treatment more than in the past. “In fact, we can make the case that specialization matters more in

ments they render. The management of the cancer benefit will be an ongoing challenge, as payers try to find the right balance between cost and efficacy. “If payers are going to spend $100,000 on a patient, they would like to see a better outcome,” said Mr Ulanet. “It’s not all about cost, but it is about outcomes for that cost. Pharmacy management and therapy management is the way in which you can assure a better and greater use of the dollars you’re spending.” As precision therapies emerge, a

“If payers are going to spend $100,000 on a patient, they would like to see a better outcome. It’s not all about cost; it is about outcomes for that cost.” —Jeff Ulanet, MBA oncology than in almost any other disease,” Mr Ulanet said, as the roles of pharmacogenomics and molecular testing expand, along with symptom mitigation and the management of nutrition, drug–food interactions, and side effects. An expected shortage of oncologists in the coming years will mean that physicians will look to pharmacists as an extension of their practice, he predicted, in an attempt to obtain better outcomes for all the drugs and treat-

at a glance ➤ The role of oncology pharmacy is expected to increase as payers seek better outcomes for their money ➤ With fewer oncologists available, physicians will look to pharmacists as an extension of their practice ➤ About 70% of a community oncologist’s revenue is generated through the dispensing of drugs ➤ Advanced electronic technologies will aid the pharmacy in the selection of patients for particular drug therapies ➤ Molecular testing will eventually be incorporated into pharmacy to ensure optimal drug delivery

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combination of technologies and activities performed within the pharmacy will advance to optimize those therapies, he said. Expect the use of advanced electronic prescribing to support decision tools for diagnostic tests and response monitoring that aid the pharmacy in the selection of patients for particular drug therapies, said Mr Ulanet. Molecular testing will eventually be incorporated into the pharmacy as a more efficient way to ensure optimal drug delivery. Electronic medical records and third-party payers will play a role in automating the integration of molecular testing and drug

“The biggest challenge with taking these drugs out of the physician’s office is…that the waste goes up dramatically, and the amount that gets billed goes up dramatically.” —Alan M. Lotvin, MD

delivery. Tools for enhancing patient selfmanagement may also emerge, as the average patient with cancer is receiving a complex drug regimen that includes 10 oral drugs daily, he said. Cost-Effective Delivery of Cancer Care In today’s market, keeping the buyand-bill option in the physician’s office is the best strategy for a commercial payer to deliver cancer care, said Alan M. Lotvin, MD, President and Chief Executive Officer, ICORE Healthcare. It provides physicians a purchasing advantage of about 17%, on a weighted average basis, over any pharmacy. The logistics of oncology drug dispensing is also in favor of the physician distributing the drug, because of waste in oncology drug delivery. “There’s no way around that problem unless you have a compounding pharmacy close to the doctor’s office that will deliver on demand…it’s not necessarily an easily scalable approach,” he said. The second challenge to removing buy-and-bill from the physician is economics. When a vial of an oncology drug is shipped to the physician’s office, “the plan is going to be billed for an entire vial,” said Dr Lotvin. Most physicians still want to be in the buy-and-bill business, because it is a revenue generator that inflates at 7% to 8% annually. “The biggest challenge with taking these drugs out of the physician’s office is not just that the physician has a lot of cost built into it, but that the waste goes up dramatically and the amount that gets billed goes up dramatically,” he said. “If you want to get rid of incentives, change the pricing to eliminate incentives; don’t worry about the distribution model, and if you want to think about the distribution model and where the drugs are coming from, the doctors pulling them off the shelves is often the least costly and least wasteful.” About 70% of a community oncologist’s top-line revenue flows through the dispensing of drugs, said Kimberly

Bergstrom, PharmD, Chief Clinical Officer, McKesson Specialty Care Solutions. Traditionally, “we have focused on fixing the reimbursement issue, but the real issue is appropriate utilization,” she said. One method for managing drug distribution is to pay physicians more for choosing a generic when appropriate, providing them with an incentive to act in the plan’s best interest while ensuring that they’re never “under water” in their drug purchases, said Dr Lotvin.

“We have focused on fixing the reimbursement issue, but the real issue is appropriate utilization.” —Kimberly Bergstrom, PharmD

Dr Bergstrom agrees that a differentiated reimbursement for the use of generics would allow community oncologists to administer them without losing money. But the way reimbursement is currently designed, providers stand to lose money by choosing generics. As more equivalent oncologic drugs (eg, more vascular endothelial growth factors) make their way through the pipeline, Dr Lotvin sees some of the decision-making in their use shifting from provider to payer. “We’re still a few years away from having enough competition; part of that is the pipeline rate coming out of the FDA, and part is due to every drug having a unique indication, so it is hard to call them clinically equivalent,” he said. “We’ll see it more with the common therapies, but we’re not there yet.” ■

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KNOW YOUR PATIENTS’ HISTOLOGY AND BUILD A TREATMENT STRATEGY WITH EXTENDED SURVIVAL ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. Limitations of Use: ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer. Myelosuppression is usually the dose-limiting toxicity with ALIMTA therapy. ALIMTA is available in 100 mg and 500 mg vials.

Important Safety Information for Contraindication ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. Warnings and Precautions Patients must be instructed to take folic acid and vitamin B12 with ALIMTA as a prophylaxis to reduce treatment-related hematologic and GI toxicities. Pretreatment with dexamethasone or its equivalent has been reported to reduce the incidence and severity of skin rash. ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia). Reduce doses for subsequent cycles based on hematologic and nonhematologic toxicities. ALIMTA should not be administered to patients with a creatinine clearance <45 mL/min. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min).

PM70198

Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicities. Patients should not begin a new cycle of treatment unless the ANC is *1500 cells/mm3, the platelet count is *100,000 cells/mm3, and creatinine clearance is *45 mL/min. Pregnancy Category D—ALIMTA may cause fetal harm when administered to a pregnant woman. Women should be apprised of the potential hazard to the fetus and should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA. The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration.

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ALIMTAÂŽ (pemetrexed for injection) Drug Interactions Concomitant administration of nephrotoxic drugs or substances that are tubularly secreted could result in delayed clearance of ALIMTA. See Warnings and Precautions for specific information regarding ibuprofen administration. Use in Specific Patient Populations It is recommended that nursing be discontinued if the mother is being treated with ALIMTA or discontinue the drug, taking into account the importance of the drug for the mother. Efficacy of ALIMTA in pediatric patients has not been demonstrated. The most common toxicities reported in the studied pediatric patients were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. Dose adjustments may be necessary in patients with hepatic insufficiency. Dosage and Administration Guidelines Complete blood cell counts, including platelet counts and periodic chemistry tests, should be performed on all patients receiving ALIMTA. Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy.

Modify or suspend therapy according to the Dosage Reduction Guidelines in the full Prescribing Information. Abbreviated Adverse Reactions (% incidence)â&#x20AC;&#x201D; 1st-line NSCLC The most severe adverse reactions (grades 3/4) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, for the 1st-line treatment of patients with advanced non-small cell lung cancer (NSCLC) were neutropenia (15 vs 27); leukopenia (5 vs 8); thrombocytopenia (4 vs 13); anemia (6 vs 10); fatigue (7 vs 5); nausea (7 vs 4); vomiting (6 vs 6); anorexia (2 vs 1); and creatinine elevation (1 vs 1). Common adverse reactions (all grades) with ALIMTA in combination with cisplatin versus gemcitabine in combination with cisplatin, respectively, were nausea (56 vs 53); fatigue (43 vs 45); vomiting (40 vs 36); anemia (33 vs 46); neutropenia (29 vs 38); anorexia (27 vs 24); constipation (21 vs 20); leukopenia (18 vs 21); stomatitis/pharyngitis (14 vs 12); alopecia (12 vs 21); diarrhea (12 vs 13); thrombocytopenia (10 vs 27); neuropathy/ sensory (9 vs 12); taste disturbance (8 vs 9); rash/desquamation (7 vs 8); and dyspepsia/heartburn (5 vs 6). For additional safety and dosing guidelines, please see brief summary of Prescribing Information on adjacent page. PM_HCP_ISI_NSCLC1_04052011

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ALIMTA® (pemetrexed for injection) BRIEF SUMMARY. For complete safety, please consult the full Prescribing Information. 1 INDICATIONS AND USAGE 1.1 Nonsquamous Non-Small Cell Lung Cancer - Combination with Cisplatin ALIMTA is indicated in combination with cisplatin therapy for the initial treatment of patients with locally advanced or metastatic nonsquamous non-small cell lung cancer. 1.5 Limitations of Use ALIMTA is not indicated for the treatment of patients with squamous cell non-small cell lung cancer [see Clinical Studies (14.1, 14.2, 14.3) in the full Prescribing Information]. 2 DOSAGE AND ADMINISTRATION 2.1 Combination Use with Cisplatin Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. The recommended dose of cisplatin is 75 mg/m2 infused over 2 hours beginning approximately 30 minutes after the end of ALIMTA administration. Patients should receive appropriate hydration prior to and/or after receiving cisplatin. See cisplatin package insert for more information. 2.2 Single-Agent Use Nonsquamous Non-Small Cell Lung Cancer The recommended dose of ALIMTA is 500 mg/m2 administered as an intravenous infusion over 10 minutes on Day 1 of each 21-day cycle. 2.3 Premedication Regimen Vitamin Supplementation To reduce toxicity, patients treated with ALIMTA must be instructed to take a low-dose oral folic acid preparation or multivitamin with folic acid on a daily basis. At least 5 daily doses of folic acid must be taken during the 7-day period preceding the first dose of ALIMTA; and dosing should continue during the full course of therapy and for 21 days after the last dose of ALIMTA. Patients must also receive one (1) intramuscular injection of vitamin B12 during the week preceding the first dose of ALIMTA and every 3 cycles thereafter. Subsequent vitamin B12 injections may be given the same day as ALIMTA. In clinical trials, the dose of folic acid studied ranged from 350 to 1000 mcg, and the dose of vitamin B12 was 1000 mcg. The most commonly used dose of oral folic acid in clinical trials was 400 mcg [see Warnings and Precautions (5.1)]. Corticosteroid Skin rash has been reported more frequently in patients not pretreated with a corticosteroid. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction. In clinical trials, dexamethasone 4 mg was given by mouth twice daily the day before, the day of, and the day after ALIMTA administration [see Warnings and Precautions (5.1)]. 2.4 Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations Monitoring Complete blood cell counts, including platelet counts, should be performed on all patients receiving ALIMTA. Patients should be monitored for nadir and recovery, which were tested in the clinical study before each dose and on days 8 and 15 of each cycle. Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min. Periodic chemistry tests should be performed to evaluate renal and hepatic function [see Warnings and Precautions (5.5)]. Dose Reduction Recommendations Dose adjustments at the start of a subsequent cycle should be based on nadir hematologic counts or maximum nonhematologic toxicity from the preceding cycle of therapy. Treatment may be delayed to allow sufficient time for recovery. Upon recovery, patients should be retreated using the guidelines in Tables 1-3, which are suitable for using ALIMTA as a single-agent or in combination with cisplatin. Table 1: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Hematologic Toxicities 75% of previous dose (pemetrexed and Nadir ANC <500/mm3 and nadir platelets ≥50,000/mm3. cisplatin). Nadir platelets <50,000/mm3 without bleeding regardless of nadir ANC. 75% of previous dose (pemetrexed and cisplatin). 50% of previous dose (pemetrexed and Nadir platelets <50,000/mm3 with bleedinga, regardless of nadir ANC. cisplatin). a These criteria meet the CTC version 2.0 (NCI 1998) definition of ≥CTC Grade 2 bleeding. If patients develop nonhematologic toxicities (excluding neurotoxicity) ≥Grade 3, treatment should be withheld until resolution to less than or equal to the patient’s pre-therapy value. Treatment should be resumed according to guidelines in Table 2. Table 2: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Nonhematologic Toxicitiesa,b Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) Any Grade 3 or 4 toxicities except mucositis 75% of previous dose 75% of previous dose Any diarrhea requiring hospitalization 75% of previous dose 75% of previous dose (irrespective of Grade) or Grade 3 or 4 diarrhea Grade 3 or 4 mucositis 50% of previous dose 100% of previous dose

Discontinuation Recommendation ALIMTA therapy should be discontinued if a patient experiences any hematologic or nonhematologic Grade 3 or 4 toxicity after 2 dose reductions or immediately if Grade 3 or 4 neurotoxicity is observed. Renally Impaired Patients In clinical studies, patients with creatinine clearance ≥45 mL/min required no dose adjustments other than those recommended for all patients. Insufficient numbers of patients with creatinine clearance below 45 mL/min have been treated to make dosage recommendations for this group of patients [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Laboratory Monitoring and Dose Reduction/Discontinuation Recommendations (2.4) in the full Prescribing Information]. Caution should be exercised when administering ALIMTA concurrently with NSAIDs to patients whose creatinine clearance is <80 mL/min [see Drug Interactions (7.1)]. 3 DOSAGE FORMS AND STRENGTHS ALIMTA, pemetrexed for injection, is a white to either light-yellow or green-yellow lyophilized powder available in sterile single-use vials containing 100 mg or 500 mg pemetrexed. 4 CONTRAINDICATIONS ALIMTA is contraindicated in patients who have a history of severe hypersensitivity reaction to pemetrexed or to any other ingredient used in the formulation. 5 WARNINGS AND PRECAUTIONS 5.1 Premedication Regimen Need for Folate and Vitamin B12 Supplementation Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and GI toxicity [see Dosage and Administration (2.3)]. In clinical studies, less overall toxicity and reductions in Grade 3/4 hematologic and nonhematologic toxicities such as neutropenia, febrile neutropenia, and infection with Grade 3/4 neutropenia were reported when pretreatment with folic acid and vitamin B12 was administered. Corticosteroid Supplementation Skin rash has been reported more frequently in patients not pretreated with a corticosteroid in clinical trials. Pretreatment with dexamethasone (or equivalent) reduces the incidence and severity of cutaneous reaction [see Dosage and Administration (2.3)].

