AUGUST 2011 VOL 2 NO 5 by Value-Based Cancer Care

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AUGUST 2011 VOL 2 NO 5

www.ValueBasedCancerCare.com ONCOLOGY BEST PRACTICES

Northwestern University Comprehensive Cancer Center Advancing patient care through state-of-the-art clinical coordination and research Interview with Al B. Benson III, MD, FACP

Photo courtesy of Northwestern University

Professor of Medicine and Associate Director for Clinical Investigations, Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL

Q: How would you define the concept of best practices, and what makes an oncology center, such as the Northwestern University Robert H. Lurie Comprehensive Cancer Center, be among the best oncology practices in the country? Dr Benson: “Best practices” is a critical area for Northwestern and, in particular, is an important area of responsibility for our cancer center as a member of the National Comprehensive Cancer Network (NCCN). The NCCN has a very productive Best Practices Committee that has been active for many years. The committee members do surveys of NCCN practices and have very Continued on page 24

Upper GI Cancers: Are We Getting Value for the Money? By Audrey Andrews Chicago, IL—“Moving the Bar in Upper GI Malignancies” was a plenary session at ASCO 2011, with 2 experts discussing whether results of recent clinical trials of targeted agents are clinically meaningful or just statistically positive, and what is the value of the enormous amount of money

Patients with Cancer at Risk for Bankruptcy Filings increase drastically at 5 years after diagnosis By Caroline Helwick Chicago, IL—Nearly 2% of patients with cancer may file for personal bankruptcy 5 years after their diagnosis, according to researchers from Fred Hutchinson Cancer Research Center in Seattle who presented their data at the 2011 American Society of Clinical Oncology (ASCO) Annual Meeting. “We found that bankruptcy is a particular risk for patients with cancer,” said Scott D. Ramsey, MD, PhD, Professor of Medicine, Fred Hutchinson Cancer Research Center, University of Washington School of Medicine, and Director, Cancer Prevention Clinic, Seattle Cancer Care Alliance. Dr Ramsey and colleagues studied data for >230,000 patients with cancer showing that rates varied widely

Continued on page 22

By Robert “Bo” Gamble and Mary Kruczynski Mr Gamble is Director of Strategic Practice Initiatives, and Ms Kruczynski is Director of Policy Analysis, Community Oncology Alliance, Washington, DC

s we move forward in the scheme of healthcare reform, we are being directed toward an integrated care model, one with high quality and economic efficiency. Recently, a model known as an ac-

countable care organization (ACO) was introduced by the US Department of Health and Human Services in the form of a proposed rule open for public comment. Although the final rule Continued on page 8

INSIDE FDA UPDATES . . . . . . . . . . . . . . . . . . . . . . . .

HEALTH POLICY

VALUE PROPOSITIONS

ONCOLOGY PHARMACY

Novel nasal spray of fentanyl citrate for cancer pain

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NICE backs thalidomide and bortezomib for multiple myeloma ASCO ANNUAL MEETING

Continued on page 10

Benchmarks for Measuring the Success of a Medical Home in Oncology

spent in treating noncolorectal gastrointestinal (GI) cancer. Clinical versus Statistical Significance Eileen Mary O’Reilly, MD, of Memorial Sloan-Kettering Cancer

across cancer types, that younger patients aged <44 years were particularly at risk, and that bankruptcies increased over time. Bankruptcy rates averaged 0.5% at 1 year but rose to 1.9% at 5 years postdiagnosis. In comparison, the bankruptcy rate in the general population of western Washington State was only 0.28%. Using the Surveillance, Epidemiology and End Results registry, the researchers identified 231,799 adults with newly diagnosed first primary cancers between 1995 and 2009 living in western Washington State. They linked these to bankruptcy filings (Chapters 7 and 13) in federal bank-

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Genomic medicine in lung cancer Emerging regimen for metastatic pancreatic cancer Off-label drug use, advanced technologies driving up Medicare costs

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What does deficit reduction mean for oncology?

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ELECTRONIC HEALTH RECORDS .

ONCOLOGY REIMBURSEMENT . . .

Dose-monitoring, split fills reduce oral chemotherapy waste, save cost Impact of EHRs on oncology practice Post-ASCO: oncologists’ and payers’ treatment and coverage decisions

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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 Editorial Assistant Jennifer Brandt jennifer@generaladminllc.com 732-992-1536 Director, Client Services Cristopher Pires cris@engagehc.com 732-992-1896 Senior Production Manager Robyn Jacobs Quality Control Director Barbara Marino

IN THE LITERATURE

ONCOLOGY PHARMACY

Combination therapy improves survival in intermediate-risk prostate cancer Vemurafenib improves survival in metastatic melanoma with BRAF V600E More….

Dose-monitoring, split-fill programs curb waste of oral chemotherapy More….

ASCO ANNUAL MEETING New regimen with an old drug boosts survival in pediatric ALL The oncology drug pipeline is promising Comparing the value of denosumab versus zoledronic acid More….

ONCOLOGY BEST PRACTICES

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

CANCER SCREENING Screening for pancreatic cancer is effective, has value More….

METASTATIC MELANOMA

HEALTH POLICY

A new era in management

CONTINUING EDUCATION Cost implications for novel therapies in the treatment of NSCLC

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

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.

Arlene A. Forastiere, MD ITA Partners Philadelphia, PA

Post-ASCO survey: oncologists’ and payers’ treatment decisions

Hanging in limbo: what does deficit reduction mean for oncology? More….

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.

ONCOLOGY REIMBURSEMENT

Northwestern Comprehensive Cancer Center

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.

ELECTRONIC HEALTH RECORDS Impact of EHRs on oncology practice

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

Tracy Gosselin, RN, MSN Duke University Medical Center Durham, NC

Philip E. Johnson, MS, RPh, CPh H. Lee Moffitt Cancer Center Tampa, FL

Jatin J. Shah, MD M. D. Anderson Cancer Center Houston, TX

Mark J. Krasna, MD Medical Director, The Cancer Institute Principal Investigator, NCI Community Cancer Centers Program Towson, MD

Jayson Slotnik, JD, MPH Partner Health Policy Strategies, LLC Washington, DC

Ira Klein, MD, MBA Aetna Hartford, CT Crystal Kuntz, MPA Astellas Pharma US Washington, DC

Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center Palm Springs, CA

Lee Newcomer, MD, MHA UnitedHealthcare Minnetonka, MN

G. Rhys Williams, ScD, MS Amgen Thousand Oaks, CA

Lynn Nishida, RPh Regence BlueCross BlueShield of Oregon Portland, OR

Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Ted Okon, BS, MBA Executive Director Community Oncology Alliance Naimish Pandya, MD University of Maryland Baltimore, MD

Scott Gottlieb, MD Mount Sinai Medical Center and American Enterprise Institute New York, NY

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

David Hom, MBA Solucia Farmington, CT

Denise K. Pierce DK Pierce & Associates Zionsville, IN

VALUE-BASED CANCER CARE

August 2011

Brian K. Solow, MD, FAAFP Prescription Solutions Irvine, CA

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS BioPharma Partners, LLC New York, NY Section Editor

Dawn Holcombe, FACMPE, MBA, ACHE President, DGH Consulting South Windsor, CT

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FDA UPDATES Novel Nasal Spray Formulation of Fentanyl Citrate for Cancer Pain The US Food and Drug Administration (FDA) approved a new nasal spray formulation of fentanyl citrate (Lazanda; Archimedes) for the rapid relief of cancer-related breakthrough pain in adults who have developed resistance to their opioid regimen. The recommended dosage is 100 µg sprayed once in each nostril for each cancer-related pain episode. If adequate analgesia is not obtained within 30 minutes, the dose should be titrated up with each subsequent episode. Approval was based on evidence from 500 patients enrolled in a doubleblind, placebo-controlled clinical trial that included an open-label titration phase. Pain relief was maintained for 60 minutes after dosing. During the titration phase, 73% of patients obtained adequate relief. The most common adverse events were nausea, vomiting, pyrexia, and dizziness. The nasal spray formulation, which is approved with a Risk Evaluation and Mitigation Strategy program, will become available in the second half of this year. (June 30, 2011)

thermography is effective in detecting breast cancer. The FDA has warned providers to stop making such claims in light of these claims appearing on provider websites. “Mammography is still the most effective screening method for detecting breast cancer in its early, most treatable stages,” said Helen Barr, MD,

Director of the Division of Mammography Quality and Radiation Programs in the FDA’s Center for Devices and Radiological Health. “Women should not rely solely on thermography for the screening or diagnosis of breast cancer. While there is plenty of evidence that mammography is effective in breast cancer detection,

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

New Molecular Test Approved to Detect HER2 in Women with Breast Cancer A new test for detecting the HER2 gene in women with breast cancer has received FDA approval. The test, called Inform Dual ISH (Ventana Medical Systems), facilitates the use of standard microscopy to measure the number of copies of chromosome 17 and HER2 genes in a tumor sample on the same slide. Unlike traditional HER2 amplification, which uses fluorescence microscopy, the Inform Dual ISH test enables laboratory staff to view samples directly under a microscope, and for longer periods. In a study involving tumor samples from 510 US patients with breast cancer, the test was effective in detecting an excessive number of copies of the HER2 gene in 96% of the HER2-positive tumor samples and a normal number of copies in 92.3% of HER2negative samples. (June 14, 2011)

FDA Warns Oncologists: Thermography No Substitute for Mammography The FDA has issued a warning to healthcare providers against substituting breast thermography for mammography in screening for breast cancer. Some providers prefer thermography over mammography because it does not expose women to radiation or breast compression. The FDA, however, points to the absence of valid evidence showing that when used alone,

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there is simply no evidence that thermography can take its place,” she said. The FDA has not approved any telethermographic devices as standalone screening or diagnostic tools for breast cancer, although the agency has cleared such devices for use as an additional method to confirm a breast cancer diagnosis. (June 2, 2011) ■

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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IN THE LITERATURE Combination Therapy Improves Survival in Men with Intermediate-Risk, Early-Stage Prostate Cancer A new large clinical trial funded by the National Cancer Institute has demonstrated the best approach to therapy for men with intermediate-

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

risk, early-stage prostate cancer that can prolong survival. In comparing treatments for early-stage prostate cancer, investigators found strong evidence that short-term androgen-deprivation therapy (ADT) in combination with radiotherapy is more effective than radiation therapy alone for men

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 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

with intermediate risk (Jones CU, et al. N Engl J Med. 2011;356:107-118). This 212-center study included 1979 men with early-stage prostate cancer. All patients had localized prostate cancer and prostate-specific antigen (PSA) levels ≤20 ng/mL. Among the patients, 395 were black men, who are

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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known to have greater rates of prostate cancer than other men. Patients were randomly assigned to treatment with radiotherapy alone (N = 992; 197 black men) or to radiotherapy plus 4 months of ADT that consisted of drugs that block the natural production of testosterone (N = 987; 198 black men). Of note, previous studies have shown that short-term ADT improves survival among patients with later-stage prostate cancer. The median follow-up in this study was 9.1 years. Results showed that short-term ADT plus radiotherapy significantly improved the 10-year overall survival (OS) compared with radiation therapy alone (62% vs 57%, respectively). The addition of short-term ADT to radiation therapy led to significantly fewer prostate cancer–related deaths (4% vs 8%, respectively; P = .001). The benefits of short-term ADT were true for white and black men. In a later analysis looking at the patients by disease risk, participants were divided into 3 groups—high, intermediate, and low risk, using various variables, including PSA levels, tumor grade, and disease stage. The patients with intermediate-risk benefited from the combination therapy, unlike those with low or high risk. In those with intermediate risk, the 10year OS rate significantly increased from 54% with radiotherapy alone to 61% with the combination of shortterm ADT plus radiotherapy, and disease-specific death rate was reduced from 10% to 3%.

No Access to Radiotherapy Cannot Explain Reduced Survival in Black Women Post–Breast Cancer Surgery Black women who undergo mastectomy or lumpectomy for advanced breast cancer have shorter survival duration than their white, Hispanic, and Asian counterparts, regardless of whether they undergo radiation therapy after the procedure, according to a new study (Martinez SR, et al. Cancer. Epub ahead of print. June 20, 2011). Radiation therapy is recommended for all patients who undergo mastectomy or lumpectomy. In a previous study, black women with advanced breast cancer were less likely than whites or Asians to receive radiotherapy. Therefore, the investigator wanted to find out whether this disparity in access to radiotherapy would explain the poorer survival in black women with metastatic breast cancer. In this new study, the researchers used data from the Surveillance, Epidemiology and End Results to Continued on page 9

VALUE-BASED CANCER CARE

August 2011

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VALUE PROPOSITIONS 77,000 Early Adopters to CMS’s EHR Incentive Program Exceed Requirements, Reflecting Value to Patients and Providers Approximately 77,000 healthcare providers have already registered by July of this year with the Centers for Medicare & Medicaid Services (CMS) for the electronic health records (EHRs) program. CMS is collecting data on early adopters to the EHR incentive program, which will begin in 2014 but is requiring providers to meet the first stage of “meaningful use” much sooner. By registering with the incentive program, the providers or clinical centers indicate that they meet the first set of requirements associated with instituting an EHR system. CMS has found that clinicians are using the EHR system for a higher proportion of their patients than is required by the program, suggesting that the value in instituting such a program is more than just the anticipated reimbursement. So far 21 states have launched the Medicaid EHR program, with the most recent 4—Arizona, Connecticut, Rhode Island, and West Virginia— registering in July 2011. (See also article on EHRs in oncology on page 32.)

Inexpensive Immunochemical Stool Test Effective Option for Colon Cancer Screening The immunochemical fecal occult blood test (iFOBT), a new version of the traditional FOBT, has demonstrated 90% specificity in detecting colon growths. This new version of the FOBT has been gradually replacing the old FOBT in screening for colon cancer. This high level of specificity firmly establishes the benefit of this test (Chiang TH, et al. CMAJ. Epub ahead of print. August 2, 2011). Although the FOBT is more expensive than the old FOBT, at a cost of approximately $30, its value is considerable compared with colonoscopy, which averages about $3000 per procedure. This newly validated level of specificity and the low cost will likely enhance the value of this newer version of the stool test as a screening option for a potentially deadly cancer.

NICE Backs Value of Thalidomide, Bortezomib for Multiple Myeloma In July, the United Kingdom’s National Institute for Health and Clinical Excellence (NICE) approved the use of thalidomide (Thalomid) for the first-line treatment of multiple myeloma in patients in whom high-dose chemotherapy with stem-cell transplantation is deemed inappropriate. At the same time, NICE also approved bortezomib (Velcade) in combination with an alkylating agent and a corticosteroid for first-line treatment of multiple myeloma when high-dose chemotherapy with stem-cell transplantation is considered inappropriate and the patient cannot tolerate or has contraindications to thalidomide. Carole Longson, the Director of the Centre for Health Technology Evaluation at NICE, said in a statement regarding the approval, “We are delighted to be able to recommend these 2 new treatment options for people with this condition.” Noting that almost 4000 cases of multiple myeloma are diagnosed every year in the United Kingdom, she added that “there is currently no cure for the disease, only treatments to stop the progress of the condition and help relieve symptoms. Thalidomide and bortezomib regimens have been shown to be more effective at delaying disease progression and improving patients’ life expectancy than the current treatment of an alkylating agent and corticosteroid alone.” These decisions by NICE indicate that these 2 treatment regimens have been found cost-effective for these indications.

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Value of Screening High-Risk Individuals for Lung Cancer Confirmed, but Who Will Pay for It? New results from the National Lung Cancer Screening Trial have shown that in individuals at high risk for lung cancer, screening with lowdose computed tomography (CT) significantly reduces mortality in this subpopulation (N Engl J Med. 2011;365:395-409). Based on these findings, the American Society of Clinical Oncology, in concert with other cancer organizations, is developing new practice guidelines to immediately affect current screening practices for those at high risk for lung cancer. However, at a price between $300 and $500 per CT procedure, the question of who will carry the cost burden remains to be determined.

FDA Grants Priority Review for Ruxolitinib for the Treatment of Myelofibrosis The US Food and Drug Administration (FDA) has granted priority review for the investigational drug ruxolitinib as a potential treatment for patients with myelofibrosis, a blood cancer with few treatment options. There are currently no FDA-approved treatments for this condition. The status of a priority review indicate that the drug either is perceived as offering a major advance in treatment or provides treatment to a condition with no approved therapies.

Personalized Approach to Mammography Most Cost-Effective, but at What Risk to Women? The most recent mammography screening recommendations call on women to begin annual screening for breast cancer at age 40 years, regardless of their risk for the disease. This “one-size-fits-all” approach, based on age alone, leads to too many screenings for some women and not enough for others, according to investigators of a recent cost-analysis (Schousboe JT, et al. Ann Intern Med. 2011;155:10-20). With a cost-effectiveness threshold of $100,000 per quality-adjusted lifeyear (QALY), biennial mammography is most cost-effective for women aged 40 to 49 years, the researchers claim. With a cost per QALY of $340,000 for annual screening, the current strategy is not cost-effective, regardless of the woman’s age or breast density, these investigators say. Nevertheless, clinicians take a different approach. The American Congress of Obstetricians and Gynecologists recently issued new screening guidelines recommending annual screening for all women aged 40 to 49 years, which was a reversal of its previous recommendation for biennial screening for that age-group. And the American Society of Breast Disease (ASBD) has recently issued a statement expressing support for this strategy. According to the ASBD, recent evidence from several studies in Canada and Sweden shows that screening this younger women group can reduce deaths from breast cancer by 40% to 50%. Younger women tend to have denser breasts and faster-growing tumors, so screening them is important, because the majority (>80%) of women with breast cancer have no known risk factors. The question of value in screening for breast cancer remains pertinent in the current economic situation, but when faced with the potential for life-threatening cancer, defining value is key to policy decisions.

www.ValueBasedCancerCare.com

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MEDICAL HOME

Benchmarks for Measuring the Success of... has not yet been released, the various submitted commentaries, at least as far as cancer care is concerned, were not very supportive of the model. When we incorporate a diagnosis of cancer into the ACO model, however, we struggle to find the perfect fit. In an effort to conform to the newly outlined standards of quality and efficiency, The Community Oncology Alliance is leaning toward a more precise model that is better able to address the many services needed by patients with cancer. That model is known as the patient-centered medical home (PCMH) in general, and as translated into cancer care, patient-centered oncology medical home. Cancer care is not well understood in the United States. One would think that because cancer ranks third in the US total healthcare expenses,1 it would get more mention in healthcare reform and accountable care proposals. A proposed rule by the Centers for Medicare & Medicaid Services for ACOs mentions “quality” 817 times, “standard” 208 times, and “cancer” only 8 times (5 of which refer to screening measures vs actual cancer care).2 The National Committee for Quality Assurance’s (NCQA) outline for the PCMH mentions “quality” 62 times, “standard” 107 times, and “cancer” only twice.3 It is perplexing and indeed ironic that cancer is not understood, particularly in the context of cancer care as a medical home. Yet, most patients with cancer would refer to their community cancer center as their “medical home” and often their actual “home,” with “home” being a place of intense nurturing, support, care, love, and encouragement. Yet, to date, there is not an organized recognition entity that promotes and supports quality, patientcentric cancer care with applicable benchmarks. The medical home model has merit, in that it has demonstrated improved efficiency, lower costs, and overall patient satisfaction.4 The incentives within this model also promote positive entrepreneurial competition, notably within an entire industry. ACOs, however, tend to create competition among themselves, which has diminishing marginal return. The medical home model appears to be more sustainable and more applicable not only for the medical community, but also for the diverse specialties within that community. Successful Components of the Medical Home Model in Oncology To be successful for all stakeholders,