Bone Marrow Suppression ALIMTA can suppress bone marrow function, as manifested by neutropenia, thrombocytopenia, and anemia (or pancytopenia) [see Adverse Reactions (6.1)]; myelosuppression is usually the dose-limiting toxicity. Dose reductions for subsequent cycles are based on nadir ANC, platelet count, and maximum nonhematologic toxicity seen in the previous cycle [see Dosage and Administration (2.4)]. 5.3 Decreased Renal Function ALIMTA is primarily eliminated unchanged by renal excretion. No dosage adjustment is needed in patients with creatinine clearance ≥45 mL/min. Insufficient numbers of patients have been studied with creatinine clearance <45 mL/min to give a dose recommendation. Therefore, ALIMTA should not be administered to patients whose creatinine clearance is <45 mL/min [see Dosage and Administration (2.4)]. One patient with severe renal impairment (creatinine clearance 19 mL/min) who did not receive folic acid and vitamin B12 died of drug-related toxicity following administration of ALIMTA alone. 5.4 Use with Non-Steroidal Anti-Inflammatory Drugs with Mild to Moderate Renal Insufficiency Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min). Other NSAIDs should also be used with caution [see Drug Interactions (7.1)]. 5.5 Required Laboratory Monitoring Patients should not begin a new cycle of treatment unless the ANC is ≥1500 cells/mm3, the platelet count is ≥100,000 cells/mm3, and creatinine clearance is ≥45 mL/min [see Dosage and Administration (2.4)]. 5.6 Pregnancy Category D Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. Pemetrexed administered intraperitoneally to mice during organogenesis was embryotoxic, fetotoxic and teratogenic in mice at greater than 1/833rd the recommended human dose. If ALIMTA 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. Women of childbearing potential should be advised to avoid becoming pregnant. Women should be advised to use effective contraceptive measures to prevent pregnancy during treatment with ALIMTA [see Use in Specific Populations (8.1)]. 5.7 Third Space Fluid The effect of third space fluid, such as pleural effusion and ascites, on ALIMTA is unknown. In patients with clinically significant third space fluid, consideration should be given to draining the effusion prior to ALIMTA administration. 6 ADVERSE REACTIONS 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates cannot be directly compared to rates in other clinical trials and may not reflect the rates observed in clinical practice. In clinical trials, the most common adverse reactions (incidence ≥20%) during therapy with ALIMTA as a single-agent were fatigue, nausea, and anorexia. Additional common adverse reactions (incidence ≥20%) during therapy with ALIMTA when used in combination with cisplatin included vomiting, neutropenia, leukopenia, anemia, stomatitis/pharyngitis, thrombocytopenia, and constipation. Non-Small Cell Lung Cancer (NSCLC) - Combination with Cisplatin Table 4 provides the frequency and severity of adverse reactions that have been reported in >5% of 839 patients with NSCLC who were randomized to study and received ALIMTA plus cisplatin and 830 patients with NSCLC who were randomized to study and received gemcitabine plus cisplatin. All patients received study therapy as initial treatment for locally advanced or metastatic NSCLC and patients in both treatment groups were fully supplemented with folic acid and vitamin B12. Table 4: Adverse Reactions in Fully Supplemented Patients Receiving ALIMTA plus Cisplatin in NSCLCa ALIMTA/cisplatin Gemcitabine/cisplatin Reactionb (N=839) (N=830) All Grades Grade 3-4 All Grades Grade 3-4 Toxicity (%) Toxicity (%) Toxicity (%) Toxicity (%) All Adverse Reactions 90 37 91 53 Laboratory Hematologic 10 46 6 33 Anemia 27 38 15 29 Neutropenia 8 21 5 18 Leukopenia 13 27 4 10 Thrombocytopenia Renal Creatinine elevation 10 1 7 1 Clinical Constitutional Symptoms Fatigue 43 7 45 5 Gastrointestinal 4 53 7 56 Nausea 6 36 6 40 Vomiting 1 24 2 27 Anorexia 0 20 1 21 Constipation 0 12 1 14 Stomatitis/Pharyngitis 2 13 1 12 Diarrhea 0 6 0 5 Dyspepsia/Heartburn Neurology Neuropathy-sensory 9 0 12 1 Taste disturbance 8 0c 9 0c Dermatology/Skin Alopecia 12 0c 21 1c Rash/Desquamation 7 0 8 1 a For the purpose of this table a cut off of 5% was used for inclusion of all events where the reporter considered a possible relationship to ALIMTA. b Refer to NCI CTC Criteria version 2.0 for each Grade of toxicity. c According to NCI CTC Criteria version 2.0, this adverse event term should only be reported as Grade 1 or 2. No clinically relevant differences in adverse reactions were seen in patients based on histology. In addition to the lower incidence of hematologic toxicity on the ALIMTA and cisplatin arm, use of transfusions (RBC and platelet) and hematopoietic growth factors was lower in the ALIMTA and cisplatin arm compared to the gemcitabine and cisplatin arm. The following additional adverse reactions were observed in patients with non-small cell lung cancer randomly assigned to receive ALIMTA plus cisplatin. Incidence 1% to 5% Body as a Whole — febrile neutropenia, infection, pyrexia General Disorders — dehydration Metabolism and Nutrition — increased AST, increased ALT Renal — creatinine clearance decrease, renal failure Special Senses — conjunctivitis Incidence Less than 1% Cardiovascular — arrhythmia General Disorders — chest pain Metabolism and Nutrition — increased GGT Neurology — motor neuropathy Across clinical trials, sepsis, which in some cases was fatal, occurred in approximately 1% of patients. Post-Marketing Experience The following adverse reactions have been identified during post-approval use of ALIMTA. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. These reactions have occurred with ALIMTA when used as a single-agent and in combination therapies. Gastrointestinal — colitis General Disorders and Administration Site Conditions — edema

ALIMTA® (pemetrexed for injection)

NCI Common Toxicity Criteria (CTC). Excluding neurotoxicity (see Table 3). In the event of neurotoxicity, the recommended dose adjustments for ALIMTA and cisplatin are described in Table 3. Patients should discontinue therapy if Grade 3 or 4 neurotoxicity is experienced. Table 3: Dose Reduction for ALIMTA (single-agent or in combination) and Cisplatin - Neurotoxicity CTC Grade Dose of ALIMTA (mg/m2) Dose of Cisplatin (mg/m2) 0-1 100% of previous dose 100% of previous dose 2 100% of previous dose 50% of previous dose b

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Injury, poisoning, and procedural complications — Radiation recall has been reported in patients who have previously received radiotherapy. Respiratory — interstitial pneumonitis Skin — Bullous conditions have been reported, including Stevens-Johnson syndrome and toxic epidermal necrolysis, which in some cases were fatal. 7 DRUG INTERACTIONS 7.1 Non-Steroidal Anti-Inflammatory Drugs (NSAIDs) Ibuprofen Although ibuprofen (400 mg four times a day) can decrease the clearance of pemetrexed, it can be administered with ALIMTA in patients with normal renal function (creatinine clearance ≥80 mL/min). Caution should be used when administering ibuprofen concurrently with ALIMTA to patients with mild to moderate renal insufficiency (creatinine clearance from 45 to 79 mL/min) [see Clinical Pharmacology (12.3) in the full Prescribing Information]. Other NSAIDs Patients with mild to moderate renal insufficiency should avoid taking NSAIDs with short elimination half-lives for a period of 2 days before, the day of, and 2 days following administration of ALIMTA. In the absence of data regarding potential interaction between ALIMTA and NSAIDs with longer half-lives, all patients taking these NSAIDs should interrupt dosing for at least 5 days before, the day of, and 2 days following ALIMTA administration. If concomitant administration of an NSAID is necessary, patients should be monitored closely for toxicity, especially myelosuppression, renal, and gastrointestinal toxicity. 7.2 Nephrotoxic Drugs ALIMTA is primarily eliminated unchanged renally as a result of glomerular filtration and tubular secretion. Concomitant administration of nephrotoxic drugs could result in delayed clearance of ALIMTA. Concomitant administration of substances that are also tubularly secreted (e.g., probenecid) could potentially result in delayed clearance of ALIMTA. 8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Teratogenic Effects - Pregnancy Category D [see Warnings and Precautions (5.6)]. Based on its mechanism of action, ALIMTA can cause fetal harm when administered to a pregnant woman. There are no adequate and well controlled studies of ALIMTA in pregnant women. Pemetrexed was embryotoxic, fetotoxic, and teratogenic in mice. In mice, repeated intraperitoneal doses of pemetrexed when given during organogenesis caused fetal malformations (incomplete ossification of talus and skull bone; about 1/833rd the recommended intravenous human dose on a mg/m2 basis), and cleft palate (1/33rd the recommended intravenous human dose on a mg/m2 basis). Embryotoxicity was characterized by increased embryo-fetal deaths and reduced litter sizes. If ALIMTA 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. Women of childbearing potential should be advised to use effective contraceptive measures to prevent pregnancy during the treatment with ALIMTA. 8.3 Nursing Mothers It is not known whether ALIMTA or its metabolites are 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 ALIMTA, a decision should be made to discontinue nursing or discontinue the drug, taking into account the importance of the drug for the mother. 8.4 Pediatric Use Efficacy of ALIMTA in pediatric patients has not been demonstrated. ALIMTA was administered as an intravenous infusion over 10 minutes on Day 1 of a 21 day cycle to pediatric patients with recurrent solid tumors in a Phase 1 study (32 patients) and a Phase 2 study (72 patients). All patients received pretreatment with vitamin B12 and folic acid supplementation and dexamethasone. The dose escalation in the Phase 1 study determined the maximum tolerated dose was 1910 mg/m2 and this dose (or 60 mg/kg for patients <12 months old) was evaluated in the Phase 2 study of patients with relapsed or refractory osteosarcoma, Ewing sarcoma/peripheral PNET, rhabdomyosarcoma, neuroblastoma, ependymoma, medulloblastoma/ supratentorial PNET, or non-brainstem high grade glioma. No responses were observed among the 72 patients in this Phase 2 trial. The most common toxicities reported were hematological (leukopenia, neutropenia/granulocytopenia, anemia, thrombocytopenia, and lymphopenia), liver function abnormalities (increased ALT/AST), fatigue, and nausea. The single dose pharmacokinetics of ALIMTA administered in doses ranging from 400 to 2480 mg/m2 were evaluated in the Phase 1 trial in 22 patients (13 males and 9 females) aged 4 to 18 years (average age 12 years). Pemetrexed exposure (AUC and Cmax) appeared to increase proportionally with dose. The average pemetrexed clearance (2.30 L/h/m2) and half-life (2.3 hours) in pediatric patients were comparable to values reported in adults. 8.5 Geriatric Use ALIMTA is known to be substantially excreted by the kidney, and the risk of adverse reactions to this drug may be greater in patients with impaired renal function. Because elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Renal function monitoring is recommended with administration of ALIMTA. No dose reductions other than those recommended for all patients are necessary for patients 65 years of age or older [see Dosage and Administration (2.4)]. In the initial treatment non-small cell lung cancer clinical trial, 37.7% of patients treated with ALIMTA plus cisplatin were ≥65 years and Grade 3/4 neutropenia was greater as compared to patients <65 years (19.9% versus 12.2%). For patients <65 years, the HR for overall survival was 0.96 (95% CI: 0.83, 1.10) and for patients ≥65 years the HR was 0.88 (95% CI: 0.74, 1.06) in the intent-to-treat population. In the maintenance non-small cell lung cancer trial 33.3% of patients treated with ALIMTA were ≥65 years and no differences were seen in Grade 3/4 adverse reactions as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.74 (95% CI: 0.58, 0.93) and for patients ≥65 years the HR was 0.88 (95% CI: 0.65, 1.21) in the intent-to-treat population. In the non-small cell lung cancer trial after prior chemotherapy, 29.7% patients treated with ALIMTA were ≥65 years and Grade 3/4 hypertension was greater as compared to patients <65 years. For patients <65 years, the HR for overall survival was 0.95 (95% CI: 0.76, 1.19), and for patients ≥65 years the HR was 1.15 (95% CI: 0.79, 1.68) in the intent-to-treat population. 8.6 Patients with Hepatic Impairment There was no effect of elevated AST, ALT, or total bilirubin on the pharmacokinetics of pemetrexed [see Clinical Pharmacology (12.3)]. Dose adjustments based on hepatic impairment experienced during treatment with ALIMTA are provided in Table 2 [see Dosage and Administration (2.4)]. 8.7 Patients with Renal Impairment ALIMTA is known to be primarily excreted by the kidneys. Decreased renal function will result in reduced clearance and greater exposure (AUC) to ALIMTA compared with patients with normal renal function [see Dosage and Administration (2.4) and Clinical Pharmacology (12.3) in the full Prescribing Information]. Cisplatin coadministration with ALIMTA has not been studied in patients with moderate renal impairment. 8.8 Gender In the initial treatment non-small cell lung cancer trial, 70% of patients were males and 30% females. For males the HR for overall survival was 0.97 (95% CI: 0.85, 1.10) and for females the HR was 0.86 (95% CI: 0.70, 1.06) in the intent-to-treat population. In the maintenance non-small cell lung cancer trial, 73% of patients were males and 27% females. For males the HR for overall survival was 0.78 (95% CI: 0.63, 0.96) and for females the HR was 0.83 (95% CI: 0.56, 1.21) in the intent-to-treat population. In the non-small cell lung cancer trial after prior chemotherapy, 72% of patients were males and 28% females. For males the HR for overall survival was 0.95 (95% CI: 0.76, 1.19) and for females the HR was 1.28 (95% CI: 0.86, 1.91) in the intent-to-treat population. 8.9 Race In the initial treatment non-small cell lung cancer trial, 78% of patients were Caucasians, 13% East/Southeast Asians, and 9% others. For Caucasians, the HR for overall survival was 0.92 (95% CI: 0.82, 1.04), for East/Southeast Asians the HR was 0.86 (95% CI: 0.61, 1.21), and for others the HR was 1.24 (95% CI: 0.84, 1.84) in the intent-to-treat population. In the maintenance non-small cell lung cancer trial, 65% of patients were Caucasians, 23% East Asian, and 12% others. For Caucasians the HR for overall survival was 0.77 (95% CI: 0.62, 0.97), for East Asians was 1.05 (95% CI: 0.70, 1.59) and for others the HR was 0.46 (95% CI: 0.26, 0.79) in the intent-to-treat population. In the non-small cell lung cancer trial after prior chemotherapy, 71% of patients were Caucasians and 29% others. For Caucasians the HR for overall survival was 0.91 (95% CI: 0.73, 1.15) and for others the HR was 1.27 (95% CI: 0.87, 1.87) in the intent-to-treat population. 10 OVERDOSAGE There have been few cases of ALIMTA overdose. Reported toxicities included neutropenia, anemia, thrombocytopenia, mucositis, and rash. Anticipated complications of overdose include bone marrow suppression as manifested by neutropenia, thrombocytopenia, and anemia. In addition, infection with or without fever, diarrhea, and mucositis may be seen. If an overdose occurs, general supportive measures should be instituted as deemed necessary by the treating physician. ®

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In clinical trials, leucovorin was permitted for CTC Grade 4 leukopenia lasting ≥3 days, CTC Grade 4 neutropenia lasting ≥3 days, and immediately for CTC Grade 4 thrombocytopenia, bleeding associated with Grade 3 thrombocytopenia, or Grade 3 or 4 mucositis. The following intravenous doses and schedules of leucovorin were recommended for intravenous use: 100 mg/m2, intravenously once, followed by leucovorin, 50 mg/m2, intravenously every 6 hours for 8 days. The ability of ALIMTA to be dialyzed is unknown. 13 NONCLINICAL TOXICOLOGY 13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility No carcinogenicity studies have been conducted with pemetrexed. Pemetrexed was clastogenic in the in vivo micronucleus assay in mouse bone marrow but was not mutagenic in multiple in vitro tests (Ames assay, CHO cell assay). Pemetrexed administered at i.v. doses of 0.1 mg/kg/day or greater to male mice (about 1/1666 the recommended human dose on a mg/m2 basis) resulted in reduced fertility, hypospermia, and testicular atrophy. 17 PATIENT COUNSELING INFORMATION See FDA-Approved Patient Labeling. Patients should be instructed to read the patient package insert carefully. 17.1 Need for Folic Acid and Vitamin B12 Patients treated with ALIMTA must be instructed to take folic acid and vitamin B12 as a prophylactic measure to reduce treatment-related hematologic and gastrointestinal toxicity [see Dosage and Administration (2.3)]. 17.2 Low Blood Cell Counts Patients should be adequately informed of the risk of low blood cell counts and instructed to immediately contact their physician should any sign of infection develop including fever. Patients should also contact their physician if bleeding or symptoms of anemia occur. 17.3 Gastrointestinal Effects Patients should be instructed to contact their physician if persistent vomiting, diarrhea, or signs of dehydration appear. 17.4 Concomitant Medications Patients should be instructed to inform the physician if they are taking any concomitant prescription or over-the-counter medications including those for pain or inflammation such as non-steroidal anti-inflammatory drugs [see Drug Interactions (7.1)]. To report SUSPECTED ADVERSE REACTIONS, contact Eli Lilly and Company at 1-800-LillyRx (1-800-545-5979) or FDA at 1-800-FDA-1088, or www.fda.gov/medwatch.

Literature revised March 17, 2011

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HEALTHCARE REFORM

Implications of Healthcare Reform for Oncologists and Cancer Care Interview with Joseph S. Bailes, MD Oncologist and Partner, Texas Oncology, Houston, TX Q: What concerns do you have about how healthcare legislation might affect oncology?

Q: What do you see as some of the positive things in the healthcare reform bill?

Dr Bailes: The healthcare reform legislation involves many potential issues that can affect oncology, for example, how minimum benefits are defined. First, there are required minimum benefits that all health plans and other insurers have to meet, and we have to make sure that cancer care is included. Second, the group called the Independent Payment Advisory Board (IPAB) has the ability—the way the law is set up—to make recommendations that could be implemented in Medicare through the Centers for Medicare & Medicaid Services (CMS), unless Congress overrides these recommendations. Third, the reform bill relies on Medicaid expansion to a great extent; and because Medicaid is a joint federal/state program, Medicaid expansion means more pressure on states. State budgets are already under pressure, and we worry about adding potential barriers to access. These barriers would require patients with cancer to jump through hoops and perhaps not get needed therapy. Those are just some of the big issues that those involved in oncology care are worried about within the context of the healthcare reform bill.

Dr Bailes: There are many positive things in the healthcare reform bill, especially for individuals with serious diseases, such as cancer. There is the elimination of preexisting conditions, so patients can get any insurance, regardless of whether they have cancer or have had cancer. There is the elimination of lifetime caps on insurance; if patients have a serious illness or have to have a transplant, they won’t face being told they can’t have further care because they have reached their lifetime maximum benefits.

“We worry about adding potential barriers to access, which would require patients with cancer to jump through hoops and perhaps not get needed therapy.”

There is also the elimination of what is known as rescissions, where people are denied coverage because of something on an insurance application from previous years. In addition, there is

“There are many positive things in the healthcare reform bill, especially for individuals with serious diseases, such as cancer. There is the elimination of preexisting conditions, so patients can get any insurance, regardless of whether they have cancer or have had cancer.”

coverage for patients’ costs that are associated with participation in clinical trials in private insurance.

Q: Do you think the provision will ultimately lead to lower costs for the healthcare system overall? Dr Bailes: Ultimately, yes. If we look at malignancy, the most expensive treatment is when it is diagnosed late or not diagnosed correctly. If we screen early, we find cancers at a stage where they are treatable. That is where the treatment is cost-effective for the individual, because the patient is treated and is back to work. There are a lot of benefits to the system in being able to access the healthcare system early and get the appropriate treatment.

Q: Will the IPAB committee—that is going to make recommendations to Medicare—include an oncologist? Dr Bailes: The IPAB is set up by the healthcare reform bill to replace the Medicare Payment Advisory Committee. It will be able to make recommendations within certain parameters that are in the law that CMS could then implement, unless Congress stopped it. There is no explicit provision to require an oncologist on the IPAB.

2011 REGIONAL MEETINGS September 24 Chicago, IL

October 1 San Francisco, CA

November 19 Tampa, FL

VALUE-BASED CANCER CARE

July 2011

Q: Do you think the debate over healthcare reform may hurt the ability of an oncologist to talk about terminal care with patients? Dr Bailes: I do not think it will hurt, but the unfortunate thing about the debate was that it got off topic from what is important, that is, the need for oncologists, patients with cancer, and their families to have a candid discussion about the benefits, or lack of ben-

efits, of a particular therapy at a specific time. We saw that in the rule when that part of the proposed physician fee schedule was decided. I believe we got off on a tangent in that case and lost sight of what was important. Many organizations—the American Society of Clinical Oncologists among them—have guidelines and much background material on how to speak with individuals who have a terminal illness and evaluate with the individual and the family which therapy makes sense. That is the responsibility of the oncologist and the health oncology team. The more we can do to help the oncology team with that, the better.

Q: Do you think some oncologists hesitate following parts of the law that are already in practice because it is being disputed in the courts? Dr Bailes: I do not think that is an issue right now. Oncologists are dedicated individuals, and they see there has been a lot of publicity about the positive parts of the healthcare reform law. And many of the other parts have not been implemented yet.