The medical home model has demonstrated improved efficiency, lower costs, and overall patient satisfaction. When we incorporate a diagnosis of cancer into the ACO model, however, we struggle to find the perfect fit.

the medical home requires several qualities. Collaboration. According to the NCQA’s white paper, 7676 clinicians and 1506 practices have achieved recognition as a PCMH, mostly through hard work and perseverance.5 The goal is to remain self-assured that this model is right for patients and for practices alike. What is needed now is recognition of this significant achievement. Most recognition models are either provider-driven with hopes that payers will follow, or payer-driven with hopes that providers will follow. The oncology community is developing a medical home model that includes representation of the major stakeholders. The oncology-specific PCMH is steered by patients, oncologists, oncology practice administrators, payers, patient advocate groups, oncology support organizations, and other value-added partners. “Quality” has been defined by some people as “when you get what you thought you bought.” Each of these entities has its own definition of “get,” and that perspective of the deliverable needs to be considered and measured, if there is going to be a comprehensive approach to establishing and nurturing a medical home. Easy implementation. The prevailing theme of oncology practices, and those who are supporting and encouraging these teams of passionate mission-minded caregivers, is “please, not another project.” Oncology practices are busy trying to keep quality patient

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Continued from cover

care a priority, while trying to implement physician quality-reporting initiatives, e-prescribing, and meaningful use, and simultaneously lobbying for legislative support for cancer care, maintaining staff and physician morale, and hundreds of other toppriority issues. Oncology practices will need assistance with implementing the policies, procedures, and workflow changes to achieve any type of recognition program. However, these tools and techniques need to be balanced to the point of promoting ownership and action, while easing the administrative burden of yet another major project. Benchmarked quality measures. The largest obstacle and one of the most critical components to a successful program will be the standardized, comprehensive, and automated submission of key quality measures. Many of the current quality programs require manual chart abstractions or consist of subjective questions that are not measurable (eg, yes/no answers). Quality measures need to include ratio-oriented and well-defined numerators and denominators; automation through systematic data capture techniques from valued electronic medical records (EMRs) or middleware vendors; and allowances so that practices can readily compare themselves to their peers. Physicians and practice administrators will need to encourage their EMR vendors and group purchasing vendors to automate the reporting and submission of quality measures to a common data repository. This may also require database engineers to create discrete data dictionaries, where they currently do not exist. Standardized patient satisfaction measures. Most oncology practices gather patient satisfaction information on an ongoing basis, or they have done so in the past. The typical textual results include, “My physician walks on water”; “You guys are great—keep up the great work”; “So thankful to have such a team”; “Your kindness makes my day”; “Perfect—do not change a thing.” However, if we standardized the questions with a numeric scale, a consistent score of 95% may pale in comparison to benchmarked scores of ≥99%. The benchmarking repository should also include submitted patient satisfaction scores. This survey needs to be simple, easily gathered at strategic points during the patient’s treatment, quantitative, and reflective of how a patient perceives quality. Value. All these benchmarks must

be structured and wrapped so that each group of stakeholders receives perceived value. The barometer of achievement needs to be high enough to allow for a real sense of accomplishment. Payers need to understand and support the significance of the effort and be willing to support the value financially. The practice team should note the differences in the process through perceived increased efficiency and collaborative teamwork within all disciplines of care. Most important, patients and their families need to perceive and receive greater value through higher patient satisfaction. Quality, Value, and Efficiency in Cancer Care We are in a season of transition in the cancer care delivery system. Patients, payers, other providers, and government entities are campaigning and demanding quality, value, and increased efficiency. All these expectations will best be met through a model that encourages, promotes, and endorses ongoing achievement of these attributes. Although most oncology practices are meeting these expectations, a lack of understanding and clarity remains regarding how well these expectations are being achieved. Benchmarking key ratios of consistent quality, value, and efficiency will go far to bridge the gap between the expected, perceived, and actual quality achieved. The biggest challenge is shifting the mindset of the entire cancer community toward a new emphasis on tools, processes, and measurements that promote and validate why cancer care in the United States is the best. Only then will we get what we thought we bought. ■ References 1. Stanton MW. The High Concentration of US Health Care Expenditures. June 2006. Rockville, MD: Agency for Healthcare Research and Quality. Research in Action; Issue 19. AHRQ Pub. No. 06-0060. www.ahrq. gov/research/ria19/expendria.htm. Accessed August 1, 2011. 2. Centers for Medicare & Medicaid Services, Medicare Shared Savings Program: Accountable Care Organizations. March 24, 2011. CMS-1345-P, RIN 0938AQ22. www.ftc.gov/opp/aco/cms-proposedrule.PDF. Accessed August 1, 2011. 3. Standards and Guidelines for NCQA’s PatientCentered Medical Home 2011. Washington, DC: National Committee for Quality Assurance. March 28, 2011. 4. Grumbach K, Grundy P. Outcomes of implementing patient-centered medical home interventions: a review of the evidence from prospective evaluation studies in the United States. Washington, DC: PatientCentered Primary Care Collaborative; November 16, 2010. www.pcpcc.net/files/evidence_outcomes_in_ pcmh.pdf. Accessed August 1, 2011. 5. National Committee for Quality Assurance. NCQA’s Patient-Centered Medical Home 2011 overview white paper. January 31, 2011. www.ncqa. org/LinkClick.aspx?fileticket=l_KicggGGsQ%3d&tab id=1302&mid=5343&forcedownload=true. Accessed August 1, 2011.

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IN THE LITERATURE No Access to Radiotherapy... Continued from page 6

identify women with breast cancer associated with ≥10 metastatic lymph nodes diagnosed between 1988 and 2005. A total of 12,653 met the study eligibility criteria. Radiation therapy was associated with a 22% all-cause decreased risk of death and a 19% disease-specific reduced mortality risk from breast cancer; however, black race was associated with a 54% all-cause increased mortality and a 53% breast cancer– specific increased mortality risk. This pattern did not change after stratifying the results by type of surgery and the use of radiation therapy. The use of radiation therapy improved OS and disease-specific survival in whites and Asians, but not in blacks. The persistence of this disparity in survival regardless of use of radiation therapy and type of surgery, the investigators note, suggests that limited access to radiotherapy does not explain the poorer survival rates among black women with metastatic breast cancer. They add that black women may be less responsive to radiation therapy, and their poorer OS rates may be associated with comorbidities, or with tumor-related biology that require further investigation in this specific subpopulation. A study that focuses on black women with metastatic breast cancer is, therefore, warranted, the authors note, to elucidate the cause for this disparity in survival rates.

Vemurafenib Improves Survival in Metastatic Melanoma with BRAF V600E Mutation The prognosis for patients with metastatic melanoma is poor, ranging from 8 to 18 months, with only 1 drug currently approved in the United States for this patient population. Results of a phase 3 trial comparing that drug with the investigational agent vemurafenib show promise for patients with BRAF V600E mutation (Chapman PB, et al. N Engl J Med. 2011; 364:2507-2516). Approximately 40% to 60% of cutaneous melanomas involve mutations in the BRAF gene that can activate tumor growth through the mitogenactivated protein kinase pathway. Previous studies have suggested that melanomas with the BRAF V600E mutation are more aggressive and less sensitive to chemotherapy than those with the BRAF wild-type mutation. In early-phase clinical trials, vemurafenib, a BRAF kinase inhibitor that

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targets the BRAF V600E mutation, was associated with response rates >50% in patients with BRAF V600E mutation melanoma. Now, in the phase 3 BRAF Inhibitor in Melanoma (BRIM)-3 clinical study, the benefits of vemurafenib and dacarbazine (DTIC-Dome)—the only US and Food and Drug Admin-

istration–approved chemotherapeutic agent for the treatment of metastatic melanoma—were compared in patients with metastatic cancer. A total of 675 patients with previously untreated, unresectable stage IIIC or stage IV melanoma with the BRAF V600E mutation were random-

ly assigned to oral vemurafenib 960 mg twice daily (N = 337) or to dacarbazine 1000 mg/m2 infused every 3 weeks (N = 338). At 6 months, the OS was 84% among patients receiving vemurafenib versus 64% among those receiving dacarContinued on page 19

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ASCO ANNUAL MEETING

Patients with Cancer at Risk for Bankruptcy... ruptcy court records to determine the rates of bankruptcy after cancer. “We found that persons filing for bankruptcy tended to be younger, female, and nonwhite, and to be diagnosed with local or regional disease rather than distant disease,” Dr Ramsey said. “Also, across all cancers we studied, young patients were at particular risk. We think this is likely due to the fact that young people have lower incomes, fewer assets, and less access to insurance.” The 5 cancers with the highest association with bankruptcy at 5 years were: • Lung cancer, 7.7% • Thyroid cancer, 4.8% • Leukemia/lymphoma, 3.6% • Uterine cancer, 3.2% • Colorectal cancer, 3.1%. The next 3 top cancers were mela-

Table

The 5-Year Postdiagnosis Trend For the 231,799 patients investigated, after mean follow-up of 4.3 years, 4805 (2.1%) filed for bankruptcy. Median time to bankruptcy was 2.5 years. Rates of bankruptcy filings generally began to rise 1 year after diagnosis and peaked before the Bankruptcy Abuse Prevention and Consumer Protection Act of 2005. Rates then declined sharply, before climbing again after 2007 in conjunction with the recent “financial crisis.” For all patients, regardless of the cancer, rates steadily climbed to 5 years postdiagnosis. “The bankruptcy laws of 2005 influenced the timing of bankruptcy filings. There was a huge spike prior to enact-

Young Age a Risk Factor Across all cancer types, a strong trend was evident for increased rates in younger populations, in a multivariate model adjusted for cofactors. The hazard ratios (HRs) by age, in this non-Medicare population, are shown in the Table. In the multivariate model, other factors were shown to be influential: • Enforcement of new bankruptcy laws in 2005: HR, 0.31-0.42 • Female sex versus male: HR, 0.75 (lung) • Regional stage of disease at diagnosis versus local stage: HR, 1.32-1.77 • Married versus nonmarried: HR, 0.61 (breast cancer). ■

—Scott D. Ramsey, MD, PhD

Age-Related Risk for Filing Bankruptcy Hazard ratio, age 21-44 yrs

Hazard ratio, age 45-64 yrs

Lung

2.8

2.3

Breast

5.5

3.1

Prostate

3.6

1.8

Colorectal

4.1

2.8

Thyroid

3.0

2.3

Melanoma

4.7

2.5

Leukemia/lymphoma

3.8

2.2

Uterine

4.6

2.8

Cancer type

insurance coverage, because they may be less likely to be employed. Thyroid cancer treatment is fairly straightforward, but treatment actually costs more than one would think. A course of radioactive iodine is about $40,000, so this could be a factor as well.”

ment, followed by a very large decline, then a big increase after the financial crisis,” Dr Ramsey said. Uncertainties regarding the potential impact of the bankruptcy law led to a rush to file. For example, one of the law’s features is a “means test” that can disqualify some individuals from bankruptcy protection. Many lawyers, therefore, counseled patients who felt they were at risk to file before implementation of the law. “After the law was passed and experience with the procedures was gained, lawyers realized the barriers were not as great as they had assumed. As the legal community became comfortable, there was a rebound in filing, which was accelerated by the financial crisis,” he added.

“We found that bankruptcy is a particular risk for patients with cancer….Persons filing for bankruptcy tended to be younger, female, and nonwhite, and to be diagnosed with local or regional disease rather than distant disease.”

noma, 3.0%; breast cancer, 2.9%; and prostate cancer, 1.7%. “We were puzzled that thyroid [cancer] was one of the most common,” Dr Ramsey said. “We think it’s because this is a cancer that occurs often in young women who may have fewer assets, lower income, and perhaps less

Continued from cover

Genome-Forward Medicine in Lung Cancer Mutation rates are high in this malignancy By Caroline Helwick Chicago, IL—Whole genome sequencing was the topic of a session at the 2011 ASCO annual meeting in which specialists discussed the implications of “genome-forward medicine” in lung cancer. This entails “how to get to the nature of tumors and their heterogeneity,” said Elaine Mardis, PhD, Codirector of the Genome Institute at Washington University, St Louis, MO. Next-generation sequencing, she said, will eventually guide treatment decisions. “Cancer is well known to be a disease of the genome,” Dr Mardis stated. “This is not limited to point mutations on genes but to the full spectrum of somatic alterations.” According to Dr Mardis, the genomic discovery methods used by researchers are being applied to end-

stage and difficult-to-diagnose patients to shape genome-guided treatment decisions. Currently, the patient popu-

“We have to compress the process into a time frame that is meaningful and appropriate for the patient, which is the time between diagnosis and decisions about treatment—about 4 weeks.” —Elaine Mardis, PhD lation is small, “but this is actively happening today at some medical centers,” she explained.

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The next step is to make the process user-friendly in the clinic. “We have to compress the process into a time frame that is meaningful and appropriate for the patient, which is the time between diagnosis and decisions about treatment—about 4 weeks,” she pointed out. The stage is also being set, she said, for moving genome-forward medicine into clinical trials, to test expensive targeted agents in more enriched patient subsets. Targeted Agents Work in NSCLC Ramaswamy Govindan, MD, also of the Genome Institute, emphasized that “targeted therapies in targeted patients work. With mutation-targeted agents such as the epidermal growth factor receptor [EGFR] inhibitors in non– small-cell lung cancer [NSCLC], re-

sponses can be durable.” The challenge now is to identify all the other targets in lung cancer. Most targets that can be treated with drugs have been identified for adenocarcinoma; fewer have been established for squamous-cell carcinoma. “No one believes that EGFR is the only player. Large populations of mutations are virtually unknown,” he noted. Researchers at the International Cancer Genome Consortium Cancer Genome Projects and the Cancer Genome Atlas Research Network are sequencing thousands of genes in an intelligent fashion. They will prospectively collect fresh tumor samples from primary, recurrent, and metastatic tumors, to be optimized for genomic analysis of genetic mutations, as well Continued on page 11

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New Regimen with an Old Drug Boosts Survival in Pediatric ALL A new standard of care in children with high-risk disease By Neil Canavan Chicago, IL—The use of high-dose methotrexate (HD-MTX) has demonstrated a significant improvement in event-free survival in patients with pediatric acute lymphoblastic leukemia (ALL) at 5 years compared with the standard regimen. The results of this large randomized clinical trial were reported at the ASCO 2011 annual meeting. “Pediatric ALL was once a deadly form of leukemia, and now it’s one of the most curable,” said the study’s lead investigator, Eric C. Larsen, MD, Director of the Maine Children’s Cancer Program and the Division of Pediatric Hematology/Oncology at the Barbara Bush Children’s Hospital, Portland. “With these results, we now have an approach that will raise cure rates even higher,” he remarked. Dr Larsen was quick to point out the oddity of finding a new approach to treatment using such an old drug— methotrexate has been available in one form or another for more than 50 years. “To be perfectly honest with you, when this study was conceived 10 years ago, we didn’t have some new targeted therapy to be excited about, so we decided to see if we could optimize an agent

“Results showed that the 5-year event-free survival rate was 82% for HD-MTX versus 75% for C-MTX— a statistically significant difference. With these results, we now have an approach that will raise cure rates even higher.” —Eric C. Larsen, MD

Genome-Forward Medicine... Continued from page 10 as other cancer processes. “By the end of this year we will see important papers coming from this research,” Dr Govindan predicted. The clinical implications of genetic analysis in NSCLC are the identification of new targets that can be treated with drugs; discovery of mechanisms of tumor resistance to treatment; subcategorization of the disease that will dictate treatment approaches; and prediction, through genetic profiling, of persons at risk for lung cancer. “One thing has become obvious so far: lung cancer is a more complex disease than we once thought,” he pointed out. “Compared to childhood malignancies, for example, the mutation rates are much higher.” An example of the complexity is the “stunning difference” in the number of mutations observed in tumors that come from nonsmokers versus smokers. Smokers’ tumors have multiple

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mutations in DNA repair pathways that are completely absent in tumors of nonsmokers.

“Lung cancer is a more complex disease than we once thought….We must get used to the notion that cancer is heterogeneous. We are unlikely to find common mutations in more than about 5% of patients.” —Ramaswamy Govindan, MD “We must get used to the notion that cancer is heterogeneous. We are unlikely to find common mutations in more than about 5% of patients,” Dr Govindan stated. ■

that’s been around for a long time.” Methotrexate blocks the ability of leukemia cells to use the essential B vitamin folate, which leads to the death of leukemia cells. An early form of methotrexate, aminopterin, was used by renowned cancer researcher Sidney Farber, MD, to induce the first leukemia remissions in children in 1947. It later became an essential component of standard treatment in children with ALL; however, there have been longstanding debates regarding the optimization of the methotrexate dosing. The current clinical trial was designed to test a higher-than-standard dose of methotrexate—the socalled Capizzi regimen—in pediatric patients with high-risk ALL—children with a very high white blood cell count at diagnosis, which indicates poorer cure rates. A total of 3154 patients (aged 1-30 years) were randomized to either HDMTX or the standard Capizzi escalating methotrexate dose plus asparaginase (C-MTX) during a 2-month interim maintenance phase of therapy after standard induction and consolidation chemotherapy. The trial began enrolling and treating patients in 2004 and was stopped early in 2011, after a planned interim analysis demonstrated that the HDMTX was clearly superior to the standard regimen. “Results showed that the 5-year event-free survival rate was 82% for HD-MTX versus 75% for CMTX—a statistically significant difference,” said Dr Larsen. It was thought that the higher dose of methotrexate might incur greater rates of adverse events in patients; however, no significant increases in

at a glance ➤ High-dose methotrexate has demonstrated a significant improvement in event-free survival in pediatric acute lymphoblastic leukemia at 5 years compared with the standard regimen ➤ Methotrexate blocks the ability of leukemia cells to use the essential B vitamin folate, thereby leading to the death of leukemia cells ➤ The results of this trial will change the approach to therapy of this patient population ➤ The Children’s Oncology Group will soon be updating its treatment guidelines based on these new results side effects were observed. In fact, the incidence of febrile neutropenia was significantly lower in the HD-MTX group, although the reason for this finding remains unclear. The overall impact of these findings was striking. “The implementation of HD-MTX in children with high-risk ALL changed immediately as soon as we stopped the protocol,” said Dr Larsen. “Patients in the trial who had been randomized to Capizzi and were not too far into therapy were given the choice of coming back and switching, and most did,” he said. “We feel this is now the new standard of care for children with high-risk ALL,” Dr Larsen said. Based on these results, the Children’s Oncology Group will soon be updating its treatment guidelines. ■

October 1 San Francisco, CA

November 19 Tampa, FL

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ASCO ANNUAL MEETING

Emerging Regimen for Metastatic Pancreatic Cancer Has Survival Benefit, but Is It Cost-Effective? By Neil Canavan Chicago, IL—A cost analysis presented at ASCO 2011 and performed at the University of Toronto, Odette Cancer Center, Ontario, showed that the emerging combination regimen that includes oxaliplatin (Eloxatin), irino tecan (Camptosar), fluorouracil (Adrucil) and leucovorin (FOLFIRINOX) is not cost-effective when considered within the framework of a willingness-to-pay threshold of $100,000 per quality-adjusted life-year (QALY). Nevertheless, treatment with FOLFIRINOX may provide the most clinical benefit for patients with metastatic pancreatic cancer. The $100,000 per QALY amount is the benchmark generally used in the United States to consider cost-effectiveness of a treatment. “Right now the standard treatment for metastatic pancreatic cancer is gemcitabine [Gemzar],” said Vincent C. Tam, MD, lead investigator and

at a glance ➤ The emerging regimen FOLFIRINOX is more costly than the current standard therapy for metastatic pancreatic cancer but has shown a 3- to 4-month survival benefit ➤ It can be expected that this regimen will become a treatment option for this patient population ➤ The higher cost of this regimen, however, is likely to invoke a debate among providers, payers, and patients ➤ Whether health plans will reimburse for this new combination regimen remains to be seen

Table

“This is going to be the emerging treatment. We need to now consider the price tag. Patients will be pushing for this treatment.” —Vincent C. Tam, MD Gastrointestinal Oncology Fellow at Odette Cancer Center. In the setting of metastatic pancreatic cancer, “there are also variants on the gemcitabine theme—adding capecitabine [Xeloda] for instance, or the targeted-agent erlotinib [Tarceva]…. But most treatments have been shown to be effective only by way of metaanalysis, because of the small number of patients enrolled in many trials,” Dr Tam said. Dr Tam and colleagues undertook the current cost analysis, because FOLFIRINOX has recently been shown in another study to have superior survival rates when compared with the standard therapy with gemcitabine. Those results were presented last year at ASCO 2010 and have just been published (Conroy T, et al. N Engl J Med. 2011;364:1817-1825). “This is going to be the emerging treatment,” said Dr Tam. “We need to now consider the price tag.” Cost Analysis To determine cost-effectiveness, a Markov model was constructed for a hypothetical cohort of patients with

Cost and Clinical Outcomes: Gemcitabine versus FOLFIRINOX Gemcitabine

Gemcitabine + Gemcitabine + capecitabine erlotinib FOLFIRINOX

Cost, $a

29,658

34,139

46,874

65,924

Life expectancy, yr

0.677

0.762

0.790

1.005

QALY

0.529

0.583

0.613

0.764

—

82,982

204,952

154,323

ICER vs gemcitabine alone, $a/QALY a

Canadian $. FOLFIRINOX indicates oxaliplatin, irinotecan, fluorouracil, and leucovorin; ICER, incremental costeffectiveness ratio; QALY, quality-adjusted life-year.