Q: What are some improvements that you would make to the bill? Dr Bailes: There needs to be a little more flushing out of what the patientoriented research authority—the comparative effectiveness research group— does, and what their authority is. Those in charge of benefit design in health plans need to make sure that there is input from all parties involved, such as patient advocates, physicians, specialty societies, policymakers, and states. ■

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CARE MANAGEMENT MODELS

Medical and Pharmacy Directors’ Strategies to Improve Cancer Care Management By Wayne Kuznar Philadelphia, PA—Implementing pathways to sustain community oncology and offering additional nursing and care management models are recent strategies being adopted by various practices and payers to reduce the medical and pharmacy costs in cancer management and improve the quality of care. Care Management Model “We want to create a sustainable model where community oncology can be ‘buy and bill,’” said Daniel McCrone, MD, Chief Medical Officer, New Century Health in California. “The way that we support the physician is a 4-step approach.” As can be seen in Figure 1, the 4-step model combines “fee schedule normalization, which leads to consistent payments; prior authorization, which leads to evidence-based treatment; quality improvement programs, which lead to aligned physician interests; and a high-performance provider network, which leads to quality care at optimal cost,” added Dr McCrone. “We believe this 4-step process is exactly the way to manage the escalating pharmacy trends,” he said. “Of the 20% we could reduce a payer’s expense by, 5% to 25% of that 20% is in fee normalization, and prior authorization brings it up to about 55%. When we include the pathways, the savings is up to 75%, and consolidating the network would save 75% and more.” Care management is about improving quality of care, and the focus, said Dr McCrone, should be on reducing hospital admissions and emergency

“We believe this 4-step process is exactly the way to manage the escalating pharmacy trends.” —Daniel McCrone, MD

department visits. A care management program requires the following: • Oncology nurses or oncologytrained nurses • Patient treatment plan and schedule • Financial incentive to physicians to refer patients • Patient support, such as home administration of intravenous fluids, and manufacturer support. “Our idea was that this additional nursing would more than pay for itself by less utilization of hospital and emergency room visits,” Dr McCrone said. The duration of the active care management model is about 5 months per patient; 2500 patients enrolled in the program in its first year. Emergency department visits decreased by 10%, regardless of the treatment plan. For

Figure 1 Oncology Management Approach

• Sustainable savings requires a • An integrated approach is focused on

Optimal care + cost

total cost management—this allows us to achieve quantifiable savings over the short- and long-term

Outcomesbased

Utilize a “phase-in” approach that allows us to individually target each key component of oncology care

Phase II

Phase I

Phase III

Fee schedule normalization

Prior authorization via nationally accepted guidelines

Consistent payments

Evidence-based treatment

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Treatment pathways

Technology

comprehensive management model

Quality improvement program

Reduced facility cost

Phase IV High-performance provider network

Savings Opportunity Aligned physician interests

➤

Quality care at optimal cost

stable regimens for the management of breast, prostate, lung, and bladder cancers, hospital admissions decreased by 9%. But for rapidly evolving regimens, such as those for head/neck, colon, and brain cancers, there was a 10% increase in hospitalizations during the first year of the program. “In addition, because of our nurse program, 70% of patients who expired were in hospice or home hospice,” Dr McCrone added. Care Integration Networks According to Craig Deligdish, MD, Chief Medical Officer, Florida Comprehensive Care Network (FCCN), although much of the effort to manage cancer costs revolve around drug costs, other contributing cost factors are molecular diagnostics, advanced imaging, radiation therapy, supportive care, maintenance therapy, and endof-life care. The FCCN is based on a partnership of physicians through this clinically integrated network. This network works with technology solutions, advanced care, palliative care programs, and oncology benefit management programs, working with payers who also face challenges from their self-insured clients to try to reduce the cost of cancer treatment. FCCN “provides physicians and health plans with the tools to manage pathway and guideline adherence, creates physician guidelines, and realigns incentives around buy and bill,” Dr Deligdish said. The goals of the network include sustaining community oncology, pro-

viding technology for consistent delivery of quality care that allows both practices and health plans to measure outcomes and monitor adherence to pathways, and decreasing the administrative burden by simplifying and obviating the prior authorization process and using technology. “We focus to a large degree as a clinically integrated network,” Dr Deligdish added. “Clinical integration is an active and ongoing program to evaluate and modify practice patterns by the network’s physician participants to create a high degree of interdependence and cooperation to control costs and ensure quality.” Dr Deligdish suggested that advanced care and palliative care programs need to feature an integrated care plan, focused education and patient intervention, and 24-hour access. The benefits of these programs include improved patient/physician satisfaction, decreased hospitalizations, and increased hospice enrollment.

“We’ve taken a different approach at CareFirst, and we’re actually trying to collaborate with our physicians.” —Winston Wong, PharmD Payer–Physician Collaboration The community tries to pit managed care organizations (MCOs) against providers, saying they are 2 pieces of sandpaper coming together, said Winston Wong, PharmD, Associate Vice President, Pharmacy Management, CareFirst Blue Cross Blue Shield. In reality, MCOs and providers Continued on page 46

www.ValueBasedCancerCare.com

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CARE MANAGEMENT MODELS

Medical and Pharmacy Directors’ Strategies... are in agreement on current issues, challenges, and goals. “We are all looking at the perfect storm coming together,” Dr Wong said. “The basis of the storm right now is the biological pipeline, which is rich in expensive oncologic agents. We also have the threat of an increase in the uninsured population becoming covered through government programs.” He said that “we’re looking at an increase in utilization overall in oncology care, which means an increase in cost. But the real issue is variability of cost because of variability of care.” What do MCOs do when faced with an increase in cost? The typical kneejerk reaction is to tighten the fee schedule. To change this, payers and physicians need a new paradigm. “We’ve taken a different approach at CareFirst, and we’re actually trying to

at a glance ➤ Implementing pathway programs and care management models can reduce the cost of cancer care and improve its quality ➤ Flexible fee schedules encourage individualized medicine and provide significant incentives for compliance ➤ The focus of care management programs should be on reducing hospital admissions and emergency department visits ➤ A clinically integrated network provides physicians and health plans with the tools to manage pathway and guideline adherence, create guidelines, and realign incentives

collaborate with our physicians. We’re using a paradigm, and we’re pulling together representatives out of our oncology network and creating an oversight committee to take a look at oncology care,” Dr Wong said. His company is partnering with P4 Healthcare, which helps facilitate pathway development with physician groups, as well as monitoring data and educating physicians. This paradigm promotes individualized medicine and physicians’ discretion and provides incentives for compliance, creating a win-win-win scenario for patients, physicians, and the health plan. Dr Wong began this pathway program in 2008. “It’s a true pay-for-quality program, in that physicians who elect not to participate in our program are reimbursed at our standard fee schedule,” he said. “However, physicians who comply with our pathway standards are reimbursed at our standard fee schedule plus a differential. Hence, we are not hurting any practices who are not participating; we’re

“Pathway-based care should represent an evidence-based and holistic patient-centric approach. To do this with providers, we need new contractual relationships that drive quality improvements.” —Ira Klein, MD

simply giving the incentive to work with us on the program.” At the end of the 2-year period, pathways for breast, lung, and colon cancers resulted in savings of approximately $17 million, the net of the incentive that was provided to physicians (Figure 2). “We were able to show that the use of a pathway program, where you have physicians working with us, can

24-Month Breast, Colon, and Lung Savings: Antineoplastics, Supportive Figure 2 Care, and Service Costs $20,000,000 $17,203,405

$18,000,000 $16,000,000 $14,000,000

$12,354,845

$12,000,000 $10,000,000 $8,000,000 $6,000,000 $8,811,862

$4,000,000 $1,036,698

$2,000,000

VALUE-BASED CANCER CARE

$0 Antineoplastics Supportive care

July 2011

Continued from page 45

Service costs

Total

actually function pretty well,” he said. The reason behind the program is to try to maintain the viability of the community practice, he added. Ira Klein, MD, Senior Medical Director, Aetna Oncology Strategy, agrees that to improve quality management, payers and providers need to work together. Based on results of a collaborative study between Aetna and US Oncology (Neubauer MA, et al. J Oncol Pract. 2010;6:12-18), the use of pathways did not alter the overall morbidity or mortality in patients with non– small-cell lung cancer (NSCLC) treated in the outpatient community setting. However, it did reduce the cost of drugs for patients with NSCLC. The study demonstrated a cost-savings of 35% over 12 months. “But that’s really the beginning,” Dr Klein said. “Pathway-based care should represent an evidence-based and holistic patient-centric approach. To do this with providers, we need new contractual relationships that drive quality improvements and changes, and these are about aligning incentives while keeping the focus on the cancer patient.” ■

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Image: Colored scanning electron micrograph (SEM) of a pancreatic cancer cell.

goal One goal: discovering and delivering breakthrough medicines to combat cancer. Millennium: The Takeda Oncology Company is developing an extensive pipeline — among the top in oncology worldwide — with more than 17 compounds in development for a broad range of solid and hematological cancers. Our pipeline — rich in novel compounds — includes multiple candidates that target seven disease pathways: protein homeostasis, anti-angiogenesis, growth-signaling inhibition, cell-cycle inhibition, apoptosis, immunomodulators and hormone regulation. We are dedicated to a strong partnership with the oncology community. Together we can make a dramatic impact on cancer therapeutics over the next decade.

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THERAPY FRAGMENTATION

The Impact of Therapy Type on Clinical Fragmentation in Oncology Care By Wayne Kuznar Philadelphia, PA—Fragmentation in oncology care significantly influences physicians’, payers’, and patients’ understanding of how cancer therapies lead to improved quality of care. The main reason for fragmentation is the challenge in linking pharmacy and medical data in a way that generates usable information, according to Atheer A. Kaddis, PharmD, Vice President, Managed Markets, Diplomat Specialty Pharmacy. The Oncology Drug Marketplace “Improving the capture of data on the medical and pharmacy benefits sides and integrating data to apply this information to decision-making will help us meet the challenge,” Dr Kaddis said. The oncology drug market is undergoing a major shift from injectable to oral oncolytics, which to a large extent revolves around Medicare. Plans offering Medicare Part D prescription drugs must include in their formulary all approved drugs in a specific category or class.

“My bold prediction is that there’s going to be a bigger role for specialty pharmacies going forward when it comes to oncology. Part of that is being driven by oral oncolytics.” —Atheer A. Kaddis, PharmD A significant evolution has occurred in the number and types of medications. Before 1985, specialty disease states had limited or zero drug treatment choices. Today, several specialty disease states—including multiple myeloma, breast cancer, and transplant—are treated mostly with oral therapies. And several specialty disease states are expected to have an oral drug option within 2 years, including

acute myelogenous leukemia and melanoma. As a result of the increased number of specialty therapies, Dr Kaddis said, “My bold prediction is that there’s going to be a bigger role for specialty pharmacies going forward when it comes to oncology. Part of that is being driven by oral oncolytics, and also it is because of what’s going on in clinical pathways, accountable care organizations, and even 340B programs and the trend toward contracted pharmacies.” The clinical and economic implications of oncology drugs are: • Reimbursement remains the primary method for controlling chemotherapy costs and utilization from a managed care perspective • Oral oncolytics are changing the direction of channel management • Integration of pharmacy and medical data presents a significant challenge. Management Challenges The oncology drug management challenges are directly related to health insurance or payer benefit design, according to Kirby J. Eng, RPh, Director, Medical Pharmacy Management, CVS Caremark. The clinical challenges include the site of service and coordination of care, therapy information, and adherence to therapy. The drug formulation has several implications to health plans (Figure). If a drug is a tablet or a capsule, the site of service typically would be a pharmacy channel. Benefit coverage, given the site of service and drug formulation, overwhelmingly, would fall under pharmacy benefit. For selfadministered injectable drugs, the site of service would be the physician’s office or, increasingly, the pharmacy—

VALUE-BASED CANCER CARE

July 2011

retail or specialty. Health plans were split on benefit coverage for selfadministered injectables; increasingly it is placed under the pharmacy rather than the medical benefit. If a drug is intravenous or injectable, it is likely going to be administered in a physician’s office or a specialty pharmacy, and coverage would fall under medical benefit. Mr Eng said that the stakeholder implications of oncology drug therapy management depends on the party involved, in the following way: • Patients: –Out-of-pocket costs –Therapy information (eg, from the Web, physician, nurse, pharmacy) –Therapy adherence and coordination of care

• Payers: –Providing access to quality and costeffective care –Benefit coverage determination • Pharmacy: –Medication therapy management, including education and patient adherence –Coordination of care • Physicians: –Education and coordination of care • Manufacturers: –Market management of hospitals, patients, payers, pharmacy, and prescribers. Another health plan, Excellus Health Plan, Blue Cross Blue Shield, initiated a review of all the drugs going through their medical benefit, as well as the high cost of these therapies a few years ago, said Kristen M. Reimers, RPh, Clinical Pharmacy Operations Manager, Excellus, and Director of Specialty Pharmacy Programs at FLRx Pharmacy Management. Excellus actively targeted some of the clinical fragmentation of the oncology drug market. On the pharmacy side, the plan evaluated the therapies and determined there needed to be a group that would manage high-cost therapies, said Ms Reimers. Excellus formed a team of specially trained, highly specialized nurses and pharmacists and medical directors to initially manage 3 therapies. Now the health plan manages >60 therapies, Continued on page 49

Figure Drug Formulation Implications Drug formulation

Tablet or capsule

Benefit coveragea

Site of service (outpatient)

➤

Pharmacy PBM Retail Specialty

➤

Pharmacy (93%)

Medical (7%)

Physician office

Medical (53%) Injectable (self-administered)

➤

Physician office Pharmacy

➤

Retail Specialty

Intravenous or injectable

➤

Physician office Pharmacy Retail Specialty

Pharmacy (47%)

➤

Medical (98%)

Pharmacy (2%)

EMD Serono Digest, 5th edition. PBM indicates pharmacy benefit manager.

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THERAPY FRAGMENTATION which are primarily focused in oncology. Management tools for the pharmacy benefit include specialty pharmacy contracts, formulary management and physician reimbursement, and operational improvements. Critical to specialty pharmacies is the patient-centered approach, such as patient adherence. The hot issue in specialty drug management, according to Ms Reimers, is related to oral oncolytics management. The challenges identified by Excellus are: • Lack of respect for some drugs when first introduced • Lack of control: physicians were used to ordering therapies in the offices, and patients would then receive them in the office • Therapeutic and clinical risk if patients were not taking drugs (nonadherence) or were not taking them as prescribed; risk of drug interactions and severe adverse effects; no feedback loop to physician offices, so physicians are left in the dark as to whether patients were getting the therapies • Cost issues, including high-cost therapies and risk of waste. Among physicians, patients, and payers, there were similar concerns with regard to oral oncology management. For one, oncologist offices had lack of control, because they didn’t know if patients were taking the medications and if they took them as prescribed. In addition, getting drugs covered for the patient can be difficult when therapies are available only in limited distribution channels. On the payer’s side, there was high

at a glance ➤ Medicare Part D benefits are driving the shift from injectable to oral oncolytics ➤ Oncologists often cannot confirm if their patients are taking their medications as prescribed ➤ Patients often cannot get coverage for drugs that are available only through limited channels ➤ Specialty pharmacies will play a larger role as oncology therapy shifts more toward oral oncolytics ➤ A high-touch specialty drug program for oral oncology agents can help to ensure appropriate utilization of the medications and improve adherence

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cost and risk of high waste. “Payers don’t want to pay for drugs that patients aren’t taking,” Ms Reimers said. From a member’s perspective, the concern is simple—expense. “Patients don’t know if they can afford therapies or if it’s even worth it for them to take these therapies,” she said. Specialty Drug Program Excellus worked with specialty pharmacies to develop a high-touch specialty drug program for oral oncology agents to ensure appropriate utilization of the medications. Education was deemed necessary to the program to address adverse events and how to manage such events.

Health plans were split on benefit coverage for selfadministered injectables; increasingly it is placed under the pharmacy rather than the medical benefit.

patient was actually getting their therapy,” Ms Reimers said. The program included a concise 1page document in the form of a progress note that included information about when patients started and stopped therapy and whether there were adverse events. Everything was documented. In the first 18 months of running the high-touch specialty pharmacy program, 400 patients were using oral oncology therapies, and 256 of those opted into the program. (They were considered in the program unless they chose not to participate.) Patients had access to clinicians and pharmacists 24 hours a day, 7 days a week. There were follow-up reminders, assessments on patients, and reports back to physicians and the health plan. The adherence rate of patientmissed doses was only 8.2%. The discontinuation rate on advice of physicians was 10% (27 of 256 patients). This is in contrast to the national discontinuation rate of oral oncology medications, which is about 30%. To prevent future fragmentation, the health plan has instituted new ongoing strategies to manage drug therapies: • Monitoring the drug pipeline for drugs being developed • Off-label use program • Development of unique medical drug treatment to manage intravenous therapies • Continue to manage provider fee schedule • Seek ways to manage waste and vials

“Payers don’t want to pay for drugs that patients aren’t taking. Excellus also wanted to…close the loop on what they [physicians] saw as fragmentation in not knowing whether the patient was actually getting their therapy.” —Kristen M. Reimers, RPh

• Development of adherence programs, especially on the medical side • Provider discussions with community oncologists seeking input on our programs • Tracking health plan data and trends to determine where to eliminate fragmentation. ■

—Kirby J. Eng, RPh “The program was designed to be high-touch so patients felt they were part of their own care,” Ms Reimers said. As part of the program, oral oncology agents were incorporated into the mandatory specialty network. All patients using these therapies were required to receive them from one of Excellus’ specialty pharmacies; they could then participate in programs that were clinician based at the pharmacies. Nurses and pharmacists who were trained in oncology would make assessments. When therapy was first initiated, assessments occurred every 7 to 10 days. Patients were instructed in how to manage issues such as adverse effects. “Excellus also wanted to address concerns of the physician and close the loop on what they saw as fragmentation in not knowing whether the

2011 REGIONAL MEETINGS September 24 Chicago, IL

October 1 San Francisco, CA

November 19 Tampa, FL

www.ValueBasedCancerCare.com

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CONTINUING EDUCATION

The Evolving Role of Outcomes and End Points in Evaluating Therapy for Hematologic Malignancies: Value-Driven Benefit Design and Utilization Management Strategies Program P11067E

Initial Release Date: July 15, 2011 • Expiration Date: July 15, 2012. Estimated time to complete activity: 1 hour. SPonSor

This activity is jointly sponsored by Medical Learning Institute, Inc. (MLI), a nonprofit medical accreditation company, and Center of Excellence Media, LLC. TargET audiEncE

For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609-333-1693 or cgusack@mlicme.org. rEgiSTErEd Pharmacy dESignaTion

Medical Learning Institute, Inc., is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.0 contact hour (0.1 CEU) of continuing education credit. The universal activity number for this activity is 0468-9999-11-029-H01-P.

This activity was developed for health-system pharmacists and oncology pharmacists.

diScLoSurES

LEarning objEcTivES

Before the activity, all faculty and anyone who is in a position to have control over the content of this activity and their spouse/life partner will disclose the existence of any financial interest and/or relationship(s) they might have with any commercial interest producing healthcare goods/services to be discussed during their presentation(s): honoraria, expenses, grants, consulting roles, speakers’ bureau membership, stock ownership, or other special relationships. Presenters will inform participants of any off-label discussions. All identified conflicts of interest are thoroughly vetted by Medical Learning Institute, Inc., for fair balance, scientific objectivity of studies mentioned in the materials or used as the basis for content, and appropriateness of patient care recommendations. Shelly Chun, PharmD, a reviewer for MLI, has nothing to disclose. Linda Ritter, PhD, Center of Excellence Media, has nothing to disclose.

At the end of this activity, participants will be able to: • Compare and contrast the primary end points used in pivotal clinical trials for hematologic malignancies • Determine which end points are the most appropriate and clinically relevant for assessing the efficacy of novel targeted agents for multiple myeloma, chronic myeloid leukemia, and non-Hodgkin lymphoma • Evaluate surrogate end points as they relate to optimal long-term outcomes for patients with hematologic malignancies • Analyze the results from clinical trials to assess the justification of incorporating novel targeted agents into standards of care and effective benefit design and utilization management approaches

Chair

James T. Kenney Jr., RPh, MBA, has nothing to disclose.

commErciaL SuPPorT acknowLEdgmEnT

Faculty

This activity is supported by educational grants from Millennium Pharmaceuticals and Novartis Pharmaceuticals. inSTrucTionS for crEdiT

Michael Mauro, MD, receives research grants from Novartis Oncology and Bristol-Myers Squibb. Gary Yee, PharmD, FCCP, BCOP, has nothing to disclose.

There is no fee for this activity. To receive credit, participants must read this CE activity in its entirety and complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/p10067E.html. Upon completion of the evaluation and scoring 70% or better on the posttest, you will immediately receive your certificate online. If you do not achieve a score of 70% or better on the posttest, you will be asked to take it again. Please retain a copy of the certificate for your records.

The information provided in this CE activity is for continuing education purposes only and is not meant to substitute for the independent medical judgment of a healthcare provider relative to diagnostic and treatment options of a specific patient’s medical condition. Recommendations for the use of particular therapeutic agents are based on the best available scientific evidence and current clinical guidelines. No bias toward or promotion for the agent discussed in this program should be inferred.

diScLaimEr

The Evolving Role of Outcomes and End Points in Evaluating Therapy for Hematologic Malignancies: Value-Driven Benefit Design and Utilization Management Strategies While healthcare reform is on the horizon, the pipeline for new cancer therapies continues to grow and cancer care costs are on the rise. More than 90% of the anticancer agents approved by the US Food and Drug Administration (FDA) between 2004 and 2008 cost more than $20,000 for a 12-week course of treatment.1 The practice of managed care pharmacy frequently involves making decisions about whether a given drug or a regimen is covered under a patient’s pharmacy benefit or health insurance plan. The question that managed care payers are asking is, will the health outcomes produced by these expensive therapies justify the increased cost? Payers are increasingly insisting that newly introduced agents and regimens demonstrate improvement in patient outcomes before their cost will be fully reimbursed. End Point versus outcome: what is the difference? Avedis Donabedian, MD, MPH,

public health pioneer, defined outcomes as the “consequences to the health and welfare of individuals and of society.”2 He noted that “outcomes, by and large, remain the ultimate validation of the effectiveness and quality of medical care.”2 Ultimately, cure is the desired outcome for patients with any disease. However, this is not currently a realistic goal for most patients with cancer who are undergoing the therapies available today. As advances are made in our understanding of molecular oncology and new targeted therapies are developed, many malignancies are being treated as chronic diseases, and patients diagnosed today may expect to live longer than patients diagnosed in years past. A patient’s quality of life and freedom from disease progression may become more important outcomes than survival if differences in overall survival (OS) are not apparent when comparing therapies and regimens. The economic evaluations involved in making managed care decisions

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July 2011

often consider the likely costs and outcomes of new therapies over time, based primarily on safety and efficacy end point data from the clinical trials that led to the approval. A clinical trial will usually define or specify a primary end point as an objective measure that will indicate the success of the therapy being investigated. A trial may also define 1 or more secondary end points that will be measured and are expected to be met. Some of these end points may be surrogate end points, which are biomarkers that may correlate with a real clinical outcome but do not necessarily have a guaranteed relationship. In addition, a primary end point that supports efficacy in previous and ongoing clinical trials may be different from the primary end point in subsequent trials, making it difficult to compare agents and regimens and their effect on the desired outcome. Although an improvement in OS had historically been the gold standard end point for a new oncology

drug approval, 68% of the regular approvals and 100% of the accelerated approvals for oncology drugs between 1990 and 2002 were based on clinical trial end points other than survival, including the objective response rate, progression-free survival (PFS), disease-free survival (DFS), and time to progression (TTP).3 In 2003, the FDA began a project to evaluate potential end points for cancer drug approval.4 End points were examined for the most common cancers during public workshops, important issues were identified, and these issues were discussed in meetings of the Oncologic Drugs Advisory Committee. Subsequently, a guidance document was published in 2007, describing the FDA’s current thinking on end points for cancer drug approval.5 Although the FDA still regarded OS as the preferred end point in a cancer trial, FDA members found a clear disadvantage in the necessity of a long observation period. During this same Continued on page 51

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CONTINUING EDUCATION period (2001 to present), the targeted therapies for multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and chronic myeloid leukemia (CML) that are in common use today entered the clinical arena. Multiple Myeloma MM is the second most frequently diagnosed hematologic malignancy.6 Although MM remains incurable, outcomes have significantly improved in recent years with the introduction of novel agents, such as the immunomodulatory drugs thalidomide and lenalidomide and the proteasome inhibitor bortezomib, and with advancements in supportive care (Table). The early introduction of effective management strategies that include ≥1 of these novel agents have improved survival for patients with MM. In fact, between 1975 and 1979, a patient receiving a diagnosis of MM had only a 53% probability of surviving 2 years.7 In comparison, 2-year survival rates for patients diagnosed within the past few years have been reported as high as 88%, and the 5year survival rate has increased to more than 40% for patients diagnosed in 2003.7 Consistency in the conduct of clinical trials and in the analysis and reporting of results is essential to ensuring valid and reliable results that can be compared with those of other trials. Early in 2011, the International Myeloma Workshop Consensus Panel 1 recommended PFS as the primary end point for clinical trials in lieu of long-term OS data.8 An analysis of PFS includes all patients and is calculated