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August 2011

metastatic pancreatic cancer to assess the costs and outcomes of the 4 treatment options—gemcitabine, gemcitabine plus capecitabine, gemcitabine plus erlotinib, and FOLFIRINOX— over a 2-year period. The primary outcome was the incremental cost-effectiveness ratio (ICER), measured in dollars per QALY. Efficacy data for all 4 treatments were obtained from the published results of phase 3 clinical trials. Resource utilization data were derived from reviewing charts of consecutive patients treated at Princess Margaret Hospital between 2008 and 2009, and supplemented with resource utilization data from the medical literature. Unit costs were obtained from

the Ontario Ministry of Health and Long-Term Care, Sunnybrook Health Sciences Centre, and the literature. Both cost and effectiveness were discounted at 3%. The results of this analysis show that the ICERs of gemcitabine plus capecitabine, gemcitabine plus erlotinib, and FOLFIRINOX compared with gemcitabine were $82,982/QALY, $204,952/QALY, and $154,323/QALY, respectively (Table). “The model is mostly driven by the acquisition cost of drugs, and it may be sensitive to the relative efficacy of treatments,” reported Dr Tam. He said that in Canada, the unit price of FOLFIRINOX (primarily the oxaliplatin component) would have to be reduced to attain the $100,000 greenlight threshold. As is, the gemcitabine plus capecitabine regimen is more cost-effective. Significant Survival Advantage The issue of price and the newly published results showing a 3- to 4-month survival advantage for FOLFIRINOX will certainly become the subject of debate among providers, patients, and payers. “Patients will be pushing for this treatment,” said Dr Tam, while drug manufacturers will be pushing for FOLFIRINOX to be reimbursed. How this will play out in drug formularies in the United States remains to be seen. ■

Bevacizumab Maintenance Reduces Disease Progression Risk in Ovarian Cancer Potential new option for recurrent platinum-sensitive disease By Audrey Andrews Chicago, IL—The “big news” in metastatic ovarian cancer presented at ASCO 2011 involved the investigational poly (ADP-ribose) polymerase (PARP) inhibitor olaparib, which prolonged progression-free survival (PFS) by nearly 4 months versus placebo. The results of this study were reported in the June issue of VBCC. In addition, 2 other studies reported in the meeting show that maintenance therapy with bevacizumab (Avastin) reduced the risk of disease progression, both in the metastatic setting and in early-stage disease.

The OCEANS Trial The phase 3 randomized, doubleblind, multicenter OCEANS trial evaluated the use of bevacizumab plus carboplatin (Paraplatin) and gemcitabine (Gemzar) versus chemotherapy alone in 484 women with recurrent platinum-sensitive ovarian cancer. After 6 cycles, those receiving the bevacizumab-containing regimen continued to receive bevacizumab alone as maintenance therapy until disease progression. Patients in the bevacizumab arm Continued on page 13

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ASCO ANNUAL MEETING

Impressive Results with New Drugs for Advanced Prostate Cancer By Neil Canavan Chicago, IL—The potential of 2 novel agents still in clinical trials, and 1 drug that was recently approved, offer new hope to patients with metastatic castrate-resistant prostate cancer (mCRPC), a disease with a dire prognosis and few good current treatment options. First-in-Class R-223 One of the investigational agents, alpharadin (radium-223 chloride [R223]), may have just earned a chance for an expedited approval by the US Food and Drug Administration (FDA) because of its positive results. R-223 is a first-in-class alpha-emitter radioisotope pharmaceutical, which targets bone metastases with its highenergy alpha radiation, thereby affecting prostate metastatic cells. However, because of its short-range effects, it spares the patient’s bone marrow. In 2 phase 2 clinical trials reported at the 2011 ASCO Annual Meeting, R-223 was tested in mCRPC patients with bone metastasis (N = 101). The combined aim of the trials was to determine if normalization of levels of alkaline phosphatase (ALP), a marker of

bone metabolism, could be taken as a surrogate for R-223 efficacy. In both trials—one a randomized, placebo-controlled study (N = 64) and the other a dose escalation trial (N = 117)—ALP normalization was strongly correlated with overall survival (OS). In both trials, the median survival was 102 weeks in patients with ALP

“Approximately 90% of men with advanced prostate cancer have bone metastases, which are the main cause of disability and death in this disease.” —Chris Parker, MD

normalization versus <58 weeks for those without ALP. In the dose-escalation study, treatment response increased with the increasing dose. Of note, approximately 50% of patients treated with R-223 did not

Bevacizumab Maintenance Reduces Disease... Continued from page 12

had a median PFS of 12.4 months compared with 8.4 months with chemotherapy alone (P <.001), representing a 52% reduction in the risk of progression, said Carol Aghajanian, MD, Memorial Sloan-Kettering Cancer Center, New York. “OCEANS is a positive study. We met our primary end point,” Dr Aghajanian said at a press briefing. “The safety data are also reassuring and consistent with the known side effect profile. We believe this regimen should be considered a new option for recurrent platinum-sensitive ovarian cancer.” ICON7 Updated A second analysis presented at the meeting was the updated results from the ICON7 trial of 1528 women with early- or advanced-stage ovarian cancer who received carboplatin and paclitaxel (Taxol), with or without bevacizumab, for 6 cycles. In the experimental arm, at the end of the 6 cycles, bevacizumab monotherapy was

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continued as maintenance therapy for a total of 12 cycles. In this study, the PFS was 19.8 months in the bevacizumab arm and 17.4 months with chemotherapy alone—a 13% reduction in progression risk (P = .039). In addition, a 15% reduction in risk of death was also seen in this study, but this was not statistically significant, reported Gunnar Kristensen, MD, Norwegian Radium Hospital in Oslo, Norway. Subgroup analysis showed that patients deemed at highest risk for disease recurrence—those with suboptimally debulked stage III cancer—had even better outcomes, experiencing a significant 36% reduction in the risk of death (P = .002). Median overall survival was 36.6 months in the bevacizumab arm compared with 28.8 months in the control arm. Dr Kristensen noted that the study revealed a treatment effect that is greater in high-risk patients, “and this may be of clinical relevance.” ■

achieve ALP normalization, indicating ALP as a potentially good marker to gauge patient response. Phase 3 Trial Terminated Early Within hours of these findings being reported at the meeting, R-223 manufacturer announced off-site that an interim analysis of their R-223 phase 3 trial in mCRPC (N = 922) produced such impressive results that the trial was immediately halted in accordance with the recommendation of the Independent Data Monitoring Committee. In patients with mCRPC and bone metastases, R-223 treatment resulted in an OS of 14.0 months versus 11.2 months for placebo. Lead investigator Chris Parker, MD, of the Royal Marsden Hospital, said, “Approximately 90% of men with advanced prostate cancer have bone metastases, which are the main cause of disability and death in this disease.” Based on the observed survival benefits of these 3 trials, R-223 is expected to become an important treatment option for this patient population. Surprising Results with Cabozantinib A second surprise was reported for the novel agent cabozantinib, an inhibitor of tumor growth and metastasis signaling pathways involving MET and vascular endothelial growth factor receptor 2. In a phase 2 clinical trial, patients with mCRPC and progressive measurable disease received 100 mg of cabozantinib daily; response was assessed at 6 and 12 weeks. Although the trial was slated to recruit up to 200 patients, accrual was halted at 168 patients, because of early observed rates of robust clinical activity. Interim analysis for cabozantinibtreated patients showed bone metastases shrinking in 76% of subjects. Of the 108 patients evaluable for bone scan, 21 demonstrated complete resolution of bone lesions and 61 had partial shrinkage—these lesions can lead to bone fractures, severe pain, and eventual death. Study investigators reported that, “Cabozantinib showed clinical activity regardless of prior treatment with docetaxel,” indicating that patients were still responsive to agents like cabozantinib. Progress with Abiraterone After an expedited 6-month review,

at a glance ➤ Alpharadin (R-223) is a first-inclass alpha-emitter radioisotope pharmaceutical that targets bone metastases but spares the patient’s bone marrow ➤ Alkaline phosphatase (a marker of bone metabolism) normalization was strongly correlated with overall survival in patients with metastatic castrate-resistant prostate cancer (14.0 months vs 11.2 months for placebo) ➤ Interim analysis for cabozantinib-treated patients showed bone metastases shrinking in 76% of subjects ➤ Abiraterone therapy induced a ≥50% decline in PSA at 12 weeks in 3 of 14 patients, and a ≥30% decline in 6 of 14 patients the novel agent abiraterone acetate (Zytiga) was approved by the FDA in April 2011. Since then, physicians have been using the drug in patients who have been previously treated with the standard treatment ketoconazole (Nizoral), a molecule with a similar mechanism of action to abiraterone. As the transition from the old standard treatment to the one showing superior efficacy goes forward, the question is, would patients receiving ketoconazole before treatment be resistant to abiraterone? (Patients taking ketoconazole were excluded from the abiraterone registration trial.) An interim analysis for the first 14 ketoconazole-experienced patients with mCRPC was reported at the meeting. Median follow-up was 13.1 weeks. Treatment response was defined as percent decline in prostate-specific antigen (PSA) from baseline. Results showed that abiraterone therapy induced a ≥50% decline in PSA at 12 weeks in 3 of 14 patients, and a ≥30% decline in 6 of 14 patients. Of the patients without a ≥30% PSA decline, 1 had developed Response Evaluation Criteria In Solid Tumors– defined disease progression at 12 weeks and the remainder had stable disease. Although accrual for this trial is ongoing, results thus far are promising. Trial investigators did comment, however, that the lower responses observed in this study compared with ketoconazole-naïve patients with mCRPC suggests the potential for overlapping mechanisms of resistance. ■

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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

VBCC_Aug_11_2_Follow ASCO Tabloid 8/11/11 9:28 AM Page 16

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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ASCO ANNUAL MEETING

Off-Label Drug Use, Advanced Technologies Driving Up Medicare Cost of Cancer Care Value of aggressive utilization in late-stage cancer questioned By Neil Canavan Chicago, IL—A series of studies presented at this year’s ASCO annual meeting suggest that the use of unwarranted high-cost imaging procedures, a surge in the use of innovative treatment technologies, and off-label use of supportive cancer agents are helping to escalate Medicare costs, leading researchers to suggest that further regulation may be needed to rein in unnecessary expenses. The first study examined trends in the use of advanced imaging techniques in elderly patients with metastatic cancer. “Like all interventions in patients with metastatic solid tumors, imaging may contribute to palliation but is unlikely to lead to long-term survival,” said investigator Yue-Yung Hu, MD, a surgical research fellow at Brigham and Women’s Hospital, Boston, MA. “We wanted to determine pattern use, because costs have been rising so rapidly.” Dr Hu and colleagues compared 2 retrospective data sets from Surveillance, Epidemiology and End Results (SEER)-Medicare claims dating from 1999 to 2005. The first set accounted for the use of high-cost imaging procedures—such as computed tomography, magnetic resonance imaging, positron-emission tomography, and

at a glance ➤ Use of unwarranted high-cost imaging procedures, innovative treatment technologies, and off-label use of supportive cancer agents are escalating Medicare costs ➤ Patients with stage IV disease underwent a mean of 2.4 highcost imaging procedures during their first 60-day diagnostic period compared with 0.8 procedures in patients with early-stage disease ➤ After initial diagnosis, terminally ill elderly patients were imaged on average once every 43 days; 41% of these patients underwent an imaging procedure in the last month of life ➤ Intensity-modulated radiation therapy has replaced standard 3D-CRT as the most common prostate radiotherapy

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“One of the things we’ll be looking at in the future is if there was some change in management that happens around the time of these scans that could justify the procedure—but really, in the last 30 days of life, what useful information could be new?” —Yue-Yung Hu, MD

nuclear medicine—in elderly patients with metastatic disease (stage IV; N = 64,267); the second data set consisted of orders for imaging studies in patients with early-stage disease (N = 127,827).

“With Medicare reimbursement for IMRT averaging $48,000 per beneficiary versus $22,000 for 3D-CRT, this trend has significant budgetary implications.” —Michaela Dinan

Excess High-Cost Imaging in Late-Stage Disease The results were striking: stage IV patients underwent a mean of 2.4 high-cost imaging procedures during their first 60-day diagnostic period compared with 0.8 procedures in patients with early-stage disease. In addition, after the initial diagnosis, elderly patients were imaged on average once every 43 days, and 41% of the terminally ill patients underwent an imaging procedure in the last month of life (regardless of tumor type). “We thought that the longer you’re expected to live, the more imaging would be done, but that was not the case,” said Dr Hu. “It’s hard to say exactly what all these scans were for. One of the things we’ll be looking at in the future is if there was some change in management that happens around the time of these scans that could justify the procedure—but really, in the last

30 days of life, what useful information could be new?” Trends in Prostate Cancer Treatment A second study looked at the escalating use of intensity-modulated radiation therapy (IMRT) for the treatment of prostate cancer compared with other, less costly standards of care. “In the last decade, a number of novel treatment options have been developed, including minimally invasive radical prostatectomy and IMRT,” said coinvestigator Michaela Dinan, Duke Clinical Research Institute, Durham, NC. Ms Dinan and colleagues were interested in the financial implications of the availability of these new technologies. Based on Medicare records for patients with prostate cancer from 1999 to 2007 (N = 20,399), IMRT has replaced standard 3-dimensional conformal radiation therapy (3D-CRT) as the most common method of prostate radiotherapy, which was used in 66% of all Medicare patients with prostate cancer who were receiving radiotherapy. “With Medicare reimbursement for IMRT averaging $48,000 per beneficiary versus $22,000 for 3D-CRT, this trend has significant budgetary implications,” stated Ms Dinan, especially given the aging of the US population and the inevitable increase in future prostate cancers. Prescribers of Off-Label Use A third study examined prescribing trends for the already well-known offlabel use of erythropoiesis-stimulating agents (ESAs), which are approved to treat debilitating anemia in chemotherapy patients.

“These are drugs that are associated with significant costs to the overall healthcare system,” said Jason D. Wright, MD, Columbia University, New York. “And we already know that these are drugs that are often utilized in a way that’s different from what they were approved for by the FDA.” Dr Wright and colleagues wondered if it was possible to identify the physician characteristics responsible for the varied patterns of ESA misuse. In a retrospective analysis of prescribing patterns using a SEERMedicare data set dating back over the past 10 years, records of 21,091 patients with cancer were reviewed. Of these patients: • 5099 (24.2%) received ESAs for <1 week (misuse) • 1601 (7.6%) received ESAs for >14 weeks (prolonged use is often misuse) • 2876 (13.6%) patients received ESAs while not actively receiving chemotherapy (off-label).

“This study further bolsters the argument that a lot of noncancer-related factors are driving how we prescribe ESAs.” —Jason D. Wright, MD In a multivariable analysis, ESA misuse was associated with physicians with an MD degree and greater number of years since medical school graduation. Treatment by high-volume oncologists, private-practice physicians, and oncologists who graduated from US medical schools predicted prolonged duration of ESA use. ESA use should be limited to times of chemotherapy administration. Female oncologists were less likely to prescribe prolonged ESA use. “This study further bolsters the argument that a lot of noncancer-related factors are driving how we prescribe ESAs,” said Dr Wright, although he is quick to point out that off-label use is not by definition irresponsible. “Each patient is a unique individual. There are circumstances where use beyond the label is reasonable,” he said. The problem is not so much unreasonable use as it is increasingly untenable expense. ■

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ASCO ANNUAL MEETING

The Oncology Drug Pipeline Is Promising By Neil Canavan

tudies presented at the 2011 annual meeting of the American Society of Clinical Oncology (ASCO) suggest that patients with metastatic melanoma or with non– small-cell lung cancer (NSCLC)—2 disease states with very high rates of mortality—may soon have new treatment options. Other reports suggest the ongoing promise of drugs in various stages of development for the treatment of metastatic castration-resistant prostate cancer (mCRPC), as well as metastatic sarcoma, myelofibosis, and ovarian cancer. Although it is by no means a comprehensive list of investigational agents with positive data reported at ASCO 2011, this summary represents some of the top highlights as indicated by the opinions of clinical experts, the attention paid by financial analysts, and overall attendance at given ASCO presentations. Lung Cancer “Truly brilliant,” said Nasser H. Hanna, MD, Associate Professor of Hematology/Oncology at Indiana University, Indianapolis, commenting on the ongoing investigational results presented for crizotinib. Since entering its first human trials, crizotinib has garnered considerable attention not only for its observed activity in patients with NSCLC, but also for its “adaptive” trial design.

“The striking activity of crizotinib in ALK-positive lung cancer was apparent very early in clinical development.” —D. Ross Camidge, MD, PhD Molecular targeting to the anaplastic lymphoma kinase (ALK) is key to the efficacy of crizotinib; the ALK oncogene pathway is highly active in a small subset of patients with NSCLC. “The striking activity of crizotinib in ALK-positive lung cancer was apparent very early in clinical development,” said study investigator, D. Ross Camidge, MD, PhD, Associate Professor, Division of Medical Oncology, University of Colorado, Denver. Dr Camidge reported the results of a phase 2 investigation, which looked at the overall survival (OS) of patients with ALK-positive lung cancer that

had been involved in 2 phase 1 trials with crizotinib. The results of this analysis showed that among the 82 patients with ALKpositive lung cancer treated with crizotinib, the 1-year OS was 77% and the 2-year OS was 64%, which compares highly favorably with historical controls. In addition, when looking at patients by line of therapy, survival of 32 patients treated with second- or thirdline crizotinib was significantly longer than that of 24 controls with ALK-positive lung cancer (P = .004): 1-year OS was 71% versus 46%, respectively, and 2-year OS was 61% vs 9%, respectively. Metastatic Melanoma “Unprecedented” is how lead investigator Paul Chapman, MD, of Memorial Sloan-Kettering Cancer Center, New York, described the outcome of his clinical trial with vemurafenib in patients with metastatic melanoma, a condition that is invariably fatal. Vemurafenib is a targeted agent, specifically designed to inhibit the tumor-generating activity of a mutation in the BRAF signaling pathway, an error found in 60% of all melanomas. In Dr Chapman’s phase 3 study, treatment with vemurafenib was compared with that of the current standard, dacarbazine (DTIC) in 675 metastatic melanoma patients with the BRAF mutation. The superior efficacy of vemurafenib was observed almost immediately. “The survival curves separated very early,” said Dr Chapman at a press conference heralding the results. Although not enough time had passed to calculate a median OS, the estimated 6month survival for patients receiving vemurafenib was 84% compared with 64% for those treated with dacarbazine. “That’s a 63% decrease in risk of death—a huge difference,” said Dr Chapman. Large differences were also observed for disease progression-free survival (PFS). (See full story in the June 2011 issue of VBCC.) Prostate Cancer Cabozantinib, an inhibitor of tumor growth and metastasis signaling pathways involving MET, and vascular endothelial growth factor 2 was shown to have impressive activity in a phase 2 investigation—so impressive that enrollment to the trial was suspended based on the results from an interim analysis.

VALUE-BASED CANCER CARE

August 2011

“That’s a 63% decrease in risk of death—a huge difference.” —Paul Chapman, MD

The interim results showed that in patients with mCRPC, 76% of subjects achieved shrinkage of their bone metastases, including 21 patients who demonstrated a complete resolution of bone lesions, which are often the cause of severe pain and eventual death in patients with mCRPC. The radioactive, bone-seeking compound, radium-223, was also tested in patients with mCRPC. The results of this investigation were so unexpectedly positive that its manufacturer, Algenta ASA, in partnership with Bayer, immediately halted the trial following the recommendation of the Independent Data Monitoring Committee.

“The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with ridaforolimus will provide a new option for patients.” In a large trial with more than 900 CRPC patients with bone metastases, treatment with radium-223 was able to extend OS to 14.0 months compared with 11.2 months for patients receiving a placebo. (See article on page 13.) Sarcoma The novel compound ridaforolimus targets the mTOR signaling pathway, which is activated in most sarcomas. In a phase 3 investigation of this new agent, 711 patients with metastatic sarcoma were randomized to either

ridaforolimus or placebo as maintenance therapy following stable disease or better response to prior chemotherapy. The primary end point of this study was PFS, with a secondary end point of OS and safety end points. Results showed that treatment with ridaforolimus achieved median PFS of 17.7 weeks versus 14.6 weeks for placebo, an improvement of 21%. Although data accrual for OS is ongoing, currently observed events indicate a trend favoring ridaforolimus, with median OS of 88.0 weeks for ridaforolimus versus 78.7 weeks for placebo. The incidence of stomatitis was high in the ridaforolimus cohort (52%), but these levels are considered in line with previous experience with other mTOR inhibitors. Commenting on these results, study investigators stated, “The rapid progression of metastatic sarcomas demonstrates the aggressive nature of these malignancies, and maintenance therapy with ridaforolimus will provide a new option for patients.” Ovarian Cancer Poly (ADP-ribose) polymerase (PARP) inhibitors have previously shown impressive activity in animal studies, capturing the attention of a number of leading researchers. However, after recent and very surprising negative results for the use of the PARP inhibitor iniparib in triple-negative breast cancer patients, interested parties have been on the lookout for other potential disease settings that may be more responsive to PARP inhibitors (which interferes with DNA repair in tumor cells). This interest confirmed at ASCO where olaparib data in ovarian cancer were presented. The first study presented was a phase 2 trial where either olaparib or placebo was used as a maintenance treatment in 117 patients with platinum-sensitive ovarian cancer. Patients were treated until their disease progressed. Results showed that olaparib treatment extended PFS to 8.4 months versus 4.8 months for patients receiving placebo—a significant improvement. In addition, the iniparib regimen was well tolerated by patients. “This is the first study demonstrating a significant PFS benefit following maintenance treatment with a PARP inhibitor,” said lead investigator, Jonathan Ledermann, University College, London, United Kingdom. Continued on page 20

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IN THE LITERATURE Vemurafenib Improves Survival... Continued from page 9

bazine, and the estimated median progression-free survival (PFS) was 5.3 months and 1.6 months, respectively. Compared with dacarbazine, vemurafenib was associated with a 63% relative risk reduction for death and a 74% risk reduction of either death or disease progression. The response rate with vemurafenib was 48% versus 5% with dacarbazine. The results show improved OS and PFS with vemurafenib monotherapy in this patient population. Furthermore, a survival benefit was observed in all subgroups of patients receiving vemurafenib, including those with stage M1c disease or an elevated lactate dehydrogenase level, conditions associated with an especially poor prognosis. The most common adverse events associated with vemurafenib were arthralgia, rash, fatigue, alopecia, secondary neoplasia (keratoacanthoma or squamous-cell carcinoma), photosensitivity, nausea, and diarrhea. In all cases of secondary neoplasia (18%) associated with vemurafenib, the lesions were removed by simple excision and no modifications in drug dose were necessary.

Intensified BEACOPP Does Not Provide Long-Term Advantage in Hodgkin Lymphoma For patients with advanced Hodgkin lymphoma, an intensified initial regimen of bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPP) may provide better initial tumor control but not long-term clinical benefits than the standard regimen with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), especially in patients who require highdose salvage therapy afterward (Viviani S, et al. N Engl J Med. 2011; 365:203-212). Previously, the German Hodgkin Lymphoma Group had advocated its escalated BEACOPP regimen (which includes higher than standard doses of etoposide, doxorubicin, and cyclophosphamide) as the preferred standard treatment over ABVD in the treatment of high-risk, advanced Hodgkin lymphoma, based on data showing better tumor control and long-term OS. To determine whether these claims applied to patients who require highdose salvage therapy after the initial treatment, Italian researchers compared the 2 regimens over a median 61

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months in 331 patients with untreated stage IIB, III, or IV Hodgkin lymphoma from 3 centers. Patients were randomized to initial therapy with 6 or 8 cycles of ABVD (N = 168) or 8 cycles (4 escalated, 4 standard) of BEACOPP (N = 163), followed by radiotherapy, as needed. Those who demonstrated a less-than-

complete response or relapsed disease received salvage chemotherapy consisting of a standard ifosfamidebased reinduction regimen followed by 1 high-dose course of therapy with carmustine, etoposide, cytarabine, and melphalan, supported by autologous hematopoietic stem-cell rescue.

The estimated 7-year rate of PFS, the primary end point, was 85% with BEACOPP versus 73% with ABVD (P = .004). However, when discontinuation was calculated, that rate did not differ significantly. Neither did the rate of freedom from second progression or OS after salvage therapy in 65 patients. Continued on page 35

The The Greenspan Greenspan Meeting Meeting XXVIII XXVIII November The XXVIII November The Greenspan Greenspan Meeting Meeting XXVIII

8-12, 8-12, 2011, 2011, New New York York City City November 2011, City CHEMOTHERAPY FOUNDATION SYMPOSIUM November 8-12, 8-12, 2011, New New York York City

CHEMOTHERAPY FOUNDATION SYMPOSIUM ® ® CHEMOTHERAPY FOUNDATION SYMPOSIUM November 8-12, 2011, NewFOR York City INNOVATIVE CANCER THERAPY TOMORROW CHEMOTHERAPY FOUNDATION SYMPOSIUM INNOVATIVE CANCER THERAPY FOR TOMORROW ® ® INNOVATIVE CANCER THERAPY FOR TOMORROW CHEMOTHERAPY FOUNDATION SYMPOSIUM Emerging Developments in Cancer Therapeutics INNOVATIVE CANCER THERAPY FOR TOMORROW Emerging Developments in Cancer Therapeutics ® New Agents, Clinical Trials, Personalized Medicine New Agents, Clinical Trials, Personalized Medicine INNOVATIVE CANCER THERAPY FOR TOMORROW Emerging Developments in Therapeutics Emerging Developments in Cancer Cancer Therapeutics Practical Applications for the Practicing Oncologist

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Practical Applications for thePersonalized Practicing Oncologist New Agents, Clinical Trials, Medicine New Agents, Clinical Trials, Personalized Medicine The Changing Environment of Health Care Delivery Emerging Developments inofCancer The Changing Environment HealthTherapeutics Care Delivery Practical Applications for the Practicing Oncologist Practical Applications for the Practicing Oncologist NewChanging Agents, Clinical Trials, Personalized Medicine The Environment of Health Delivery Tuesday, November 8 Care The Changing Environment of Health Care Delivery Tuesday, November 8 Practical Applications for the Practicing Oncologist Pediatric Oncology PediatricNovember Oncology Tuesday, The Changing Environment of Health Care Delivery Therapeutic AdvancesNovember in Cancers of8 Tuesday, 8 Childhood TherapeuticPediatric Advances in Cancers of Childhood Oncology

Pediatric Oncology

Saturday, 12 Therapeutic AdvancesNovember in Cancers of Tuesday, November 8 Childhood Saturday, November 12 Therapeutic Advances in Cancers of Childhood Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Pediatric Oncology Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Saturday, November 12 Therapeutic Advances, Treatment Related Complications, Saturday, November 12 Therapeutic Advances in Cancers of Childhood Therapeutic Advances, Treatment Related Complications, Oncology Nurses, Physician Assistants, Case Managers, Pharmacists Care, Symptom Management, Targeted Therapies Oncology Supportive Nurses, Physician Assistants, Case Managers, Pharmacists Supportive Care, Symptom Management, Targeted Therapies Therapeutic Advances, Treatment Related Complications, Saturday, November 12 Therapeutic Advances, Treatment Related Complications, Care, Symptom Management, Targeted Therapies Oncology Nurses, Assistants, Case Managers, Pharmacists ScheduleSupportive Conference Highlights SupportivePhysician Care, Symptom Management, Targeted Therapies Schedule Conference Highlights Wednesday, November 9 Nov. 8 Pediatric Oncology Therapeutic Advances, Treatment Related Complications, Wednesday, November 9 Time Warp Nov. 8 Pediatric Oncology Keynote Lecture: The Oncology Schedule Conference Highlights Nov. 9 Hematology, GI Cancers Keynote Lecture: The Oncology Time Warp Supportive Care, Symptom Management, Targeted Therapies James Holland,November MD Schedule Conference Highlights Nov. 9 Hematology, GI Cancers Wednesday, 9 Nov. 8 Pediatric Oncology James Holland, MD Nov. 10 GYN, Thyroid, Head & Neck, Wednesday, November Nov. 8 Pediatric Oncology Thursday, November 109 Time Warp Keynote Lecture: The Oncology Nov. 10 GYN, Thyroid, & Neck, Nov. 9 Hematology, GIHead Cancers Breast Cancers Thursday, November 10 Lecture: Keynote Lecture: The Oncology Time Warp Schedule Conference Highlights Ezra M. Greenspan Memorial James Holland, MD Nov. 9 Breast Hematology, GI Cancers Cancers Ezra M. Greenspan Memorial Lecture: James Holland, MD Nov. 10 GYN, Thyroid, Head & Neck, Wednesday, November 9 11 Pediatric GU, Lung, Melanoma, Cure of Her2 November Positive Breast10 Cancer with No 8 Oncology Thursday, 10 Breast GYN,Lung, Thyroid, Head & Neck, Nov. 11 GU, Melanoma, Cure of Her2 Positive Breast Cancer with No Keynote Lecture: The Oncology Time Warp or Minimal Chemotherapy at the Door Step? Thursday, November 10 Cancers Novel Agents, Ezra M. Greenspan Memorial Lecture: Nov. 9 Novel Hematology, GI Cancers or Minimal Chemotherapy at the Door Step? Breast Cancers Agents, James MD Memorial Martine Piccart, MD Ezra M.Holland, Greenspan Lecture: Melanoma, Nov. 11 Neuroendocrine, GU, Lung, Melanoma, Cure of Her2 Positive Cancer with No Martine Piccart, MD Breast Nov. GYN, Thyroid, Head & Neck, Melanoma, Nov. 10 11 Neuroendocrine, GU, Lung, Melanoma, Cure of Her2 Positive Breast Cancer with No Thursday, November Practice Issues Friday, November 11at10 or Minimal Chemotherapy the Door Step? Novel Agents, Breast Cancers Practice Issues Friday, November 11atLecture: or Minimal Chemotherapy the Door Step? Novel Agents, Ezra M. Greenspan Memorial Lecture: Judah Folkman Memorial Martine Piccart, MD Nov. 12 Neuroendocrine, New PerspectivesMelanoma, in Judah Memorial Lecture: Martine Piccart, MD Melanoma, 11 Neuroendocrine, GU, Lung, Melanoma, Cure ofFolkman Her2 Positive Breast Nov. 12 New Perspectives in Anti-Angiogenesis: Paradise Lost? with No Practice Issues Friday, November 11 Cancer Oncology Practice Anti-Angiogenesis: Paradise Lost? or Minimal Chemotherapy at the Door Step? Norman Wolmark, PhD Practice Issues Friday, November 11 Novel Agents, Oncology Practice Judah Folkman Memorial Lecture: Norman Wolmark, PhD Nov. 12 Neuroendocrine, New PerspectivesMelanoma, in Martine Piccart, MD Judah Folkman Memorial Lecture: Nov. 12 Oncology New Perspectives in Anti-Angiogenesis: Paradise Lost? Complimentary Breakfasts, Lunches, Dinners Practice Anti-Angiogenesis: Paradise Lost? Practice Friday, November 11 Complimentary Breakfasts, Lunches, Dinners Norman Wolmark, PhD OncologyIssues Practice Norman Wolmark, PhD Lecture: Judah Folkman Memorial Nov. 12 New Perspectives in Complimentary Breakfasts, Lunches, Dinners Anti-Angiogenesis: Paradise Lost? Oncology Practice Complimentary Breakfasts, Conference Lunches, Dinners A CME Oncology Norman Wolmark, PhD A CME Oncology Conference presented the Dinners Complimentary Breakfasts,by Lunches, presented by the A CME Oncology Conference Mount Sinai SchoolConference of Medicine A CME Oncology Mount Sinai School Medicine presented byofthe and The Chemotherapy Foundation presented by the and Chemotherapy AThe CME Oncology Mount Sinai SchoolConference ofFoundation Medicine Mount Sinai School of Medicine presented by the and The Chemotherapy Foundation line www.chemotherapyfoundationsymposium.org and The Chemotherapy Foundation line at at www.chemotherapyfoundationsymposium.org Mount Sinai School of Medicine Contact: jaclyn.silverman@mssm.edu, (212) 866-2813 and The Chemotherapy Foundation line at www.chemotherapyfoundationsymposium.org Contact: jaclyn.silverman@mssm.edu, (212) 866-2813

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ASCO ANNUAL MEETING

Prolonged Treatment with Imatinib for High-Risk GIST Increases Survival, Reduces Recurrence Phase 3 clinical trial results will likely change standard of care Chicago, IL—Results from a phase 3 clinical trial presented at a plenary session at ASCO 2011 could lead to prolonged treatment with adjuvant imatinib for gastrointestinal stromal tumors (GIST). The extension of imatinib (Gleevec) treatment to 3 years, compared with the usual 1 year, resulted in a 54% reduced risk of recurrence and 55% reduced risk of death within 5 years for patients with high-risk disease, reported Heikki Joensuu, MD, Helsinki University Central Hospital, Finland. “These data are pretty compelling,” Dr Joensuu said. “I would not be surprised if the standard will be 3 years of adjuvant imatinib in the near future.” Mark G. Kris, MD, who moderated a press briefing and is Chair of the ASCO Cancer Communications Committee, agreed. “The entire oncology community was extremely excited when we saw the survival curve and those numbers at 5 years. It’s one of the amazing stories in oncology, and it is the kind of data that change guidelines,” he said. Study Details The Scandinavian Sarcoma Group and Sarcoma Group of the AIO, Germany, conducted the SSGXVIII/ AIO study, a phase 3 open-label clinical trial that evaluated 36 months versus 12 months of adjuvant imatinib

Photo courtesy ASCO/GMG/Scott Morgan 2011

By Audrey Andrews

“The entire oncology community was extremely excited when we saw the survival curve and those numbers at 5 years. It’s one of the amazing stories in oncology, and it is the kind of data that change guidelines.” —Mark G. Kris, MD administered after surgical resection to 400 patients with GIST at high risk of recurrence. At a median follow-up of 54 months, recurrences or death occurred in 50 of 198 (25%) patients receiving 36 months of imatinib compared with 84 of 199 (42%) patients receiving only 12 months of treatment. The recurrence-free survival rate was

86.6% at 3 years and 65.6% at 5 years with 36 months of treatment compared with 60.1% and 47.9%, respectively, with 12 months of treatment, representing a significant 54% reduction in risk of recurrence (P <.001). Overall survival was 96.3% at 3 years and 92.0% at 5 years with 36 months of treatment compared with 94.0% and 81.7%, respectively, with 12 months of imatinib, representing a 55% mortality risk reduction (P = .019). However, grade 3 or 4 adverse events were more common with longer treatment, and more patients discontinued GIST in the 36-month arm. More May Be Better, Experts Agreed Charles D. Blanke, MD, Chief of Medical Oncology, University of

“The overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to ‘catch up’ when a patient has recurrent metastatic disease.” —Charles D. Blanke, MD

British Columbia, Vancouver, commented on the study, noting that its conclusions were “valid.” He suggested that oncologists who typically initiate imatinib on relapse might want to rethink this strategy. “If you have a patient who has high-risk GIST, at least as defined by the study, giving him or her 3 years of imatinib represents the new gold standard,” he maintained. “The overall survival benefit demonstrated with immediate postoperative imatinib means it is no longer acceptable to withhold treatment in the adjuvant setting, hoping to ‘catch up’ when a patient has recurrent metastatic disease.” He acknowledged, however, continuing treatment for 3 years could be problematic for many patients, as suggested by a higher rate of side effects and more than a doubling in the dropout rate among patients who received imatinib for that long. Although it is possible that treatment even beyond 3 years could be even more beneficial, he noted, “Difficulties on the 3-year arm of SSGXVIII/AIO may bode poorly for therapy lasting even longer.” “For now, if I were a patient with a resected GIST and I had a compliant oncologist, I would request more,” he said. “As a compliant oncologist, I personally will offer patients treatment… indefinitely.” ■

The Oncology Drug Pipeline... Continued from page 18 A second, much smaller study of 41 patients suggested that iniparib might be beneficially partnered with the standard chemotherapeutic agent gemcitabine. Results for the combination demonstrated an overall response of 65% and a PFS of 9.5 months in patients with platinum-sensitive ovarian cancer. Stomach Cancer Targeting the ability of tumors to generate a sufficient blood supply is the mechanism behind the antiangiogenic agent telatinib. In a phase 2 investigation of 39 inoperable metastatic stomach cancer patients, results demonstrated a rapid and sustained tumor regression in 66% of patients when telatinib was combined with chemotherapy. (Antian-

giogenic drugs are not used as singleagent treatments.) These results were observed regardless of the tumor location or whether it had already spread to the liver. The median PFS was 140 days, and safety end points suggest that the chemotherapy combination with telatinib was well tolerated. “Antiangiogenic agents are an important class of drugs for the treatment of gastrointestinal cancers,” said Jaffer A. Ajani, MD, Professor of Medicine at the University of Texas M.D. Anderson Cancer Center in Houston. The efficacy of telatinib without a significant increase in side effects when combined with chemotherapy suggests a potent new approach for patients with stomach cancer. ■

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August 2011

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ASCO ANNUAL MEETING

Upper GI Cancers: Are We Getting Value...