Table

from the beginning of treatment to disease progression or death from any cause. TTP has also been used as the primary end point in clinical trials for MM. An analysis of TTP is essentially the same as that for PFS, but deaths that are not directly related to the disease are not counted in TTP. However, as data from trials initiated in the past decade mature, a PFS or TTP trial end point benefit does not always translate into an OS benefit. Transplant-ineligible patients The combination of melphalan and prednisone (MP) had historically been the regimen of choice for newly diagnosed MM in patients who were not eligible for autologous stem-cell transplant (ASCT). In 2008, the FDA approved bortezomib “for the treatment of patients with multiple myeloma.” This approval was based on the VISTA (Velcade as Initial Standard Therapy in Multiple Myeloma) trial, in which the combination of bortezomib, melphalan, and prednisone (VMP) was compared with MP in 682 patients with newly diagnosed MM who were ineligible for ASCT.9 The median TTP—the primary efficacy end point in the study—was 24.0 months in the VMP group compared with 16.6 months in the MP group (P <.001). In December 2009, survival benefit was added to the VMP label after further analysis of the VISTA trial demonstrated that OS continued to improve significantly in the VMP arm during a median follow-up of 36.7 months despite subsequent therapies, including bortezomib-based regimens.10 Median OS was not reached with VMP

versus 43.1 months with MP (P <.001); after 3 years, the OS rates were 68.5% versus 54.0%, respectively.9 Several phase 3 trials have compared the use of melphalan, prednisone, and thalidomide (MPT) with that of MP for the treatment of newly diagnosed MM in patients who were not eligible for ASCT,11-15 showing mixed results. Although these trials have consistently shown better response rates with MPT than with MP, only 4 of the 5 trials showed a significant improvement in PFS, and only 2 showed a significant improvement in OS (P <.05). A meta-analysis of these 5 trials (N = 1568) showed a pooled hazard ratio (HR) of 0.68 for PFS (P <.001; 95% confidence interval [CI], 0.55-0.82) and 0.80 for OS (P = .07; 95% CI, 0.631.02) in favor of MPT.16 Although the addition of thalidomide to MP results in significantly improved PFS, MP alone demonstrates only a nonsignificant improvement in OS, with the additional burden of significantly increased toxicity. Recently, data were reported from a phase 3 trial comparing the combination of lenalidomide plus MP (MPR) with MP in patients aged ≥65 years who were ineligible for ASCT (N = 459).17 Patients were randomized to receive either MP alone, MPR (fixed dose schedule), or MPR followed by continuous lenalidomide maintenance (MPR-R). At a median follow-up of 25 months, patients who received MPR-R demonstrated a significant improvement in PFS (31 months) compared with patients who received MPR (14 months) or MP (13 months; P <.001). However, the significant PFS advan-

Label Indication and Registration Trial Information for Thalidomide, Lenalidomide, and Bortezomib Registration trial

Drug

Indication a

Thalidomide

Design/patients

In combination with dexamethasone Newly diagnosed patients with MM for the treatment of patients with N = 207 newly diagnosed MM TD vs high-dose dexamethasone

Primary end point

Result

ORR, %

51.5 vs 35.6

Lenalidomideb In combination with dexamethasone for the treatment of patients with MM who have received at least 1 previous therapy

Relapsed/refractory MM (at least 1 previous treatment) Study 1: N = 353 Study 2: N = 351 LD vs high-dose dexamethasone

Median TTP, mo

Study 1: 13.9 vs 4.7 P <.001 Study 2: 12.1 vs 4.7 P <.001

Bortezomibc

Newly diagnosed patients with MM N = 682 VMP vs MP

Median TTP, mo

20.7 vs 15.0 P <.0001

Relapsed/refractory MM (after 1-3 previous therapies) N = 669 Bortezomib vs high-dose dexamethasone

Median TTP, mo

6.2 vs 3.5 P <.0001

Treatment of patients with MM

Thalomid [package insert]. Summit, NJ: Celgene; 2010. Revlimid [package insert]. Summit, NJ: Celgene; 2010. Velcade [package insert]. Cambridge, MA: Millennium; 2010. LD indicates lenalidomide/dexamethasone (high-dose); MM, multiple myeloma; MP, melphalan/prednisone; ORR, overall response rate; TD, thalidomide/dexamethasone (high-dose); TTP, time to progression; VMP, bortezomib/melphalan/prednisone.

b c

tage did not apply to patients aged >75 years (MPR-R vs MPR; P = .118). Although a median OS has not been reached among any of the 3 arms, there is currently no significant difference between the arms in the estimated 1-year and 2-year OS rates. Transplant-eligible patients The quality of posttransplantation response, especially the achievement of complete response (CR), is now well established as a prognostic indicator of improved long-term survival for previously untreated MM in patients who receive high-dose therapy and ASCT.18,19 In a retrospective analysis of 344 patients with MM who underwent transplantation between 1989 and 1998, after a median follow-up of 12.75 years, the OS rate at 12 years was 35% for patients achieving CR, 22% for those demonstrating near CR (nCR), and 16% for those achieving very good partial response (VGPR).20 Significant differences in OS and PFS were found between the CR and nCR groups (P = .01 and P = .002, respectively), as well as between CR and VGPR (P = .0001 and .003). A plateau in OS was observed after 11 years; 35% of patients achieving CR are alive at 17 years. For patients who are transplanteligible, recent clinical trials have evaluated combined modality induction regimens with the novel agents in an attempt to increase the rate of response to induction therapy to improve the quality of response to transplantation. In the HOVON-65/GMMG-HD4 (Dutch-Belgian Hemato-Oncology/ German Cooperative Groups) trial, patients were randomized to induction therapy with bortezomib, doxorubicin, and dexamethasone (PAD) or with vincristine, doxorubicin, and dexamethasone (VAD).21 After undergoing high-dose therapy and ASCT, patients who were randomized to PAD received bortezomib as maintenance therapy for as long as 2 years, and those randomized to VAD received thalidomide. The postinduction response rate of VGPR or bet ter was 42% in patients receiving PAD and 15% in those receiving VAD (P <.001). The response rates improved to 61% and 36%, respectively, posttransplantation and to 76% and 55% during maintenance. Patients receiving PAD induction with bortezomib maintenance showed significantly improved PFS (HR = 0.75; P = .005) and OS (HR = 0.73; P = .02). In the phase 3 GIMEMA (Gruppo Italiano Malattie Ematologiche dell’ Adulto) trial, the safety and efficacy of induction therapy and consolidation with thalidomide plus dexamethasone Continued on page 52

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CONTINUING EDUCATION

The Evolving Role of Outcomes and End Points... (TD) is being compared with that of bortezomib, thalidomide, and dexamethaone (VTD) in combination with double ASCT and dexamethasone maintenance.22 The addition of bortezomib to TD significantly improved the CR rate after induction, first transplantation, second transplantation, and consolidation. Treatment with VTD resulted in a significant 37% reduction in the relative risk for progression or death (HR = 0.63; P = .0061), but at a median follow-up of 36 months, no difference in OS has been seen (HR = 0.76; P = .3071). Two additional promising novel combination regimens in phase 2 studies have reported high rates of CR after induction. One is the combination of bortezomib, lenalidomide, and dexamethasone (VRD), and the other is that of bortezomib, dexamethasone, and cyclophosphamide (VDC).23,24 VRD showed a VGPR rate of 74%, and VDC (modified to add an additional dose of cyclophosphamide at day 15) showed a VGPR rate of 53%. In addition, until more data and longer follow-ups are available, consolidation and maintenance therapy with novel agents may improve posttransplant responses and provide patients with a significant survival advantage. Chronic Myeloid Leukemia Approximately 0.6 to 2.0 cases of Philadelphia chromosome-positive (Ph+) CML are diagnosed globally per 100,000 persons each year. Approximately 1.5 cases per 100,000 persons are diagnosed each year in the United States.7,25 Historically, chemotherapy with alkylating agents and hydroxyurea provided a median survival of only 3 to 4 years.26 Median survival improved to 6 to 7 years in the early 1980s with the advent of interferonalpha, but the 10-year survival rate was still only 30% to 40%, and patients had few options after the failure of first-line therapy.27 Before 2000, survival was the primary goal of therapy for patients with CML in chronic phase (CML-CP). The introduction of the tyrosine kinase inhibitor (TKI) imatinib in 2001 has revolutionized management strategies, refocusing the outcome on prevention of progression rather than on survival. The annual mortality rate has decreased to approximately 1% to 2%, and the estimated 5-year survival rate has increased to approximately 90%.7 This translates to an increasing prevalence that may exceed 200,000 cases in the United States within the next 20 years.26

The importance of early optimal response It was established that patients with CML had prolonged survival after achieving a cytogenetic response (CyR) to interferon-alpha.28 In 2001, imatinib was approved for newly diagnosed CML-CP based on the surrogate end points of major CyR and complete CyR (CCyR).29 Since then, much has been learned regarding the accepted milestones for response to first-line therapy and the timing of those responses. Patients with suboptimal or poor response within the first 6 months of therapy are far more likely to experience early disease progression to advanced phase or blast crisis, in which long-term responses to TKIs are unlikely to occur and overall healthcare costs are much higher. In a study comparing patients with a suboptimal response or failure within 6 months of initiating imatinib therapy and those who responded during that same period, the likelihood of achieving CCyR was 39% versus 96%, respectively (P <.0001), the rate of PFS was 87% versus 98% (P = .04), and the rate of OS was 70% versus 92% (P = .001).30 In the IRIS (Insulin Resistance Intervention after Stroke) trial, patients who achieved a CCyR had a lower annual incidence of events (loss of response, transformation to advanced phase or blast crisis, or death) than the overall group after 5 years of followup.31 In addition, 100% of patients in the imatinib arm of the IRIS trial who had achieved both a CCyR and a major molecular response (MMR) by 12 months were free from progression to advanced phase or blast crisis at 8 years, and the achievement of CCyR by 12 months was associated with improved survival.32 Second-generation TKIs Second-generation TKIs (nilotinib, dasatinib, and bosutinib) are being compared with imatinib in clinical trials in patients with newly diagnosed CML-CP. Nilotinib (300 mg twice daily) received FDA approval in June 2010 for the treatment of newly diagnosed CML, based on results from the ENESTnd (Evaluating Nilotinib Ef ficacy and Safety in Clinical Trials— Newly Diagnosed Patients) trial. The primary end point in this trial is the MMR rate at 12 months. After a median follow-up of 18.5 months, the rate of MMR for nilotinib at 12 months (44%) was twice (22%) that for imatinib (P <.0001).33 By 12 months, the rate of CCyR was also significantly higher among patients receiving nilo-

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tinib (80%) than among those receiving imatinib (65%; P <.001). The Kaplan-Meier estimate of the median time to MMR was shorter (8.6 months) for patients receiving nilotinib than for those receiving imatinib (median not yet achieved). An updated analysis of data covering a median follow-up of 24 months was presented at the 2010 American Society of Hematology’s (ASH) annual meeting.34 At 24 months, the MMR rate was 62% for nilotinib versus 37% for imatinib (P <.0001) and the CCyR rates were 87% versus 77%, respectively (P = .0018). In addition, significantly fewer patients receiving nilotinib (0.7%) than those receiving imatinib (4.2%) had progressed to advanced phase or blast crisis or had died (P = .0059). Fewer patients receiving nilotinib discontinued therapy because of adverse events. Dasatinib received FDA approval for newly diagnosed CML-CP in October 2010 based on results from the DASISION (Dasatinib versus Imatinib Study in Treatment-Naïve CML Patients) trial, which compared dasatinib with imatinib. The primary end point was the rate of confirmed CCyR at 12 months.35 After a median followup period of 14 months, the rate of confirmed CCyR at 12 months was significantly higher in patients receiving dasatinib (77%) than in those receiving imatinib (66%; P = .007). In addition, the rate of MMR at any time was significantly higher among patients receiving dasatinib (52%) than among patients receiving imatinib (34%; P <.0001). Among patients who achieved an MMR, the median time to MMR was 8.3 months for dasatinib and 11.8 months for imatinib. Fewer patients receiving dasatinib (1.9%) than those receiving imatinib (3.5%) had progressed to advanced phase or blast crisis. The rates of discontinuation as a result of adverse events were similar for dasatinib and imatinib. An updated analysis of data covering a median follow-up of 18 months was presented at ASH 2010.36 First-line second-generation TKIs provide optimal outcomes In January 2011, nilotinib and dasatinib were added to the National Comprehensive Cancer Network (NCCN) treatment guidelines as category 1 options for the primary treatment of Ph+ or BCR-ABL+ CML. With 3 FDA-approved and NCCN-recommended therapies, what will drive the choice of treatment? Should the higher cost of the second-generation TKIs be a

factor? A recent study examined the association between adherence to imatinib therapy and direct healthcare costs and resource utilization in a large group (N = 592) of privately insured patients with CML.37 Patients with CML who do not adhere to treatment may have suboptimal outcomes and higher rates of progression to advanced phase or blast crisis. In this study, patients with low adherence had more all-cause inpatient visits (4.1) compared with those who demonstrated higher adherence (0.4; P <.001) and more all-cause inpatient days (14.8 days vs 1.8 days, respectively; P <.001). In regression models, non-imatinib costs were 283% higher in the nonadherent group ($324) than in the adherent group ($56; P <.001). Therapy failure occurred in approximately 22% of patients receiving first-line imatinib therapy (the vast majority of failures being early events) compared with approximately 4% of patients receiving first-line therapy with a secondgeneration TKI. One may ask, “Why not wait until patients have a suboptimal response to imatinib or fail treatment before prescribing a higher-priced second-generation TKI?” This may be too risky, and, in the long run, incur higher costs. Treatment at suboptimal response or failure is salvage therapy. In such cases, the likelihood that the patient has developed drug-resistant mutations has increased, requiring the use of a third-generation TKI or a very expensive stem-cell transplant. The 8-year analysis of the IRIS trial demonstrated that imatinib was effective in preventing prospective events but not the loss of response or progression events that occur early (Figure).32 The ENESTnd and DASISION trials suggest that frontline therapy with second-generation TKIs produces higher rates of CCyR and MMR than the standard-dose imatinib, and these responses are achieved at earlier time points. On the basis of data derived from the IRIS trial that highlighted the prognostic importance of achieving early CCyR and MMR, it is reasonable to expect that the use of nilotinib or dasatinib in the frontline setting might render higher rates of event-free survival and transformation-free survival and may therefore offset the high costs associated with progression. Non-Hodgkin Lymphoma NHL is a highly heterogeneous group of cancers affecting the lymph Continued on page 53