“In the era of cost constraints, we must recognize that all these agents are palliative, all are expensive, and all have added toxicity.” —Eileen Mary O’Reilly, MD Center, examined some of the major trials. The only true “practice-changing” study, in her opinion, involved trastuzumab (Herceptin) as treatment for gastric cancer. The rationale is strong, she said, based on the discovery that HER2 is overexpressed in many gastric tumors. In the phase 3 ToGA (Trastuzumab for Gastric Cancer) trial, trastuzumab added to capecitabine (Xeloda) and cisplatin (Platinol) improved overall survival (OS) from 11.1 months to 13.8 months with chemotherapy alone, constituting

a 26% reduction in death. The effect was robust in the subset that strongly overexpressed HER2. In contrast, in pancreatic cancer, the pivotal National Cancer Institute of Canada Clinical Trials Group PA.3 trial of erlotinib (Tarceva) plus gemcitabine (Gemzar) versus gemcitabine alone is “an example of a statistically significant phase 2 trial that has clinically limited therapeutic impact,” Dr O’Reilly maintained. The median OS was improved by <1 month, as was progression-free survival (PFS); but because these small differences were statistically significant, the US Food and Drug Administration approved erlotinib for pancreatic cancer based on these results. For pancreatic neuroendocrine tumors, “we don’t yet fully know” the true benefit of everolimus (Afinitor) and sunitinib (Sutent), which have led to improvements in outcomes and represent new options for a rare malignancy. Many questions remain, such as the best time to initiate therapy with these drugs, and how to sequence and combine them with other treatments, Dr O’Reilly said. “In the era of cost constraints, we must recognize that all these agents are palliative, all are expensive, and all have added toxicity,” Dr O’Reilly said. Future investigations must be based on strong biologic rationale, robust early-phase results, and intelligent trial design. The Value of New Cancer Drugs Neal J. Meropol, MD, Associate Director for Clinical Research, Case Western Reserve University, Cleve-

Continued from cover

land, who investigates the economics of cancer care, said he was “providing perspective on how to interpret these claims.” He ranked the clinical benefit of upper GI cancer treatments, largely based on the magnitude of the statistical differences in PFS and OS compared with standard treatment, and then assessed the value of the new upper GI cancer regimens, demonstrating that clinical benefit is often not parallel with value (Table).

“Not all effective treatments have equivalent value. Costsharing can be used to discourage low-value treatment and encourage high-value treatment…. The low-hanging fruit is cost-sharing that is not based on the cost of the intervention but its value.” —Neal J. Meropol, MD

Table Value of Upper GI Cancer Treatments Cancer type/ drug regimen

Clinical benefit

Annual cost of drug, $a

Value

Pancreatic cancer Gemcitabine/erlotinib

Very low Erlotinib

53,954

Very low

Liver cancer Single-agent sorafenib

Modest

Sorafenib

115,866

Low

Gastric cancer Chemotherapy/ trastuzumab

Modest

51,225 Trastuzumab (excluding Modest loading dose)

Biliary cancer Gemcitabine/cisplatin

Modest

Cisplatin

364

Higher

Neuroendocrine tumor Single-agent sunitinib

Higher

Sunitinib

108,569

Higher

Everolimus

201,516

Modest

Neuroendocrine tumor Higher Single-agent everolimus

New drug

Based on average wholesale price for oral drugs, average sale price for intravenous drugs. GI indicates gastrointestinal.

VALUE-BASED CANCER CARE

August 2011

Dr Meropol said the “trastuzumab story” is informative regarding the future of oncology clinical trials and oncology care. He reminded the audience that although trastuzumab has become an important treatment in gastric cancer, its effect, compared with the drug’s impact on breast cancer, is minimal. In metastatic breast cancer, trastuzumab prolonged median OS by nearly 5 months; in advanced gastric cancer, it added a median of 2.7 months. In patients with highly overexpressed HER2, however, the additional benefit exceeded 4 months, thus offering somewhat higher value in this subset, he acknowledged. The “lessons,” according to Dr Meropol, are that diagnostics development must begin early and in concert with clinical development, that all can-

cers will be “rare” cancers once their molecular profile is understood, that “blockbuster drugs” will become dinosaurs (ie, no one drug will fit all), that the bar must be set high early in drug development, and that treatment based on site of origin will be replaced by treatment based on phenotype. Smaller patient populations will eventually become defined for essentially all tumor types, necessitating ever more targeted treatments as the norm. The effect of this on drug development and cost control remains unclear, according to Dr Meropol. “Will this prolong drug development time and reduce the chances of bringing drugs to market? Will the higher value of the targeted approach bring even higher prices to make up for smaller markets? The answers to these questions are unknown,” he said. Where We Need to Go Dr Meropol offered some concrete suggestions for “where we need to go” in the future treatment of cancer. His suggestions included the following: • Reduce overutilization: eliminate nonbeneficial interventions • Raise the bar for drug approval • Link payment to value via costsharing • Authorize the Centers for Medicare & Medicaid Services to negotiate price • Reduce incentives for development of marginal advances • Improve the evidence base with comparative effectiveness research. Value-based insurance design may be a viable strategy for achieving some of these goals and is gaining traction, he noted. “Not all effective treatments have equivalent value. Cost-sharing can be used to discourage low-value treatment and encourage high-value treatment, in contrast with current plans that base coverage on cost,” he said. “There would be the potential for different coverage based on the disease and stage.” “The low-hanging fruit is costsharing that is not based on the cost of the intervention but its value,” he maintained. He emphasized that in the allocation of finite resources, “the goal is to move from implicit decisions about allocation to explicit and transparent ones,” adding that politics will impact this process. “We need to weigh in as the oncology community to advocate for our patients and for the development of high-value treatments.” ■

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ASCO ANNUAL MEETING

Comparing the Value of Denosumab versus Zoledronic Acid in Preventing Cancer-Related Skeletal Events By Caroline Helwick Chicago, IL—Two agents are vying to be the preferred option for bone protection in patients with cancer—the blockbuster drug zoledronic acid (ZA; Zometa, Reclast) and the newer drug denosumab (Prolia), which was approved last year for the prevention of skeletal-related events (SREs) in patients with cancer. Denosumab has proved more effective in preventing SREs than the standard agent, ZA, in several cancer types, but its wholesale acquisition cost per injection is $1650 compared with $886 for ZA. Some oncologists have questioned whether the benefit is worth the cost. At ASCO 2011, studies sponsored by the 2 manufacturers addressed the drugs’ value, but the “winner” is still not clear. Treatment of Metastatic Breast Cancer Using a literature-based Markov model, investigators analyzed the survival, quality-adjusted life-years (QALYs), number and costs of SREs, and costs of the 2 drugs in patients with metastatic breast cancer. The conclusion was that denosumab’s cost per QALY far exceeds what is traditionally considered good value. “This analysis raises questions about the cost/benefit ratio of denosumab in metastatic breast cancer,” said John A. Carter, research analyst, Pharmerit North America, Bethesda, MD. Inputs were selected to reproduce the phase 3 trial outcomes for as long as 28 months. QALYs were estimated by assigning utilities to health states. SRE-related costs and utilities were obtained from the literature; per-event SRE costs ranged from $4039 (vertebral

including serious AEs ($644,000 when excluding them). “Relative to ZA, the use of denosumab for the prevention of SREs in metastatic breast cancer is estimated to reduce SRE-related costs over 28 months of treatment. However, one must invest more than $9000 in additional drug costs and thus incur a net cost of $7000 over 28 months to achieve these benefits,” Mr Carter concluded. “The resultant cost per QALY…is far above what is traditionally considered to be good value for a medical intervention in the US ($50,000-$100,000 per QALY),” he noted.

“The resultant cost per QALY…is far above what is traditionally considered to be good value for a medical intervention in the US ($50,000-$100,000 per QALY).” —John A. Carter fracture) to $20,734 (bone surgery). In a sensitivity analysis, serious adverse events (AEs) of $15,441 per patient were included. Scenario analyses were also assessed. All costs and outcomes were discounted at 3% annually. Compared with ZA, denosumab resulted in fewer SREs, more QALYs, and lower SRE-related costs, but higher drug-related and total costs. This resulted in an incremental cost of $6884 per patient. The cost per QALY gained was $613,000 per QALY when

Treatment of Castration-Resistant Prostate Cancer Using the same study design as the breast cancer study, Sonya J. Snedecor, Associate Director of Health Economics, Pharmerit North America, Bethesda, MD, similarly concluded that the cost per QALY of denosumab in men with metastatic castration-resistant prostate cancer (mCRPC) is “far higher than what is considered in the US to be good value for a medical intervention, thus raising questions about the value of using denosumab in mCRPC.”

“These low NNT values demonstrate the therapeutic efficacy of denosumab.” —Gary Richardson, MD

The use of denosumab was predicted to result in an incremental cost per QALY gained of $1.25 million. The

high cost was attributed to denosumab being associated with higher drug acquisition costs, limited prevention of SREs, and no additional overall survival or disease progression benefits versus ZA. The cost of drug administration and monitoring was figured at $12,963 for ZA and $20,277 for denosumab, Dr Snedecor said. Low Number Needed to Treat Demonstrates Efficacy However, in another analysis, investigators found a low number needed to treat (NNT) to prevent 1 SRE. Gary Richardson, MD, of Cabrini Hospital in Malvern, Australia, reported the results of this international randomized double-blind trial. In this study, denosumab was compared with ZA in 1776 patients with cancer. Results showed that denosumab was superior to ZA in preventing SREs and bone metastases and was noninferior when patients with multiple myeloma (MM) were included. The NNT to prevent the first SRE and the first and subsequent on-study SREs were determined based on data from the initial placebo-controlled trials. The NNT to prevent 1 additional first SRE during 1 year was 7.8 for denosumab versus ZA and only 3.0 for denosumab versus placebo. For the analysis of time to first and subsequent SREs (ie, multiple SREs), the NNT with denosumab versus ZA was 6.5. When patients with MM were included, the NNT was 9.9 versus ZA and 3.0 versus placebo. “These low NNT values demonstrate the therapeutic efficacy of denosumab,” Dr Richardson said. ■

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ONCOLOGY BEST PRACTICES

Northwestern University Comprehensive Cancer Center... focused discussions on the quality and effectiveness of care, with the goal of improving the care for patients with cancer. Among the areas of high interest for the Best Practices Committee is quality assurance. The goal is to ensure that NCCN’s institutions, such as our Northwestern Robert H. Lurie Comprehensive Cancer Center, are following clinical guidelines for patient management, and that we verify how concordant our institutions are in following clinical guidelines and quality indicators that are based on the guidelines. Another very important aspect of best practices is the integration of practice models to enhance comprehensive cancer care delivery. Practice models include defining the role of different providers of care, such as the role of nurse practitioners in the oncology practice. This is a multifaceted concept that encompasses the overall goal of providing the best comprehensive services possible for each individual patient. It can also include other areas, such as looking at reimbursement patterns. The way patient services are delivered can vary significantly, depending on the type of practice and practice location, for example.

Q: What are some of the unique features offered at your Northwestern center, and what makes it one of the leading cancer centers in the country? Dr Benson: One significant advantage we have is a centralized clinical cancer center, which enables us to provide broad-based services. We have had to divide our clinical cancer center into 2 different buildings, principally because of our patient volume and space limitations. The bulk of the clinical cancer center is on one floor of our ambulatory care tower (the Galter Pavillion), where we provide a full range of services, including full infusion services. Our clinical nurse specialists, who provide treatment to patients, also work closely with individual

at a glance ➤ NCCN’s institutions must follow clinical guidelines for patient management and be concordant in following clinical guidelines and quality indicators ➤ A significant advantage at Northwestern is having a centralized clinical cancer center, which facilitates delivery of a wide range of services ➤ An EMR system enhances care coordination, which is critical for optimal cancer care ➤ A much more integrated comprehensive program is required in this country to merge all the components of what it takes to deliver oncology care in a cooperative venture ➤ Participation in research programs by clinicians and patients in far greater numbers has to become the norm rather than the exception

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Continued from cover

that recommendation to our patients and schedule the appropriate follow-up visits and interventions based on these conferences. This centralization and ready availability of the various disciplines are important for patient care, as are our financial counselors, social workers, psychologists, dieticians, and other important services that are integrated within the same location. We emphasize palliative care through our supportive oncology care team, which is a critical component of our comprehensive approach to cancer care.

Q: You have a huge advantage being in a big city, and you likely have good funding as well. Is this typical for most cancer centers?

A very important aspect of best practices is the integration of practice models to enhance comprehensive cancer care delivery.

physicians to develop areas of expertise in a given tumor type. For example, I have been working with the same nurse clinician for 15 years, and she knows gastrointestinal oncology inside out, which is also my area of expertise. She is an enormous resource for patients undergoing treatment. The same floor houses our surgical oncologists, hematologists, medical oncologists, the transplant team, neuro-oncology, urologic oncology, interventional radiology, psychologists, dieticians, financial counselors, and social workers. Such proximity offers a great advantage that allows us to offer services in one place that cannot always be provided by smaller centers. Our second clinical cancer center is located in Prentice Women’s Hospital. The gynecologic oncology service clinicians have moved from our original clinical cancer center to our Women’s Hospital. Patients with breast cancer are also seen in this location by the breast cancer oncologists, including the surgeons and the medical oncologists. Prentice Women’s Hospital also has a radiation unit, so patients undergoing radiation treatments can conveniently take one elevator from the oncology service down to radiation oncology. We have full laboratory services in both clinical cancer center locations, as well as radiology services in both buildings. Therefore, most patients have consolidated services all in one location. To further support patients, we try to coordinate multidisciplinary appointments, although with some exceptions—we do not have multidisciplinary clinics as is the case in some centers. We try to set up various appointments for a patient so different providers end up seeing the patient on the same day. In addition, we have weekly multidisciplinary tumor conferences for the different diseases. Many of our patients are presented at these conferences that result in a multidisciplinary opinion; we then take

August 2011

Dr Benson: Large cities often offer a number of different cancer programs. There are hospital-based cancer center programs that may not be National Cancer Institute (NCI) comprehensive cancer centers, as our center is, but they are in large hospitals that also try to offer comprehensive cancer care services. Regardless, there can be many differences in how the care is delivered. Overall, there are many permutations as to the structure of cancer programs and a multitude of challenges. For example, when there is not one center location, where people may have to go to the medical oncologist’s office or to a separate infusion center, and they may even have to go to a separate center for imaging, and maybe yet another location for radiation oncology, coordination of care can become very complicated and challenging. Another advantage we have at Northwestern is our complete electronic medical records (EMRs) system; we do not use paper records at all. An EMR system enhances care coordination, because the records are computer-based and readily available to all the medical staff at the center. Scheduling among specialists can also be more readily coordinated, for example. At Northwestern, we receive many outside referrals, so we have many outside medical records, which in turn are scanned into our own EMR system. For example, today I was referred a new patient whom I scheduled to see tomorrow. The records and scans were sent to me on a disk and have been downloaded into our system. I have already called the interventional radiology specialist and asked him to look at this patient’s liver CT [computed tomography], to see what we might have to offer for this individual patient. All of this was coordinated before I am seeing the patient (tomorrow), thanks to our EMR system.

Q: Clearly your EMR system helps care coordination for a patient with cancer. But what if that patient was also diabetic— would you have access to medical records not related to the cancer? Dr Benson: In addition to our cancer center, we have immediate access to electronic patient records from Northwestern Memorial Hospital, as well as to the outpatient records through the Northwestern Medical Faculty Foundation. Our faculty members use the same EMR; therefore, if I am referring a diaContinued on page 25

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ONCOLOGY BEST PRACTICES betic patient (with cancer) to an endocrinologist, the endocrinologist has total access to our EMR, and vice versa. The exception would be one that involved our private physicians, who are on the medical staff of the hospital, who many have offices that are off site. Their record system may therefore be totally different from ours and may not be directly linked to the outpatient system, although the off-site physicians may have access to the hospital EMR system through their office computers. As faculty members, we have the advantage of being able to go online to access the Northwestern EMR system, do charting at home, and if a patient calls when the faculty member is off site, we have immediate access to that patient’s records.

We certainly buy into this philosophy of clinical research and integrated cancer care and try to promote such an approach by our involvement with the NCCN guidelines, which actively promote clinical research. As an NCI comprehensive cancer center, clinical research is an integral part of our mission.

Q: Disparities of care is an important issue in cancer care. Does your centralized care help to reduce disparities in care? Dr Benson: Not exactly. No matter what system we have, we are going to face disparities for many reasons—some are very obvious, such as lack of insurance and limited financial resources—and a truly big area is the underinsured. With complex cancer services, there is a risk that all the required services may not be fully reimbursed. In addition, high copayments may make it difficult for some patients to receive all the medications they need. Our social and financial services try to assist patients, including trying to arrange transportation or to find other assistance programs, but often there are obstacles that make it difficult for patients to receive the comprehensive care they require. We have a big urban environment that covers a very large referral area, which, in addition to Chicago, encompasses Indiana, Michigan, Wisconsin, and even Iowa, as well as the entire state of Illinois. With such a geographically diverse population, some complex issues come up, and many of our patients, because of their geographic distance, also need services closer to their home. They may have oncologists closer to home, or they may get some testing done closer to home; when that happens, it can result in disjointed care, which may not necessarily be health disparities, but it does fragment the care. In addition, many patients have very limited resources, and it becomes a challenge how to orchestrate a comprehensive program for these individuals to ensure that they can receive the care they need.

Q: Many oncologists today are urging other oncologists to refer patients to clinical trials, especially those who have few or no therapeutic options. As one who is heavily involved in clinical research, where does clinical research fit within best practices in oncology? Dr Benson: The philosophy is that clinical trials represent a standard of care and are directly integrated into the decision process in terms of therapeutic options, and this is also part of the best practices concept of using evidence-based medicine. In gastrointestinal oncology, where we have a very vigorous clinical trials program, we actively discuss clinical trials with our patients, and we get referrals requesting us to consider a patient for our clinical trials.

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The Galter Pavilion, Northwestern Memorial Hospital

Q: Does being an NCI cancer center imply participation in clinical trials? Dr Benson: Absolutely. An NCI comprehensive cancer center must show significant funding and activity in 3 big areas of research—clinical research, laboratory research, and what we often call “cancer control,” which is a very broad area that can encompass everything from screening, prevention, symptom management, and quality-of-life measures.

One advantage we have at Northwestern is our complete EMRs system; we do not use paper vvrecords at all. An EMR system enhances care coordination and scheduling among specialists. Q: Finally, what do you see as some of the major challenges today for oncology practices? Dr Benson: There is a laundry list of massive challenges that revolve around the growing workforce shortage. It is clear that we are going to have insufficient numbers of oncologists, including medical and radiation oncologists, and in particular a shortage of oncology nurses and nurse practitioners.