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Indolent versus aggressive: desired outcomes of therapy Both B-cell and T-cell lymphomas are categorized into indolent and aggressive types. DLBCL, MCL, peripheral T-cell lymphoma, and anaplastic large-cell lymphoma (ALCL) are considered aggressive lymphomas. The goal of treatment is to cure an aggressive lymphoma; this may be achieved in 30% to 60% of patients for some subtypes.41 DLBCL can be cured in a significant proportion of patients,42 but MCL cannot.43 The response rate and OS are often the end points in clinical trials for aggressive lymphomas that are curable, whereas response rate and duration of response and PFS are end points in trials for those that are not. For aggressive lymphomas that cannot be consistently cured at this time, the search continues for treatment that can become a curative standard of care. The lack of cure along with treatment failure exacts an enormous socioeconomic toll. For example, the mean cost of treatment failure in aggressive NHL has been reported to be as high as $14,174 monthly and reaches $85,934 over a period of <2 years (in 1999-2000 dollars).44 In contrast, indolent lymphomas are characterized by long, slowly progressive clinical courses; examples include follicular lymphoma, MZL, Waldenstrom’s macroglobulinemia, and the cutaneous T-cell lymphoma mycosis fungoides. The goal of treatment is often long-term management, as indolent lymphomas are rarely cured unless diagnosed when still localized. The response rate, DFS, event-free survival, duration of response, and PFS are often the primary end points in clinical trials for indolent lymphomas. Clinical trials have attempted to improve on the best available accepted therapy by adding an additional agent

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Figure Kinetics of Resistance to Imatinib in the IRIS Trial Event rate or patients at AP/BC, %

system, with variable cytogenetic, cellular, and clinical features and natural histories that range from indolent to very aggressive.38 NHL is the most common hematologic malignancy in the United States.6 It is estimated that 65,540 Americans were diagnosed with various forms of NHL in 2010, and 20,210 deaths were attributed to the disease. The prevalence of NHL in the United States is approximately 440,000 patients.7 Most patients with NHL have a B-cell subtype: 31% of patients with NHL have diffuse large B-cell lymphoma (DLBCL), 22% have follicular lymphoma, 5% to 10% have marginal zone lymphoma (MZL), and 6% have mantle-cell lymphoma (MCL).39 T-cell lymphomas comprise about 15% of NHL cases.40

10 9 8

AP/BC

Event Loss of CHR Loss of MCyR AP/BC Death

7.5

7 6 4.8

5 4

3.3 2.8

3 2

1.8

1.7

1.7 0.9

1.4 0.8

0.5

0.3

0 1

1.3

0.4

Year AP/BC indicates advanced phase/blast crisis; CHR, complete hematologic response; IRIS, Insulin Resistance Intervention after Stroke; MCyR, major cytogenetic response. Source: Deininger M, et al. Blood. 2009;114(suppl):462. Abstract 1126.

or substituting one active agent for another; therefore, there is a virtual “alphabet soup” of therapeutic regimens available to treat this group of cancers. In the past decade, the treatment of NHL has changed dramatically, with the advent of molecularly targeted anticancer therapies. For example, the development of the CD20 monoclonal antibody rituximab has changed the treatment paradigm for B-cell lymphomas and, in some subtypes of the disease, has markedly improved prognosis. Bortezomib, lenalidomide, bendamustine, alemtuzumab, and other novel agents have also demonstrated clinical benefit in B-cell lymphomas. T-cell subtypes and ALCL are being treated with a number of approved and investigational targeted agents, including romidepsin, pralatrexate, brentuximab vedotin, denileukin diftitox, and vorinostat. The use of targeted therapies for NHL, combined with refinements in cytotoxic chemotherapy and stem-cell transplantation, continue to alter the therapeutic landscape at a rapid pace. Indolent versus aggressive: clinical trial end points In 1999, an international working group of clinicians, radiologists, and pathologists with expertise in the evaluation and management of patients with NHL published guidelines for response assessment and outcomes measurement.45 These were revised in 2007, when interobserver and intraobserver variations were identified and recommended technologies were no longer considered state-of-the-art.46 In addition to defining response criteria and making recommendations for disease evaluation, this group proposed that the major end points of clinical trials should reflect the histology, clinical

situation, and objectives of the study and be defined consistently across clinical trials. Response rates as a trial end point are greatly influenced by the defined response criteria used. In addition, response rates do not necessarily influence other measures of overall clinical benefit or outcome in patients with NHL. OS is the least ambiguous of the trial end points, but it is not optimal for use in an indolent or incurable aggressive lymphoma trial. PFS is often considered the preferred end point in lymphoma clinical trials, especially those involving incurable subtypes (indolent and aggressive). Event-free survival is generally not encouraged by the FDA, because it combines efficacy, toxicity, and patient withdrawal. However, it may be useful in the evaluation of novel agents that may be highly toxic and have a high risk-benefit ratio. Duration of response, if associated with measures of clinical benefit, may also be an important and relevant end point in lymphoma trials. One of the most important outcomes for patients with NHL has been evidence of clinical benefit. Clinical benefit may reflect improvement in quality of life or a reduction in symptoms, transfusion requirements, frequent infections, or other parameters. As the symptoms associated with lymphoma can greatly impact a patient’s quality of life, time to reappearance or progression of lymphoma-related symptoms may also be an important measure, especially for incurable lymphomas. Rituximab was first approved by the FDA in 1997 for the treatment of relapsed or refractory low-grade or follicular, B-cell NHL as a single agent based on the overall response rate.47 Since that time, rituximab has received

5 additional indications as a single agent or as part of a chemotherapeutic regimen. The Appendix (available at www.valuebasedcancercare.com/ P10067E) lists some of the targeted agents and new therapies approved within the past decade for various subtypes of NHL and the primary and secondary end points used in the registration trials. Care must be taken when making cross-trial comparisons to ensure that the patient populations are comparable and that defined end points and response criteria have been used consistently. Evolving Outcomes and End Points and Value-Based Care As progress is made in the treatment of MM, CML, and NHL, as with any cancer, the ultimate outcome of therapy for patients also evolves. Although OS remains the optimal outcome for patients with MM, surrogate end points used in clinical trials do not always translate into a survival benefit as long-term data mature. The use of TKIs for CML-CP has drastically changed the natural history of this disease. Freedom from treatment failure and from progression to advanced phase or blast crisis is the preferred outcome. Early and durable CCyR and MMR are reliable surrogate end points for this outcome. For patients with some subtypes of aggressive NHL, a cure is possible and OS is both the trial end point and the desired outcome. However, for patients with indolent and incurable-aggressive NHL, an extended period without progression that may be compounded by lymphoma-associated symptoms is preferred. PFS and duration of response are acceptable surrogate end points for this outcome. ■ References 1. Cohen H. Drug Topics Red Book 2008. 112th ed. Montvale, NJ: Thomson Healthcare/Thomson PDR; 2008. 2. Donabedian A. Evaluating the quality of medical care. Milbank Memorial Fund Quarterly. 1966;44:166-206. 3. Johnson JR, Williams G, Pazdur R. End points and United States Food and Drug Administration approval of oncology drugs. J Clin Oncol. 2003;21:1404-1411. 4. US Food and Drug Administration. The Center for Drug Evaluation and Research. Cancer Drug Approval Endpoints. www.fda.gov/AboutFDA/CentersOffices/ CDER/ucm117709.htm#background. Accessed July 23, 2010. 5. US Food and Drug Administration. Guidance for Industry: Clinical Trial Endpoints for the Approval of Cancer Drugs and Biologics. May 2007. www.fda. gov/downloads/Drugs/GuidanceComplianceRegul atoryInformation/Guidances/ucm071590.pdf. Accessed July 23, 2010. 6. Jemal A, Siegel R, Xu J, Ward E. Cancer statistics, 2010. CA Cancer J Clin. 2010;60:277-300. 7. Howlader N, Noone AM, Krapcho M, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD. http://seer.cancer. gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER Web site, 2011. Accessed June 30, 2011. 8. Rajkumar SV, Harousseau JL, Durie B, et al, for the International Myeloma Workshop Consensus Panel 1. Consensus recommendations for the uniform report-

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The Evolving Role of Outcomes and End Points... ing of clinical trials. Blood. 2011;117:4691-4695. 9. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008; 359:906-917. 10. Mateos MV, Richardson PG, Schlag R, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: updated follow-up and impact of subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010;28:2259-2266. 11. Facon T, Mary JY, Hulin C, et al, for the Intergroupe Francophone du Myélome. Melphalan and prednisone plus thalidomide versus melphalan and prednisone alone or reduced-intensity autologous stem cell transplantation in elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet. 2007;370:1209-1218. 12. Palumbo A, Bringhen S, Liberati AM, et al. Oral melphalan, prednisone, and thalidomide in elderly patients with multiple myeloma: updated results of a randomized controlled trial. Blood. 2008;112:3107-3114. 13. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 trial. J Clin Oncol. 2009;27:36643670. 14. Wijermans P, Schaafsma M, Termorshuizen F, et al, for the Dutch-Belgium Cooperative Group HOVON. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: the HOVON 49 Study. J Clin Oncol. 2010;28:3160-3166. 15. Waage A, Gimsing P, Fayers P, et al, for the Nordic Myeloma Study Group. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood. 2010;116:1405-1412. 16. Kapoor P, Rajkumar SV, Dispenzieri A, et al. Melphalan and prednisone versus melphalan, prednisone and thalidomide for elderly and/or transplant ineligible patients with multiple myeloma: a metaanalysis. Leukemia. 2011;25:689-696. 17. Palumbo A, Dimopoulos MA, Delforge M, et al. A phase III study to determine the efficacy and safety of lenalidomide in combination with melphalan and prednisone (MPR) in elderly patients with newly diagnosed multiple myeloma. Presented at the 51st American Society of Hematology Annual Meeting;

New Orleans, LA; December 5-8, 2009. Abstract 613. http://ash.confex.com/ash/2009/webprogram/Pap er22787.html. Accessed June 28, 2011. 18. Harousseau JL, Avet-Loiseau H, Attal M, et al. Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy: long-term analysis of the IFM 99-02 and 99-04 trials. J Clin Oncol. 2009;27:5720-5726. 19. van de Velde H, Liu X, Chen G, et al. Complete response correlates with long-term survival and progression-free survival in high-dose therapy in multiple myeloma. Haematologica. 2007;92:1399-1406. 20. Martinez-Lopez J, Blade J, Mateos MV, et al. Longterm prognostic significance of response in multiple myeloma after stem cell transplantation. Blood. 2011 Apr 11. Epub ahead of print. 21. Sonneveld P, Schmidt-Wolf I, van der Holt B, et al. HOVON-65/GMMGHD4 randomized phase III trial comparing bortezomib, doxorubicin, dexamethasone (PAD) vs VAD followed by high-dose melphalan (HDM) and maintenance with bortezomib or thalidomide in patients with newly diagnosed multiple myeloma (MM). Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 40. http://ash.confex. com/ash/2010/webprogram/Paper29306.html. Accessed June 28, 2011. 22. Cavo M, Perrone G, Buttignol S, et al. Bortezomibthalidomide-dexamethasone compared with thalidomide-dexamethasone as induction and consolidation therapy before and after double autologous transplantation in newly diagnosed multiple myeloma: results from a randomized phase 3 study. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 42. 23. Richardson PG, Weller E, Lonial S, et al. Lenalidomide, bortezomib, and dexamethasone combination therapy in patients with newly diagnosed multiple myeloma. Blood. 2010;116:679-686. 24. Kumar S, Flinn IW, Richardson PG, et al. Novel three- and four-drug combination regimens of bortezomib, dexamethasone, cyclophosphamide, and lenalidomide, for previously untreated multiple myeloma: results from the multi-center, randomized, phase 2 EVOLUTION Study. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 621.