When we project a growing population of individuals who will be faced with a cancer diagnosis, there are very significant issues that will magnify our challenges, including reimbursement of cancer care, the ongoing struggle to deliver comprehensive care, and the ability to afford these services. Patients having access to treatment financially is going to continue to be a big problem. In addition, if we are going to more readily advance cancer care and take advantage of rapidly emerging technologies as well as rapid development of new agents, we simply have to have a far greater percentage of patients who are participating in clinical trials, particularly trials that include tissue acquisition, so we can continue to learn more about and develop a strategy centered around tumor biology. This is where the concept of personalized medicine comes into play. We need to look at personalized medicine in providing overall comprehensive cancer services to the individual patient, and to be able to select appropriate treatment based on the host and the tumor biology profiles. To be able to do this is going to take a concerted investment not only in the science of cancer but also in supporting the infrastructure of clinical trials work. So much of what we do now represents tremendously underfunded clinical trials and a dependence on a voluntary effort, as well as institutional financial support to conduct these trials. With the economic pressures on institutions, and with the workforce shortage pressures, we have a mix of challenges that could directly impede our efforts to advance cancer research and, subsequently, cancer care. We require a much more integrated comprehensive program in this country that will merge together all the components of what it takes to deliver oncology care in a cooperative venture, as well as to maximally promote research. Advancements in research will require enhanced government support not only from the NCI but also from our regulatory agencies in the government, reimbursement branches of government, and for drug development, the pharmaceutical industry. It is going to require integration of imaging, diagnostics companies, and third-party carriers to at least help support the standard care costs for patients on clinical research trials; future research endeavors will mandate interdisciplinary collaboration including other critical people, such as surgeons, radiologists, and pathologists who have not been routinely awarded appropriately for their clinical trials efforts and are too often underfunded and underrecognized for their work. A societal commitment to the notion that scientific innovation is of critical importance—and worth the investment in capital and people—is necessary if we are to improve cancer care and expected outcomes. Participation in these research programs by clinicians and patients alike in far greater numbers will need to become the norm rather than the exception. ■

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HEALTH POLICY

Hanging in Limbo: What Does Deficit Reduction Mean for Oncology? By Jayson Slotnik and Ross Margulies Mr Slotnik is a Partner, Health Policy Strategies, LLC, Washington, DC; Mr Margulies is Health Policy Specialist, Foley Hoag, LLP

n August 2, 2011, President Obama signed the Budget Control Act of 2011 into law, the result of a month-long partisan battle over raising the federal debt ceiling and, in the long-term, reducing the federal deficit (Budget Control Act of 2011. Pub. L. No. 112-25). The Budget Control Act places an initial $917-billion cap on discretionary spending over the next decade and sets up a new Joint Select Committee on Deficit Reduction tasked with recommending $1.2 trillion to $1.5 trillion in additional deficit reduction by early December 2011. If the Joint Select Committee (or “supercommittee,” as it has come to be known) either fails to submit a report to Congress or, as an alternative, if Congress fails to pass the proposal, an automatic sequestration is triggered. Under sequestration, Medicare payments to healthcare providers and to health insurance plans would be cut across the board by 2% over the next decade—saving roughly $216 billion— starting in 2012. Medicaid and Social Security are notably exempt under this fail-safe measure, as are cuts to Medicare beneficiaries. Looking forward, the oncology community is faced with 2 very differ-

at a glance ➤ The Budget Control Act of 2011 places an initial $917billion cap on discretionary spending over the next decade ➤ The act sets up a new Joint Select Committee tasked with recommending $1.2 trillion to $1.5 trillion in additional deficit reduction by end of year ➤The Joint Select Committee is empowered to look for costsavings and increased revenue by tax increases; tax reform; or cuts to the military, domestic programs, or entitlements ➤ Reducing Medicare’s reimbursement rate for Part B drugs, rolling Medicare Part B into Part D, or reinstating the least costly alternative would have a devastating impact on cancer care as a whole, including oncologists and patients with cancer

Jayson Slotnik

Ross Margulies

ent paths—one to be shaped by the yet-to-be-named 12 members of Congress and a lot of unknowns, and the other a known fail-safe measure certain to cause pain to healthcare providers, manufacturers, and patients. Which path is the worst of these 2 evils for those involved in cancer care? Ultimately this answer comes down to what the Joint Select Committee may do to cut the federal deficit, and what would be the full impact of this action on the oncology community as a whole.

tic category). It is argued that the cost-savings could result from increased therapeutic substitution between oral and injectable drugs. • Allowing Medicare to negotiate Part B drug prices. Although increased attention has been paid to the proposal that allows the Secretary of Health and Human Services to negotiate the price on Part D drugs, one possibility for cost-savings is also to allow the federal government to negotiate lower cost with pharmaceutical manufacturers when Medicare is the major purchaser of a specific Part B drug. • Least costly alternative. Although prohibited since 2009, based on a US Court of Appeals for the District of Columbia circuit case, applying the “least costly alternative” approach would allow the Centers for Medicare & Medicaid Services to include a cost-effectiveness calculation in Medicare payment policy to limit reimbursement on costly new therapies (which would apply to many new cancer drugs and diagnostics), thereby limiting beneficiaries’ access to these potentially lifesaving options. It is evident that the adoption of one or some of these proposals could have a devastating impact on both oncology providers and on manufacturers in the oncology space. Most important, however, these cuts could have a detrimental impact on patients with cancer.

Path 1: The Joint Select Committee Recommendation The Joint Select Committee on Deficit Reduction, composed of 12 bipartisan members, is empowered to look for cost-savings and increased revenue everywhere it can, including tax increases; tax reform; or cuts to the military, domestic programs, or entitlements. The following strategies are potential proposals that the Joint Select Committee could consider that would have a negative effect on many aspects of cancer care delivery: • Reducing Medicare’s reimbursement rate for Part B drugs from average sales price (ASP) + 6% to ASP + 4% or some lower amount. This proposal would lower reimbursement for Medicare Part B drugs to a decrease of ≥2% from the current ASP + 6%. • Rolling Medicare Part B into Part D. By folding the Part B program for drugs administered in the physician’s office into the Part D program, advocates insist that increased price competition would push down drug prices among similar drugs (ie, in the same class or the same therapeu-

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August 2011

Path 2: Across-the-Board Cuts Although the sequestration process, which guarantees cuts to Part D reimbursement and Medicare providers, initially appears to be a losing proposition, when compared with the alterna-

tives as discussed above, this may be the better of 2 evils. Moreover, given the composition of the Joint Select Committee on Deficit Reduction (6 Democrats, 6 Republicans) and the current ultrapartisan atmosphere in Congress, the likelihood of the committee actually coming to a “grand bargain” appears highly unlikely. As such, unless the committee is able to beat the odds and reach a major compromise, or, in the alternative, if Congress is able to amend the Budget Control Act with a much larger deal (economists are still insisting that at least $4 trillion in cuts are necessary to avert a crisis), across-the-board cuts appear the most likely result. Under this scenario, it is still possible that the ASP percentage would be reduced, but the more sweeping policy changes mentioned above would not occur.

The oncology community is faced with 2 very different paths—one to be shaped by the yet-to-be-named 12 members of Congress and a lot of unknowns, and the other a known fail-safe measure certain to cause pain to healthcare providers.

Regardless of which path is chosen, we have a classic example of bad facts making bad law. The resulting policy changes will not take place through regular order, and will shut out many stakeholders and lawmakers. Is this really what the founders of our country had in mind? ■

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HEALTH POLICY

Accountable Care Organizations: Implications for Cancer-Related Quality Care and Spending By Caroline Helwick Chicago, IL—Accountable care organizations (ACOs) are a prominent part of the Patient Protection and Affordable Care Act (ACA), better known as the healthcare reform. ACOs are believed to hold the potential for addressing variation in quality and costs of cancer care, but their impact will depend on buy-in and leadership among oncologists, according to David Miller, MD, MPH, a urologic surgeon and health services researcher at the University of Michigan, Ann Arbor. He addressed this topic during the recent annual meeting of the American Society of Clinical Oncologists. “There is a lot of uncertainty on this topic,” noted Dr Miller. “The story is yet to be told.” Section 3022 of the ACA established a Medicare SharedSavings Program that allows for ACOs to participate in Medicare. The program is slated to be implemented by January 2012, but full details are just emerging. Quality Measures Focus of ACOs An ACO is a large group of providers that accepts responsibility for the quality and cost of care provided to a population of patients. This can be in the form of physician group practices, networks of individual or group prac-

at a glance ➤ As part of the Patient Protection and Affordable Care Act, ACOs hold the potential to address variation in quality and costs of through treatment decision-making/ therapeutic intervention, identification/ management of side effects, and delivery of end-of-life palliative care ➤ ACOs include 65 proposed measures for reporting related to quality of care in patient/ caregiver experience, care coordination, patient safety, preventive health, and at-risk population/frail elderly health ➤ Approximately 75-150 ACOs are expected to be in place over the next 3 years ➤ The ACO coverage slated for 1.5 million-4 million Medicare beneficiaries will result in a projected savings of $510 million over the 3-year period

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(Haywood TT, Kosel KC. N Engl J Med. 2011;364:e27; Ginsburg PB. N Engl J Med. 2011;364:2085-2086) that describe the controversies and criticism, much of it doubting the potential for costsavings. “On the other hand, some say we need to do even more,” Dr Miller acknowledged. This has led to a “virtual ACO economy” aimed at fine-tuning how the whole process will be engineered and fulfilled, he said.

“We need to define what constitutes efficient care in oncology, because a lot of money is at stake.” —David Miller, MD, MPH

tices, joint ventures between physician organizations and hospitals, or hospitals that employ ACO physicians. The ACO has explicit mechanisms for receiving and distributing shared savings, repaying shared losses, and performing quality measurements. “This sounds like the HMO [health maintenance organization] of the ‘90s,” Dr Miller observed, “but with quality measures and opportunities for shared savings.” Of course, the mechanisms for the proposed savings are very complex, he added. There are 65 proposed measures for reporting related to quality of care in the following 5 domains: • Patient/caregiver experience • Care coordination • Patient safety • Preventive health • At-risk population and frail elderly health. Breast and colorectal cancer screenings have strong emphasis. Performance is measured via claims, surveys, and the use of new data collection tools. High Expectations Approximately 75 to 150 ACOs are expected to be in place over the next 3 years. This means 1.5 million to 4 million Medicare beneficiaries will be covered through ACOs, with a projected savings of $510 million over the 3-year period, according to Dr Miller. “But, there are mixed emotions about ACOs,” he added, as exemplified by 2 recent perspectives in the New England Journal of Medicine

ACOs May Curb Variation in Care ACOs might be most useful, he maintained, by reducing variation in quality and cost in the “3 big-ticket areas” of treatment decision-making and therapeutic intervention, identification and management of side effects, and the delivery of end-of-life palliative care. Studies have demonstrated significant variation by specialty, geographic area, hospital, and race/ethnicity. Variation in care is relevant to ACOs for several reasons. Variation in quality suggests basic problems with cancer care delivery: overtreatment, undertreatment, or both. It also suggests the need for evidence-based medicine, quality measurements, and shared decision-making.

“If oncologists are not participating [in ACOs], there will be a huge cost center left outside of the scope of this policy lever. It will be hard to achieve savings goals without the involvement of cancer care.” —David Miller, MD, MPH

Variation in costs suggests there is a place for business in setting quality and eliminating waste, for example, by improving coordination across care settings, Dr Miller said. ACOs are relevant in this setting, he noted, because “both hospitals and physicians would have ‘skin in the game’ with respect to optimizing efficiency of cancer care,” but there is “major work ahead in defining optimally efficient practices,” he added. “We need to define what constitutes efficient care in oncology, because a lot of money is at stake,” Dr Miller emphasized.

The Challenges of ACOs for Oncology The challenges in developing ACOs for cancer care primarily reflect that cancer is so complex, encompassing a variety of specialists (in separate silos), surgeries, imaging, and medications. As such, cancer-related costs are substantial, especially in the initial diagnostic period, but there are also continuing costs pertaining to disease recurrence and end-of-life patient care. Although medical oncologists usually serve as the primary provider of care for cancer patients, primary care providers (PCPs)—who are less informed about cancer—are sometimes tapped for this role, at least after the initial treatment period. “The challenge for PCPs to manage that care and ensure high quality and low cost is monumental,” Dr Miller suggested. “We feel the locus of control is best kept in the oncology field, he said.” There are other “pragmatic issues,” he added. For example, oncologists may be unwilling to participate in an ACO led by a small hospital or primary care group. “The truth is, oncologists are unlikely to participate in an ACO voluntarily if it is led by a primary care group or small hospital,” Dr Miller said. “And if oncologists are not participating, there will be a huge cost center left outside of the scope of this policy lever. It will be hard to achieve savings goals without the involvement of cancer care.” Questions for Oncologists “There is no question that ACOs hold some promise, and we should all be considering how this and other policy reforms could be used to improve patient care,” Dr Miller said. However, he said, there are practical issues to be resolved: • Can oncology specialists form their own ACOs? • Will oncologists and cancer hospitals function as “free agents” that compete for referrals based on cost and quality? • How can quality of cancer care best be measured within an ACO? • Should oncologists be able to “lead within their ACOs,” will this translate into cost-savings? Dr Miller said that “it feels good, but whether it achieves cost-savings is unknown.” ■

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ONCOLOGY PHARMACY

Dose-Monitoring, Split-Fill Programs Reduce Oral Chemotherapy Waste, Save Costs By Caroline Helwick

ose-monitoring programs for oral chemotherapy drugs can reduce wastage and reduce the risk of serious adverse effects associated with these drugs. This translates into cost-savings for patients and for payers of >$2500 per patient, suggested researchers from Walgreens Specialty Pharmacy. The company developed an oral chemotherapy cycle management program (CMP) that offers a “split-fill” option and close monitoring of patients for adverse events. This is an optional program, and payers can elect to participate. The analysis of these programs was simultaneously published in the Journal of Oncology Practice (Khandelwal N, et al. J Oncol Pract. 2011;7:e255-e295) and The American Journal of Managed Care (2011;17[5 Spec No]:e169-e173). “Due to high drop-off rates for patients on oral chemotherapy drugs, there is a significant likelihood of medication wastage. The split-fill program has the potential to reduce wastage in members who discontinue mid-cycle. Our analysis showed that of those patients that discontinued therapy, 34% would have experienced reduced wastage had they been on a split-fill medication plan,” said lead author Nikhil Khandelwal, PhD, BPharm, of Walgreens. Nearly 20% of patients using chemotherapy are prescribed an oral oncolytic, and approximately 25% of antineoplastic agents in development are being studied as oral formulations. Although patients indicate that they prefer an oral rather than an intravenous chemotherapy, drug self-administration results in the transfer of responsibility to the patient for identifying, monitoring, and managing toxicity. This is important, because risks associated with oral drugs are insignificant. More than 90% of patients using sorafenib (Nexavar) or sunitinib (Sutent) experience adverse events; of these, as many as 33% are grade 3 to 4 (based on the 2010 package inserts for these 2 drugs). In addition to risks to the patient’s clinical outcomes, there is also the potential for a patient’s treatment discontinuation without the providers’ knowledge. Walgreens Chemotherapy Cycle Management Program In 2008, Walgreens initiated pharmacist- and nurse-facilitated clinical management and support to patients who

were receiving sorafenib, sunitinib, or erlotinib (Tarceva) as part of their oral chemotherapy management. Through the CMP, patients receive intensive education, close supervision, and counseling at predetermined intervals. To minimize medication waste, pharmacists can dispense partialmonth supplies of oral chemotherapy (split-fill), followed by the balance of the monthly supply if the patient demonstrates adherence and tolerability. The objectives of the CMP are to address factors that lead to patient nonadherence; to minimize drug wastage; to improve quality of care; and to maximize satisfaction of the patient, payer, and provider, Dr Khandelwal said. “The split-fill program reduces wastage when therapy is discontinued during the first half of the month, since the remainder of the monthly supply is withheld,” he explained. In a retrospective test-control study, Dr Khandelwal and colleagues evaluated medication wastage and potential cost-savings for 1069 patients enrolled in the CMP (June 2008-February 2010) and for 351 patients not enrolled (June 2007-May 2008). Information came from prescription claims and survey assessment data.

at a glance ➤ Dose-monitoring programs for oral chemotherapy drugs can reduce wastage and the risk of associated serious adverse effects, which translates into cost-savings of >$2500 per patient ➤ The Walgreens Specialty Pharmacy initiated an oral chemotherapy cycle management program consisting of “split-fill” and close monitoring of patients for adverse events ➤ To minimize medication waste, pharmacists can dispense partial-month supplies of oral chemotherapy, followed by the balance of the monthly supply if the patient demonstrates adherence and tolerability ➤ The estimated total potential savings using split-fill dosing versus a full-month supply for patients was $2765 per patient

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“Due to high drop-off rates for patients on oral chemotherapy drugs, there is a significant likelihood of medication wastage….The combined savings from reduced wastage and fewer hospital admissions was $1374 per patient.” —Nikhil Khandelwal, PhD, BPharm

Eliminating Wastage for 33% of Patients Participation in the CMP resulted in significantly lower wastage of medications because of early treatment discontinuation. In the first month of treatment, 261 patients discontinued treatment and 20 (7.7%) could have saved at least half of 1 cycle (14 days) had the payer used the split-fill program. Over the entire study period, 278 (33.8%) of 823 patients could have prevented wasting oral medications through use of the split-fill program, the study found. On the basis of the prevailing average wholesale price of the drug at the time of dispensing, the estimated total potential savings using split-fill dosing versus a full-month supply for the pro-

gram’s patients was $768,850 ($2765 per patient). In addition, approximately 34% of patients in the CMP group could have potentially avoided medication wastage if split-fill plans had been available to them, which could have amounted to another realized savings of $934.20 per patient. The reasons for drug wastage among patients who discontinued treatment early were: • Death—21.9% • Physician decision—10.1% • Ineffective therapy—9.7% • Medication switch—9.0% • Adverse events—7.2%. The majority of discontinuations, however, were recorded as “reason unknown” or “other.” The researchers also analyzed hospital admissions resulting from adverse events, showing that the CMP group had a 2.9% probability for fewer hospital admissions (P <.05), resulting in additional savings of approximately $440 per patient. “The combined savings from reduced wastage and fewer hospital admissions was $1374 per patient,” Dr Khandelwal reported. “Our study suggests there is a potential for health plans and other payers to improve quality and achieve significant cost-savings by participating in programs that actively manage oral chemotherapy patients through monitoring programs such as the CMP,” he said. ■

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November 19 Tampa, FL

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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

VBCC_Aug_11_2_Follow ASCO Tabloid 8/11/11 9:31 AM Page 30

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_Aug_11_2_Follow ASCO Tabloid 8/11/11 9:32 AM 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_Aug_11_2_Follow ASCO Tabloid 8/12/11 1:08 PM Page 32

ELECTRONIC HEALTH RECORDS

Impact of EHRs on Oncology Practice: Enhancing the Value of Cancer Care By Gena Cook, Chief Executive Officer and Cofounder of Navigating Cancer

idespread adoption of information technology (IT) is now regarded as a pathway to improving healthcare and achieving the highly regarded goals for redesigning care. Achieving these goals will require new approaches to health system design, including continuous improvement of relationships between physicians and patients and tools that help providers have the right information at their fingertips to provide the best care to patients and tools for patients to actively participate in their own care. The Health Information Technology for Economic and Clinical Health (HITECH) Act provides new incentives for providers to digitize their practice. The act peaks in 2012 and starts to penalize providers starting in 2015 and beyond, if they have not met the various stages of meaningful use objectives. To qualify for the incentives, providers must incorporate certified electronic health record (EHR) technology into their practices. Where Are We Today? As a result of the HITECH incentives, most providers are initiating plans to qualify for the stimulus payments, but few are ready. It is estimated that of the 12,000 US oncologists, only approximately 25% (an estimate based on oncology-specific EHR vendor-reported install base divided by the number of US oncologists) have either implemented or signed up for an EHR. But only the oncologists who are on a web-based platform are on a HITECH-certified version today. Client server applications, which are the leading oncology-specific EHRs implemented in the marketplace today, are starting to schedule their first upgrades this summer. It will take time to upgrade their entire customer base, and providers cannot certify for HITECH incentives until they have upgraded to the certified version of their HER system. In April 2011, some oncologists received their first stimulus payments. Because providers will not be penalized for waiting until 2012, many oncology practices plan to certify in 2012 to receive the maximum payments. We are therefore seeing many practices buy and adopt EHRs, plan upgrades to the certified version if necessary, and start implementing patient portals so they can meet the patient objectives.

In the next few years, the focus will be on adopting the right technology, and then working within the practice to meet the meaningful use objectives, which will continue to increase. In 2014, stage 2 criteria will need to be met, and in subsequent years, stage 3 criteria will be announced.

It is estimated that of the 12,000 oncologists, approximately 25% have either implemented or signed up for an EHR. Interoperability between information technologies will be a priority to minimize duplicate entry and work within the practice. As this evolves, the ability to implement new IT products and features to reduce duplication of efforts will become necessary to continue to improve the cancer care paradigm. Sharing Best Practices Throughout this process, providers still need to do their complex day job, which involves taking care of patients in a broken and inefficient healthcare system. To implement these changes

at a glance ➤ The HITECH Act, which provides new incentives for providers to digitize their practice, peaks in 2012 and begins to take effect in 2015 ➤ Providers, including oncologists, will be required to give patients access to their health information, allowing them to participate in their own care and providing instructions to facilitate better communication between appointments ➤ Enacting EHRs will allow practices to minimize waste and duplication and provide transparency to patients and other providers involved in these patients’ care ➤ Oncology practices must be encouraged to share best practices, and steadily improve leveraging information systems

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effectively will require commitment and participation from every staff member, because many jobs will be adjusted with the use of IT. Provider groups, state societies, and other support organizations should support providers in the effort to share best practices and work with the IT vendors to make changes that are not only necessary to meet meaningful use objectives but also to help practices do their jobs with as few keystrokes as possible. Self-Management Tools Patients today have little to no access to their healthcare data and to the information needed to participate in their care. Although 86% of patients go online to look for healthcare information,1 they still have difficulty finding the information that is pertinent to their specific condition, which is especially problematic for patients with cancer. With HITECH, patients have the most to gain, because providers will be required to give them access to their health information, information “prescriptions,” which include personalized disease-specific education and eventually secure messaging and other self-management tools to participate in their own care. The Transformed Healthcare System of Tomorrow With widespread adoption of information systems and interoperability within systems, it is conceivable that the healthcare system can be transformed. Providers and patients can envision a system that can produce better outcomes, higher quality, and lower costs than today. With IT, providers can minimize waste and duplication and provide transparency to patients and to other providers. Today, patients are transported through the healthcare system from appointment to appointment but have very little transparency to the process. Other than showing up at their appointment and adhering to their prescribed medications (which many patients do not do), little is required of a patient. In tomorrow’s system, patients will have the ability to see parts of their healthcare record, understand their laboratory values in a longitudinal way, and receive more information about their health to minimize disease and actively manage it when diag-

With information technology, providers can minimize waste and duplication and provide transparency to both patients and other providers. nosed with cancer or other illnesses. Patients will be able to use technology, and most likely be required to manage the transactions of their care online, such as requesting prescriptions, appointments, and laboratory testing. IT and Personalized Medicine Oncology providers, because of the growing complexity of cancer care in the era of targeted therapies, will have the right data to provide personalized care to each patient. Providers will be able to easily view tests, laboratory results, and care that patients have already received to avoid duplication and make better decisions. Oncologists will have decision support tools to help guide their decisionmaking as cancer becomes more complex and personalized, as well as tracking tools to eventually understand the outcomes of the various options in clinic. Because patients will have access to their own health information, providers will be able to give patients better instructions to manage and facilitate better communication between face-to-face appointments. Providers will be able to log in to their information systems to monitor patient medication adherence and side effects and provide interventions as needed throughout the care process, not just in the 15-minute time slots with patients today. This enhanced communication will help patients understand the meaning of their data and foster better postvisit adherence to medical instructions. IT Efficiencies Medical staff will enjoy the efficiencies of IT as well. Phone calls, fax machines, and clipboards of informaContinued on page 33

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ONCOLOGY REIMBURSEMENT

Post-ASCO Survey: Oncologists’ and Payers’ Treatment and Coverage Decisions By Caroline Helwick

n analysis of payer and provider responses to key clinical information presented at the ASCO 2011 annual meeting offers a glimpse of the oncology landscape shared by oncologists and health plans. The research was conducted by Xcenda (AmerisourceBergen Consulting Services), a specialty pharmaceutical research and consulting firm. The full study, led by Loreen M. Brown, MSW, Vice President of Xcenda’s Access and Reimbursement Consultancy, was published online in the Oncology Business Review (www. oncbiz.com; July 2011). “We wanted to draw connections between the new data presented at ASCO and the payer–provider responses,” said Ms Brown, “to determine if payers and providers in the oncology space are congruent or divergent in their thinking. ASCO is a great time to see what oncologists are planning to do with new data and to see if payers are paying attention.”

Ms Brown and her team conducted an online survey of oncologists and health plan decision makers. The survey included questions about the awareness of clinical trials and the changing attitudes and behaviors of oncologists, as well as views regarding incipient changes to coverage and treatment policies. “By offering real-world insight into what is important to 2 key stakeholders, our research provides an overview of how emerging oncology data influence treatment and coverage decisions, especially in the present context of skyrocketing healthcare costs,” Ms Brown told Value-Based Cancer Care. Which Novel Agents Captured Attention? Oncologists reported high awareness of clinical trial data for a number of established biologics and several novel agents in late-stage development. Not surprising, considering the amount of publicity of recent findings, ipilimumab

Impact of EHRs on Oncology... Continued from page 32 tion will become obsolete, because online tools will make the process more effective for all. We are seeing those changes in the airline industry today, where we check in online within 24 hours of a flight or through a kiosk at the airport. Today, we are already starting to see this applied to medical practices in small ways as practices and clinics implement kiosks and patient portals and create interoperability between their current and new information systems. Where Do We Go from Here? A lot will be required to get to the desired state. This transformation will take time, and we are at a critical juncture within the healthcare system and in cancer care. Healthcare is now on the national agenda, and HITECH provides incentives for providers to digitize their practices before beginning to penalize those not compliant by 2015 and beyond. Providers not meeting the objectives by then will see decreases in their Medicare fee schedule. Accountable care organizations and medical homes will require digitization to meet the requirements and establish new relationships with patients, with unique

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implications for cancer care. New payment models in oncology are being piloted today, including technology systems, with hopes of establishing new models that better align the healthcare system to improve the quality and increased cost-effectiveness of cancer care. IT is a component of all these changes, and the time is now for oncologists to become vigilant about improving efficiencies and reducing the waste that exists with inefficient processes and systems. These investments have steadily been made over the past 10 years by thousands of oncologists, but interoperability between systems and broken processes still continue to cause more administrative burden than necessary. Oncology practices need to continue on this path, sharing best practices with each other, and steadily improve leveraging information systems whenever possible to provide the highestquality cancer care for their patients. ■ Reference 1. Fox S. Looking for health information is the third most popular online activity measured in our surveys. Health Topics. PewInternet. February 1, 2011. www.pewinternet.org/Reports/2011/HealthTopics/S ummary-of-Findings/Looking-for-health-information.aspx. Accessed August 1, 2011.

“Over the next year…new disease states may be added to predetermined treatment contracts. More than 20% of providers are considering the addition of melanoma, and payers are considering the addition of multiple myeloma, chronic myeloid leukemia, and melanoma guidelines to this type of contracting arrangement.” —Loreen M. Brown, MSW

garnered the most notice (88%). Also receiving high attention were new data on bevacizumab (82%), erlotinib (75%), abiraterone acetate (75%), panitumumab (72%), and cetuximab (68%). Of note, despite the poly(ADPribose) polymerase inhibitor’s high profile and the anxiously awaited phase 3 data, iniparib was acknowledged by only 62% of providers. And only 55% of responders had heard the vemurafenib data for melanoma, which were presented in the plenary session along with the ipilimumab study. More oncologists were unaware than aware of findings related to the investigational drugs ponatinib, ruxolitinib, tivantinib, and MetMab. Increasing Use of Diagnostic Testing Not surprising, given the wealth of data supporting targeted use of many biologics, tissue-based molecular diagnostic testing for genetic factors such as epidermal growth factor receptor expression and KRAS mutations is going to increase. More testing to guide treatment decisions is expected for lung cancer, melanoma, and colorectal cancer. Two thirds (67.5%) of oncologists intend to increase their present use of diagnostic testing based on what they heard at ASCO. Another 30% predict their use will remain stable, and only 2.5% said they expected to use less diagnostic testing. Eighty percent of oncologists and payer survey respondents plan on targeting surveillance testing or imaging to situations in which benefit has been shown. “Anecdotally, from our con-

versations, we know that physicians and payers are all for diagnostic testing, which could lead to cost-savings by treating the right patient with the right drug at the right time,” Ms Brown said. “But the issue at this time is that the validity of the testing remains undetermined. Some tests, such as for HER2 expression, work beautifully, whereas others are still being evaluated. Payers and providers are on the same track—as long as the tests are reliable.” Actionable Reimbursement Strategies Although treatment guidelines aim at optimizing patient care while keeping it cost-effective, approximately 66% of oncologists do not always adhere to guidelines in their plans or practices as a means for reimbursement. Lung, breast, and colorectal cancers are the tumors for which guidelines are most likely to be adhered to and for which reimbursements are most likely to be based. “Over the next year, however, based on data presented at ASCO, new disease states may be added to predetermined treatment contracts. More than 20% of providers are considering the addition of melanoma,” she noted, “and payers are considering the addition of multiple myeloma, chronic myeloid leukemia, and melanoma guidelines to this type of contracting arrangement.” Another reimbursement issue is the policy discrepancy between infused and oral oncolytics. Here, the survey revealed that many payers are unaware of cost issues related to oral drugs. “There is a striking distinction,” Ms Brown said. Only 50% of payers seem aware of the differences between these types of agents (eg, the higher copays for patients). Aligning Interests Regarding Costs A recent article in the New England Journal of Medicine (Smith TJ, et al. N Engl J Med. 2011;364:2060-2065) suggested that oncologists can help reduce the cost of cancer care through specific behaviors and actions. This included reducing surveillance testing or imaging, using sequential monotherapy instead of combination therapy, limiting chemotherapy to patients with good performance status, replacing the routine use of growth factors with chemotherapy dose reductions in Continued on page 34

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ONCOLOGY REIMBURSEMENT Figure 1 Payers’ Views on the Role of Oncologists’ Behavior on Healthcare Costs

Figure 3 Payers’ Views on Patient Management Issues Based on Emerging Evidence

Oncologists need to recognize that the costs of care are driven by what we do and what we do not do

Target surveillance testing or imaging to situations in which a benefit has been shown

Both doctors and patients need to have more realistic expectations

Limit second-line and third-line treatment for metastatic cancer to sequential monotherapies for most solid tumors Disagree Neutral Agree

Realign compensation to value cognitive services, rather than chemotherapy, more highly

Limit chemotherapy to patients with good performance status, with an exception for highly responsive disease Replace the routine use of white cell– stimulating factors with a reduction in the chemotherapy dose in metastatic solid cancers

Better integrate palliative care into usual oncology care (concurrent care)

For patients not responding to 3 consecutive regimens, limit further chemotherapy to clinical trials

The need for cost-effectiveness analysis and for some limits on care must be accepted

100

Oncologists need to recognize that the costs of care are driven by what we do and what we do not do

Target surveillance testing or imaging to situations in which a benefit has been shown

Both doctors and patients need to have more realistic expectations

Limit second-line and third-line treatment for metastatic cancer to sequential monotherapies for most solid tumors

Disagree Neutral Agree

Realign compensation to value cognitive services, rather than chemotherapy, more highly

80 100

Unaware Neutral Agree

Limit chemotherapy to patients with good performance status, with an exception for highly responsive disease

For patients not responding to 3 consecutive regimens, limit further chemotherapy to clinical trials

The need for cost-effectiveness analysis and for some limits on care must be accepted

Replace the routine use of white cell– stimulating factors with a reduction in the chemotherapy dose in metastatic solid cancers

Better integrate palliative care into usual oncology care (concurrent care)

Figure 4 Oncologists’ Views on Patient Management Based on Emerging Evidence

Figure 2 Oncologists’ Views of Their Role in Controlling Costs

metastatic solid tumors, enrolling patients on clinical trials when chance of success is minimal, and integrating palliative care. “The New England Journal of Medicine authors also wanted oncologists to recognize that costs of care are driven by what they do and do not do and to have more realistic expectations,” Ms Brown said. Additional suggestions were to realign compensation for cognitive services to utilize cost-effectiveness analysis and to accept greater limits on care. The survey included questions about the New England Journal of Medicine article’s suggestions for cost containment. The responses showed that providers and payers generally agreed that certain evidence-based behaviors and attitudes on the part of oncologists would lower overall costs to the healthcare system (Figures 1 and 2). For example, almost all of both stakeholder groups believe that palliative care should be integrated into oncology treatment.

Unaware Neutral Agree

100

However, “there were nuances to the different payer perspectives,” according to Ms Brown. For example, >50% of the payers argued that the routine use of growth factors could be replaced by reductions in chemotherapy dose in patients with metastatic solid tumors. Only 30% of providers, however, were accepting of this strategy. Also, oncologists desired reimbursement of cognitive services, which shows “a disconnect” between “what providers seek and what payers compensate,” she said. “Time spent talking to patients about the treatment plan, side effects, end-of-life care, and so forth is time that the oncologist is not paid for.” Oncologists are also less agreeable than providers to reducing chemotherapy among patients who do not respond to 3 consecutive regimens (Figures 3 and 4). “The responses indicate that payers work more keenly toward constraining cancer costs,” Ms Brown said.

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at a glance ➤ Oncologists reported high awareness of clinical trial data for a number of established biologics and several novel agents in late-stage development ➤ More testing to guide treatment decisions is expected within lung cancer, melanoma, and colorectal cancers ➤ 67.5% of oncologists intend to increase their present use of diagnostic testing based on what they heard at ASCO and 30% predict their use will remain stable ➤ To align payers’ interest in cost containment with oncologists’ perceptions of quality care, increased collaboration and improved communication within the payer–provider relationship are required

80 100

However, 85% of providers and payers strongly agree that physicians’ and patients’ expectations must be reset to be more realistic. To align payers’ interest in cost containment with oncologists’ perceptions of quality care, increased collaboration and improved communication within the payer–provider relationship are required. How might this be done? “Payers and providers first need to understand that they are on the same side,” Ms Brown said. “Until recently, there has been an ‘us versus them’ mentality. The contract negotiations were mostly about how much physicians were paid for the drugs they used. Moving into the new healthcare reform world, with episode payments, bundling, and payment for quality, there is a broader picture of reimbursement. It is not just about individual services. And both groups are amenable to that. The question is how to come up with a system of reimbursement that is episodic and that meets the needs of both parties.” ■

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IN THE LITERATURE Intensified BEACOPP... Continued from page 19

In addition, initial therapy with BEACOPP, compared with ABVD, led to approximately 2 to 3 times higher rates of severe acute adverse events and death from toxic effects. These results, the investigators suggest, indicate the importance of selecting an initial chemotherapeutic regimen not strictly according to its cure rate but also in consideration of its toxic effect profile and of the performance of the secondary treatment. The author of an accompanying editorial points out that since the 1990s, treatment strategies involving far less intensive primary therapies have achieved very high cure rates, while avoiding the risk of infertility or secondary leukemia. Almost all cases of limited-stage Hodgkin lymphoma today, for example, can be cured with only 2 cycles of minimally toxic ABVD followed by involved-field, moderatedose radiation therapy.

insertional fusion that created a classic PML-RARA bcr3 variant, thereby confirming APL. The patient was then administered consolidation therapy with all-trans retinoic acid and remains in first remission 15 months after her first presentation. Although other laboratory methods are available for detecting potential

pathogenic RARA rearrangements, those are labor- and resource-intensive, say the investigators, and demonstrate success rates inadequate for clinical practice. The use of WGS identified the oncogene to facilitate a life-saving change of therapy. For routine use for patients with cancer, diagnostic WGS is cur-

Sav e$

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Save the Date October 13 – 14, 2011 • Chicago, Illinois Palmer House Hilton Hotel

Whole-Genome Sequencing Provides Timely Diagnosis Whole-genome sequencing (WGS) has traditionally been an important tool in nonclinical research. Recently, however, the potential clinical value of the technique was demonstrated in a patient with acute promyelocytic leukemia (APL) that was hard to identify (Welch JS, et al. JAMA. 2011;305: 1577-1584). The patient, a 39-year-old woman with acute myeloid leukemia (AML) in first remission after induction therapy with cytarabine, idarubicin, and etoposide, had been referred to the investigators for consideration of allogeneic stem-cell transplantation. A bone marrow biopsy revealed no morphologic evidence of AML, however, and routine metaphase cytogenetic testing and fluorescence in situ hybridization failed to detect the pathogenic X-RARA fusion gene. Reverse transcription polymerase chain reaction testing also revealed no evidence of PML-RARA, the gene that identifies APL. Because timely diagnosis and treatment are crucial to ensuring an optimal outcome in AML, the investigators’ primary goal was to establish an accurate diagnosis and administer appropriate therapy—either consolidation therapy with chemotherapy or allogeneic stem-cell transplantation, depending on the diagnosis—within a period of 6 to 8 weeks. Within 7 weeks, using massively parallel paired-end sequencing, they had detected and validated a novel

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rently cost-prohibitive ($40,000 for each tumor per normal pair), although its cost has been decreasing rapidly in the past several years. Because the cumulative costs of molecular testing have been increasing, the decreasing cost of WGS may be enough to encourage its use as a diagnostic and risk assessment tool. ■

CancerBusinessSummit.com 2011 Advisory Board Michael J. Anderson, M.D., Commonwealth Hematology-Oncology Ronald Barkley, M.S., J.D., Cancer Center Business Development Group Thomas R. Barr, MBA, Oncology Metrics, a division of Altos Solutions Anthony M. Berson, M.D., Aptium Oncology David C. Beyer, M.D., Arizona Oncology Services Michael L. Blau, J.D., Foley & Lardner LLP Bradford C. Burkett, Epsilon Securities, LLC Stephanie Clayton, University of Texas Southwestern John V. Cox, D.O., American Society of Clinical Oncology Allison Cuff Shimooka, The Advisory Board Company Bruce Cutter, M.D., MMM, Cutter Health Care Consulting Daniel Dosoretz, M.D., 21st Century Oncology Meredith B. Feinberg, North Shore-LIJ Health System Teri U. Guidi, MBA, FAAMA, Oncology Management Consulting Group Karen Hagerty, M.D., American Society of Clinical Oncology Richard J. Hall, Alliance Oncology John E. Hennessy, MBA, CMPE, Kansas City Cancer Center Deborah D. Hood, MBA, Catholic Health Initiatives William Jordan, D.O., The Center for Cancer & Blood Disorders Mark Krasna, M.D., St. Joseph Medical Center / CHI Pete Lawson, Health Management Associates, Inc. Kathleen G. Lokay, D3 Oncology Solutions Barbara L. McAneny, M.D., New Mexico Oncology Hematology Consultants, Ltd. Barbara Miller, Wells Fargo Equipment Finance, Inc. Steve Newman, M.D., Hematology Oncology Associates of Illinois Kent Nicaud, Memorial Hospital at Gulfport Paul O’Dea, Aptium Oncology Inc. Gitesh Patel, Comprehensive Blood & Cancer Center Barry Russo, The Center for Cancer and Blood Disorders Martin Shenk, CMPE, The Medical Oncology Group, P.A. Kelley D. Simpson, Oncology Solutions, LLC Amy Starling, Meridian Health System Elaine L. Towle, CMPE, Oncology Metrics, a division of Altos Solutions Jessica Turgon, ECG Management Consultants, Inc. Strode Weaver, University of Colorado Hospital

Achieving Accountable Cancer Care Introducing two new tracks: Hospital Track and Radiation Oncology Track Keynote: Will ACOs Bundle Off Oncology? Peter Bach, M.D., MAPP, Memorial Sloan-Kettering Cancer Center

Luncheon Keynote: A Washington Perspective on Oncology Payment Reform Karen Ignagni, President and Chief Executive Officer, America’s Health Insurance Plans

Questions – Contact Jodi Brunner at 262-770-9627 jbrunner@meetings-incentives.com

CCBD

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CANCER CENTER BUSINESS DEVELOPMENT

SUMMIT SPONSORS 21st Century Oncology • Accuray Incorporated • Alliance Oncology • AmeriPath, Inc • Aptium Oncology • athenahealth • Cancer CarePoint, Inc. CareCore National • Catholic Health Initiatives • D3 Oncology Solutions • e+ Cancer Care • Epsilon Securities, LLC • Genentech HealthCare Appraisers, Inc. • Integrated Healthcare Strategies • Integrated Oncology Network • IntrinsiQ, LLC • KEW Group, LLC McKesson Specialty Care Solutions/US Oncology • Millennium: The Takeda Oncology Company • Oncology Business Review • Oncology Management Consulting Group Oncology Metrics, a division of Altos Solutions • Oncology Practice Management • Oncology Solutions, LLC • Oncology Supply/ION Solutions • OncoMed Oncure Medical Corp. • PricewaterhouseCoopers, LLP • Proventys, Inc. • The Schwartz Center • Unlimited Systems • US Radiosurgery, LLC • VMG Health • Wells Fargo

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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.