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25. Rohrbacher M, Hasford J. Epidemiology of chronic myeloid leukaemia (CML). Best Pract Res Clin Haematol. 2009;22:295-302. 26. Kantarjian H, O’Brien S, Cortes J, et al. Therapeutic advances in leukemia and myelodysplastic syndrome over the past 40 years. Cancer. 2008;113(7 suppl):19331952. 27. Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207-219. 28. Kantarjian H, Smith TL, O’Brien S, et al. Prolonged survival in chronic myelogenous leukemia after cytogenetic response to interferon-a. The Leukemia Service. Ann Intern Med. 1995;122:254-261. 29. O’Brien SG, Guilhot F, Larson RA, et al. Imatinib compared with interferon and low dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003;348:994-1004. 30. Marin D, Milojkovic D, Olavarria E, et al. European LeukemiaNet criteria for failure or suboptimal response reliably identify patients with CML in early chronic phase treated with imatinib whose eventual outcome is poor. Blood. 2008;112:4437-4444. 31. Druker BJ, Guilhot F, O’Brien SG, et al. Five-year follow-up of patients receiving imatinib for chronic myeloid leukemia. N Engl J Med. 2006;355:2408-2417. 32. Deininger M, O’Brien SG, Guilhot F, et al. International randomized study of interferon vs STI571 (IRIS) 8-year follow up: sustained survival and low risk for progression or events in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CMLCP) treated with imatinib. Presented at the 51st American Society of Hematology Annual Meeting; New Orleans, LA; December 5-8, 2009. Abstract 1126. 33. Saglio G, Kim DW, Issaragrisil S, et al. Nilotinib versus imatinib for newly diagnosed chronic myeloid leukemia. N Engl J Med. 2010;362:2251-2259. 34. Hughes TP, Hochhaus A, Saglio G, et al. ENESTnd update: continued superiority of nilotinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP). Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 207. 35. Kantarjian H, Shah NP, Hochhaus A, et al. Dasatinib versus imatinib in newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med.

2010;362:2260-2270. 36. Shah N, Kantarjina H, Hochhaus A, et al. Dasatinib versus imatinib in patients with newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP) in the DASISION Trial: 18-month follow-up. Presented at the 52nd American Society of Hematology Annual Meeting; Orlando, FL; December 4-7, 2010. Abstract 206. 37. Wu EQ, Johnson S, Beaulieu N, et al. Healthcare resource utilization and costs associated with nonadherence to imatinib treatment in chronic myeloid leukemia patients. Curr Med Res Opin. 2010;26:61-69. 38. National Comprehensive Cancer Network. NonHodgkin’s Lymphoma. V.2.2009. www.nccn.org. Accessed June 23, 2011. 39. Fauci AS, Braunwald E, Kasper DL, et al, eds. Harrison’s Principles of Internal Medicine. 17th ed. New York: McGraw-Hill; 2008. 40. Portlock C, Vose JM, Cheson BD. T-cell lymphomas. www.lymphoma.org/atf/cf/%7B0363CDD651B5-427B-BE48-E6AF871ACEC9%7D/T-CELL% 20LYMPHOMAS.PDF. Accessed June 23, 2011. 41. PDQ (Physician Data Query) Modification of REAL Classification of Lymphoproliferative Diseases. National Cancer Institute of the National Institutes of Health. www.cancer.gov/cancertopics/pdq/treat ment/adult-non-hodgkins/healthprofessional/all pages#Section_31. Accessed June 28, 2011. 42. Coiffier B. Standard treatment of advanced-stage diffuse large B-cell lymphoma. Semin Hematol. 2006;43:213-220. 43. Witzig TE. Current treatment approaches for mantle-cell lymphoma. J Clin Oncol. 2005;23:6409-6414. 44. Kutikova L, Bowman L, Chang S, et al. Medical costs associated with non-Hodgkin’s lymphoma in the United States during the first two years of treatment. Leuk Lymphoma. 2006;47:1535-1544. 45. Cheson BD, Horning SJ, Coiffier B, et al. Report of an international workshop to standardize response criteria for non-Hodgkin’s lymphomas. NCI Sponsored International Working Group. J Clin Oncol. 1999;17:1244. 46. Cheson BD, Pfistner B, Juweid ME, et al. Revised response criteria for malignant lymphoma. J Clin Oncol. 2007;25:579-586. 47. Drugs@FDA.gov. Drug details. Rituximab. www.access data.fda.gov/scripts/cder/drugsatfda/index.cfm?fus eaction=Search.DrugDetails. Accessed June 28, 2011.

COMMENTARY

New End Points Create Novel Challenges for Health Plans in Oncology Drug Management By James T. Kenney Jr, RPh, MBA Mr Kenney is Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, MA

he management of complex oncology drugs in pharmacy and in medical benefits presents unique challenges for all parties who seek cost-effective, positive clinical outcomes for patients with cancer. New therapies are offering the exciting prospect of improved outcomes, prolonged life, and, in some cases, a cure for specific diseases. Targeted oncolytics and pharmacogenomics, which carry the promise of improved likelihood of successful treatment, have become welcome additions to the current standards of care. The concept of cancer as a chronic disease is becoming accepted in pharmacy oncology management. Targeted therapies are now standard treatments for multiple myeloma (MM), non-Hodgkin lymphoma (NHL), and chronic myelogenous leukemia (CML). Recent trials in MM have used time

to progression and progression-free survival as primary end points (as recommended by the International Myeloma Workshop Consensus Panel 1). The use of different end points in clinical trials for the same disease, however, has complicated the analysis and evaluation process for the pharmacy and therapeutics (P & T) committees of health plans in comparing competing therapies to select the most efficacious and cost-effective treatment options for their members. The ability to diagnose cancer earlier in the disease process and to begin life-saving treatments sooner place additional strain on pharmacy managers to maximize the value from all therapies in the treatment algorithm of a particular cancer type. The tyrosine kinase inhibitors (TKIs) have revolutionized the treatment of CML by extending survival. It is now

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possible to achieve long-term success with these agents if treatment is initiated early enough in the course of disease, and a positive early response can be a good predictor of long-term survival. As clinical studies are able to demonstrate clinically meaningful differentiations between first- and second-generation TKIs, health plans can consider promoting specific treatment pathways to maximize cost-savings and outcomes. NHL affects a diverse population of patients with various disease subtypes that require careful diagnosis to be matched with specific drug treatment protocols. The International Working Group has attempted to define appropriate clinical trial end points and response criteria to effectively differentiate treatments. This process is critical for managed care plans to manage specific therapies effectively and con-

trol costs in the treatment of NHL and other cancer types. It is clear that in the near-term, overall survival will remain the gold standard for P & T committees in their assessment of drug efficacy. However, other end points will continue to be assessed as clinical trial results become available. The development of pharmaceuticals with biomarkers can increasingly give providers and health plans the confidence that patients will have a greater likelihood of response. This new trend also has the potential to decrease waste and the risk of untoward side effects in patients who are not good candidates for a particular treatment. As health plans progress in the management of oncology drugs, the ability to target patients, predict outcomes, and reduce costs will drive the most successful programs. ■

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Strategies for Optimizing Value in Cancer Care Delivery The Best of the Association for Value-Based Cancer Care Conference

AVBCC is the fastest growing national specialty organization dedicated to improving the care of cancer patients and their quality of life. The organization was established to provide a network for payers and oncology healthcare professionals to interact and network in order to promote optimal care for patients and their families. October 1, 2011 Marriott Marquis 55 Fourth Street San Francisco, California

September 24, 2011 JW Marriott 151 West Adams Street Chicago, Illinois

November 19, 2011 Marriott Waterside 700 South Florida Avenue Tampa, Florida

2011 REGIONAL MEETINGS

September 24 Chicago, IL

PROGRAM OVERVIEW

As a result of the resounding success of our First Annual Conference, we have been asked to incorporate “The Best of AVBCC” into three regional meetings. We continue to be guided by the expertise of leaders in these fields providing attendees with a thorough understanding of the evolution of the value equation as it relates to cancer therapies and will be able to implement, improve, and sustain their companies and institutions, while improving access for patients and ultimately patient care.

October 1 Science Care designates this activity for a maximum of San Francisco, CA 5.25 AMA PRA Category 1 Credit(s)™. Science Care is

Chair November 19 Gary Owens, MD Tampa, FL

ACCREDITATION INFORMATION Physician Accreditation

accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. Physicians should only claim credit commensurate with the extent of their participation in the activity.

President, Gary Owens Associates

Invited Faculty

2012 NATIONAL MEETING

WHO SHOULD ATTEND

CONTINUING EDUCATION INFORMATION Goal The Association for Value-Based Cancer Care will foster an open dialogue between providers, payers, and/or other members of the oncology team in order for attendees to gain a better understanding of various points of view regarding cost, quality, and access in cancer care. •

• •

•

Medical Learning Institute, Inc. (MLI) Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 5.25 contact hours.

Stephanie Akbari, MD Donald Balfour III, MD Adam Brufsky, MD, PhD, FACP Craig Deligdish, MD John Fox, MD Scott Gottlieb, MD Gary Johnson, MD, MS, MBA Ted Okon Winston Wong, PharmD

March 29-31, Houston, TX

All stakeholders in a position to impact cancer patient care are invited to join this exciting forum. Specifically this conference is intended for: • Medical Oncologists • Advanced Practitioners • Hematologists/Oncologists • Managed Care Professionals • Surgical Oncologists • Medical Directors • Nurses • Pharmacists • Practice Managers/ • Pharmacy Benefit Managers Administrators (PBMs)

Objectives

Registered Nurse Designation

Registered Pharmacy Designation Medical Learning Institute is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 5.25 contact hours (0.525 CEUs) of continuing education credit. The Universal Activity Number for all three regional meetings is 0468-9999-11-033-L01-P. September 24, 2011 – Chicago, IL October 1, 2011 – San Francisco, CA November 19, 2011 – Tampa, FL

COMMERCIAL SUPPORT ACKNOWLEDGEMENT There is no commercial support for this activity.

CONFERENCE REGISTRATION $125 Includes 1-year association membership

Registration Information Chicago, www.regonline.com/avbcc-chicago2011 San Francisco, www.regonline.com/avbcc-sanfran2011 Tampa, www.regonline.com/avbcc-tampa2011

www.AVBCConline.org

Examine the impact of healthcare reform on all stakeholders involved in the management of patients with cancer Identify issues and potential solutions to challenges with access and affordability of oncology therapeutics Determine the value equation of cost, quality, and access when evaluating the diagnosis, treatment, and overall management of cancer patients Define appropriate comparative effectiveness research and clinical pathways as tools to evaluate current recommendations for patient management Analyze trends in the delivery of care in the management of cancer patients

PRELIMINARY AGENDA 8:00 – 9:00 am

CONTACT/SUPPORT

9:00 – 9:15 am

If you have any questions please contact: Association for Value-Based Cancer Care™ 241 Forsgate Drive, Suite 205B Monroe Township, NJ 08831 Phone: 732-992-1040 association@AVBCConline.org

Registration & Breakfast Welcome & Introduction 9:15 – 10:45 am The Challenges of Personalized Cancer Care 10:45 – 11:30 am Community Oncology Crisis: An Uncertain Future 11:30 – 12:15 pm Improving Patient Care Through Collaboration & Partnerships 12:15 – 1:45 pm Lunch Symposium 1:45 – 2:30 pm Regional Insurer’s Perspective on Cancer Care 2:30 – 3:15 pm The Impact of New Healthcare Legislation 3:15 – 3:30 pm Summary & Concluding Remarks

Sponsorship Opportunities Available Past Sponsors:

VBCC_July_11_1_Follow ASCO Tabloid 7/13/11 7:15 PM Page 56

NOW APPROVED

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Contact your Centocor Ortho Biotech Sales Representative for more information.

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