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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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SCREENING FOR CANCER

Screening for Pancreatic Cancer Is Effective, Has Value— at Least in High-Risk Individuals By Caroline Helwick ngoing efforts to screen asymptomatic persons for pancreatic cancer have been unsuccessful, but targeting persons at high risk for the disease appears to be clinically effective as well as cost-effective. Researchers have combined the use of a serum biomarker, CA 19-9, and endoscopic ultrasonography to create a screening protocol for persons at risk for the malignancy on the basis of family history and age and reported their results in the July issue of Gastrointestinal Endoscopy (Zubarik R, et al. Gastrointest Endosc. 2011;74:87-95).

using tumor marker CA 19-9 followed by targeted endoscopic ultrasonography. We also sought to determine whether this protocol was more likely to detect early-stage pancreatic cancer than standard means of detection.” This study enrolled 546 patients aged ≥50 years with at least 1 firstdegree relative with pancreatic cancer. Enrollment was initiated at age 45 if an individual had 2 affected first-degree relatives and at age 40 if the person had a BRCA2 mutation or PeutzJeghers syndrome.

High-Risk Characteristics Serum CA 19-9 has performed poorly in several previous studies, but in those studies participants were often younger than age 50 years (an age associated with low risk for pancreatic cancer) or have been tested with insensitive imaging modalities. “Our hypothesis was that a highrisk population identified by age and at least 1 first-degree relative with pancreatic cancer can be successfully screened,” said lead investigator Richard Zubarik, MD, Associate Professor of Medicine and Chief of Endoscopy, University of Vermont, Burlington. “Our objective was to determine whether early pancreatic neoplasia can be detected in a high-risk population by

“The one patient found to have adenocarcinoma of the pancreas by our screening protocol is still alive, without evidence of recurrence, 3 years after surgical resection, and is the longest survivor of pancreatic cancer detected in a published screening protocol.”

at a glance ➤ Efforts to screen asymptomatic persons for pancreatic cancer have been unsuccessful ➤ Targeting persons at high risk is clinically effective, as well as cost-effective ➤ BRCA2 mutation raises the risk of pancreatic cancer by 3.5- to 10-fold ➤ Peutz-Jeghers syndrome is associated with a 132-fold increased risk ➤ Stage I disease is more likely to be found using endoscopic ultrasonography screening protocol than standard means ➤ The cost of detecting 1 pancreatic neoplasm as part of the protocol is approximately $8430, whereas the cost of identifying 1 pancreatic tumor was $41,133

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—Richard Zubarik, MD The BRCA2 mutation raises the risk of pancreatic cancer by 3.5- to 10-fold, whereas Peutz-Jeghers syndrome is associated with a 132-fold increased risk, according to Marcia Canto, MD, Associate Professor of Medicine and Oncology, Johns Hopkins University School of Medicine, Baltimore, an expert in the field who did not participate in this study. Johns Hopkins Hospital conducts high-risk screening using multiple imaging modalities that include not only endoscopic ultrasonography but also magnetic resonance imaging, magnetic resonance cholangiopancreatographic imaging, and endoscopic retrograde cholangiopancreatography in select cases. Elevated Biomarkers Raised Suspicion In the current study, all patients underwent serum CA 19-9 level testing, and those with an elevated level (>37 U/mL) were referred for endoscopic ultrasonography. For comparison, the study included patients who were diagnosed with pancreatic cancer at the University of Vermont during the same period but were not enrolled in this study.

Serum CA 19-9 was elevated in 27 patients (4.9%). Neoplastic (potentially premalignant or malignant) findings were detected in 5 patients (0.9%); 1 (0.2%) of those lesions was identified as stage I adenocarcinoma of the pancreas. No additional cases of pancreatic cancer were identified at 1-year follow-up. In the comparison group, pancreatic cancer was diagnosed in 124 patients during the study period, and the tumors in 114 of these patients were staged, revealing that: • 1 patient (0.9%) had stage I disease • 52 patients (45.6%) had stage II disease • 20 patients (17.5%) had stage III disease • 41 (36%) had stage IV disease. “The one patient detected in the CA 19-9/endoscopic ultrasonography study had stage I disease, whereas detection of stage I cancer in the comparison group was rare (1 of 114 patients),” according to Dr Zubarik. Among the 122 patients in the comparison group for whom survival data were available, median overall survival was only 7 months, and the 2year survival rate was 10%. “The one patient found to have adenocarcinoma of the pancreas by our screening protocol is still alive, without evidence of recurrence, 3 years after surgical resection, and is the longest survivor of pancreatic cancer detected in a published screening protocol,” Dr Zubarik noted. Cost Implications Potentially curable pancreatic can-

cer can be identified with CA 19-9 testing and targeted endoscopic ultrasonography, and stage I disease is more likely to be found using this screening protocol than through standard means of detection, the investigators maintain. The cost to detect pancreatic neoplasia was determined from Medicare reimbursement data from 2010. The reimbursement for CA 19-9, physician, and facility fees for endoscopic ultrasonography S, and cytopathology were considered, but subsequent therapy after detection of the neoplastic process and secondary costs were not. The cost of detecting 1 pancreatic neoplasm as part of the protocol was approximately $8430, whereas the cost of identifying 1 pancreatic tumor was $41,133. For detecting neoplasia and adenocarcinoma, the respective breakdown of costs was $3249 and $16,276 for the CA 19-9 test; $3028 and $15,748 for the endoscopic ultrasonography facility fee; $993 and $4469 for the endoscopic ultrasonography professional fee; $795 and $3182 for endoscopic ultrasonography/biopsy professional fee; and $364 and $1458 for cytopathology professional fees. This screening approach offers “acceptable rates of disease diagnosis and exclusion as well as acceptable costs,” Dr Zubarik suggested. “Early pancreatic adenocarcinoma, associated with prolonged disease-free survival, can be detected as part of this pancreatic screening protocol.” ■

HBV Screening Recommended with Chemotherapy, but Not Cost-Effective in Solid Tumors

ost professional guidelines now recommend screening for hepatitis B virus (HBV) infection in essentially all patients receiving chemotherapy, but it is seldom performed and is not cost-effective in patients with solid (nonhematologic) tumors, according to studies presented at ASCO 2011. Researchers at the University of Texas M.D. Anderson Cancer Center, Houston, used their database to evaluate the prevalence of HBV infection before chemotherapy and of reactivation of the virus during treatment by comparing patient and treatment characteristics in those with and without HBV reactivation.

Of the 10,729 patients who received chemotherapy, 1787 (17%) patients were screened and 151 (8%) tested positive for HBV surface antigen and/or anti-HBc (core antibody). Reactivation occurred in 73 of these patients and was most common among Asians and patients with hematologic cancer. “Overall, we found low rates of HBV screening prior to chemotherapy, and we found that preventable reactivation of HBV infection is common,” Jessica Hwang, MD, MPH, said. Cost-Effectiveness Analysis A study from Australian investigaContinued on page 40

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SCREENING FOR CANCER

Colonoscopy Overused in Medicare Recipients, Adding Unnecessary Expenditures Negative screening and current recommendations too often ignored By Caroline Helwick

edicare may be paying for more screening colonoscopies than are warranted for the prevention of colorectal cancer (CRC), according to a new study (Goodwin JS, et al. Arch Intern Med. 2011 May 9 [Epub ahead of print]). All relevant authorities recommend an interval of 10 years between normal screening colonoscopies. Although much attention has been given to the underuse of CRC screening, less attention has been paid to possible overuse, according to James S. Goodwin, MD, George and Cynthia Mitchell Distinguished Chair in Geriatric Medicine and Director, Sealy Center on Aging, University of Texas Medical Branch, Galveston. Dr Goodwin led a study that assessed the timing of repeated colonoscopies after a negative screening colonoscopy finding in a population-based sample of Medicare patients. A 5% national sample of Medicare enrollees from 2000 through 2008 was used to identify averagerisk patients undergoing screening colonoscopy between 2001 and 2003. Colonoscopy was classified as a negative screening examination if no additional indications appeared in claims and if no biopsy or related procedure was performed. The time to repeated colonoscopy was calculated. Among 24,071 Medicare patients with a negative screening examination, 46.2% underwent a repeated

“Every authority says that after a normal screening colonoscopy, another examination is not needed for 10 years, but surveys suggest that individual gastroenterologists often disagree. There is a strong opinion that they should be done more frequently. —James S. Goodwin, MD

examination in less than 7 years. In 42.5% of these patients (23.5% of the overall sample), there was no clear indication for the early repeated examination, the study found. “The actual practice of colonoscopy in the community seems quite different from the assumptions made in assessing the cost-effectiveness of CRC

HBV Screening... Continued from page 39 tors suggests universal screening is not cost-effective, at least in patients with solid tumors. According to Fiona L. Day, MD, of Peter MacCallum Cancer Center, Melbourne, approximately 50% of Australian oncologists screen for HBV; only 19% screen every patient. A decision-analytic model was used to compare universal screening versus no screening in hypothetical patient cohorts, one consisting of patients receiving adjuvant chemotherapy for early breast cancer (adjuvant cohort), one of patients receiving palliative chemotherapy for advanced non– small-cell lung cancer (palliative cohort), and one in which results from all patients were pooled. Using an incremental cost-effectiveness ratio (ICER) threshold of $50,000

Australian per life-year (LY) saved, universal HBV screening was not costeffective for patients who received adjuvant chemotherapy (ICER of $88,173/LY, 13% probability of being cost-effective), patients who received palliative chemotherapy (ICER >$1.3 million/LY, 0% probability of being cost-effective), or all pooled patients with solid tumors (ICER of $149,771/ LY, 1% probably of cost-effectiveness). A sensitivity analysis showed that screening approached cost-effectiveness among patients receiving adjuvant chemotherapy who had the highest rate (65%) of undiagnosed chronic HBV infection, for whom the ICER was $51,979/LY, or the highest chance of reactivation with chemotherapy (41%), for whom the ICER was $48,779/LY.—CH ■

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screening by colonoscopy,” maintained Dr Goodwin. He acknowledged, however, that investigators lacked information on the quality of the initial colonoscopy. Early repeated colonoscopies could result from incomplete or poor-quality initial examinations, he said, although the study eliminated subjects with incomplete examinations. “Also, one would expect repeated colonoscopies to follow up on suspicious findings to occur relatively soon after the initial colonoscopy, which is not the temporal pattern we found,” he added. Repeated colonoscopies were also affected by the patient’s age. Among persons aged 75 to 79 years, 45.6% were screened within 7 years, as were 32.9% of individuals aged ≥80 years at the time of the initial negative colonoscopy result. In multivariable analyses, male sex, presence of more comorbidities, performance of colonoscopy by a high-volume colonoscopist, and performance of the test in an office setting were associated with higher rates of early repeated colonoscopy without clear indication. There were also marked geographic variations, from less than 5% in some health referral regions to greater than 40% in others. Looking for the Reasons The investigators concluded that, “A large proportion of Medicare patients who undergo screening colonoscopy do so more frequently than recommended.” Current Medicare regulations intending to limit reimbursement for screening colonoscopy to every 10 years do not appear to be effective. In an interview with Value-Based Cancer Care, Dr Goodwin noted, “Every authority (including the American Gastroenterological Association [AGA], American Cancer Society, US Preventive Services Task Force, and others) says that after a normal screening colonoscopy, another examination is not needed for 10 years, but surveys suggest that individual gastroenterologists often disagree. There is a strong opinion that they should be done more frequently. The gastroenterologists are doing what they feel is the right thing, but no other organization that lacks direct involvement in this situation, including the AGA, agrees.” Could there be a profit motive at work? “The profit motive in American

medicine is like gravity. It’s a force that will always be there,” he responded. “Clearly, when you have the people who are profiting from the procedure being the ones who decide when to do it, there will always be some force toward overuse. Yes, I think the profit motive is partly responsible for the findings.” Medicare regulations preclude reimbursement for screening colonoscopy within 10 years of a negative examination result. However, Medicare denied only 2% of the claims for early repeated colonoscopies without indication in this study. The study showed that an understanding of such cases, where an indication was lacking, is complicated by the “seeming underuse of the screening code” in colonoscopies billed to Medicare. “When we looked at the reasons for these examinations, many were exceptionally nebulous, and there was no evidence in prior billing that these indications existed. For example, if they indicated a ‘change in bowel habits,’ there was often no mention of this in previous billings. We thought this was suggestive of some ‘creative coding,’” he said. Dr Goodwin elaborated that such practice has been ingrained for years. “You have to look historically. By 1990, colonoscopy had been shown to prevent cancer, detect it early, and reduce mortality, but Medicare did not start reimbursing for screening colonoscopy until 2001. So all during the 1990s, physicians used creativity to do what they felt was the right thing—do screening colonoscopy—and to be reimbursed for it from Medicare. “Many, many examinations were done throughout the 1990s, but they were not called ‘screening colonoscopy,’ because these were not reimbursed,” he continued. “I think when Medicare finally started reimbursing, the billing staff continued to use these codes.” Fee-for-Service the Culprit? Dr Goodwin reiterated that early repeated colonoscopies without clear indication veer from national recommendations, compose a substantial proportion of the present endoscopist’s workload, and represent “substantial Medicare expenditures,” he said. “And from my personal experience as a primary care provider, my gut feeling is that this is not something unique to Medicare but could happen under any fee-for-service program.” ■

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METASTATIC MELANOMA

Ipilimumab: A New Era in Metastatic Melanoma Management Timothy G. Tyler, PharmD, FCSHP Dr Tyler is Director of Pharmacy Services, Comprehensive Cancer Center, Desert Regional Medical Center, Palm Springs, California

he development of ipilimumab (Yervoy) and its approval by the US Food and Drug Administration (FDA) in March 2011 have opened a new era in the treatment and management of patients with metastatic melanoma. The continued innovation in cancer drug development has been focused on a different mechanism of action that engages the patient’s own immune system in attacking malignancy in contrast to the more traditional myelosuppressive drugs that have been used in the past half century to kill rapidly dividing cancer cells. The hallmark of successful therapy for melanoma has always been surgical excision. Although curative, this method does not necessarily reduce the likelihood of recurrence. To minimize this potentially lethal risk, interferon therapy has historically been instituted, administered as 1 month of induction therapy followed by 11 months of injections; however, this is an intense regimen for patients, who therefore benefit from a multidisciplinary approach to treatment that can include pharmacy management of symptoms. Even then, the disease can recur and progress. As a result, bioimmunotherapy, a rudimentary type of immunotherapy, was developed in the late 1990s.1 Like interferon therapy, however, bioimmunotherapy is intense and necessitates hospital services, sometimes including the intensive care unit. Despite these efforts, melanoma all too often still claims a large number of lives. Although the cure rate is high for patients whose disease is detected early and surgically resected, the 5-year survival rate is fairly low for those with disease that has metastasized—less than 15% according to the 2010 data from the American Cancer Society.2 In the United States alone, just under 70,000 new cases of melanoma were diagnosed in 2010, and 8700 deaths occurred, mostly from advanced or metastatic disease.3 For some time now, researchers have focused on the development of immune stimulants and vaccines designed to enlist a patient’s immune system to attack cancer cells, culminatReprinted with permission from the Journal of Hematology Oncology Pharmacy. 2011, Vol 1, No 2.

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ing with the March 25, 2011, FDA approval of ipilimumab—the first Tcell–mediated therapy for unresectable or metastatic melaonoma.4 This drug is a monoclonal antibody that binds CTLA-4 (cytotoxic T-lymphocyte antigen 4), thereby blocking its interaction with the ligands CD80/CD86. This appears to result in T-cell overproduction, which in turn stimulates an activated immune response.4 My professional experience with 5 patients provides a unique perspective for those who have not yet treated any patients with this novel medication. My center is a multidisciplinary center involved in a robust clinical trials program that includes active pharmacist participation in symptom management. In one of these trials, 3 of our patients were treated with ipilimumab before the FDA approval of the drug; in addition, 1 patient was in the expanded access program created by Bristol-Myers Squibb (BMS) while awaiting final FDA approval for the drug, and 1 patient had just begun to receive it on April 11, 2011, the day ipilimumab became commercially available. Our experience with these 5 patients shows that the drug indeed has a novel mechanism of action, and it quite simply “revs up” the immune system and then stands back. There have been many previous attempts to develop vaccines and other products to stimulate the immune system in patients with melanoma by killing the melanoma-affected cells, but ipilimumab is the first product to receive FDA approval. Although the activity of ipilimumab is impressive, it is also associated with a wide range of potential toxicities, which can manifest in almost any system in the body, including gastrointestinal, liver, skin, neurologic, and endocrine toxicities that are highlighted in the Risk Evaluation and Mitigation Strategy (REMS) program for this agent. There is currently no way to predict the focus of any of the immune system’s responses. What is predictable is the response to ipilimumab therapy, which is associated with a 34% risk of death.5 Unlike traditional chemotherapy, the goal with ipilimumab is not to deliver as much drug as possible but rather to stimulate the immune system properly—only 4 doses maximum can be

Despite the associated risks involved, this new therapy offers benefits beyond the standard myelosuppressive agents or monoclonal antibody drugs that we have become accustomed to in the past decade and a half, when these therapies proliferated on the oncology scene. given, according to the FDA approval.4 Also noteworthy is the agent’s cost, which has captured much media attention. The price is in the same range as the prostate cancer drug sipuleucel-T (Provenge). Both drugs have a limited number of cycles (3 administrations for sipuleucel-T and 4 for ipilimumab). Ipilimumab will be distributed only through the wholesaler McKesson and the distributor Oncology Supply. Because ipilimumab is approved with a REMS program, BMS has designed a comprehensive plan that employs sales and medical science liaisons in coordinated teams to ensure clinicians are properly educated about the risks and benefits of the drug. The REMS program also includes a medication guide for patients. At its center is a wallet card that a patient carries to alert any potential urgent care and emergency department physicians to the possibility of immune-related toxicity and the resultant need for steroids. The copious and early use of steroids has been found to ameliorate many toxicity-related problems, because the toxic effects in this case are not from myelosuppressive chemotherapy but rather from stimulated T lymphocytes. In addition, BMS has initiated a sur-

veillance and peer-to-peer education program in which medical service liaisons will contact clinicians within a very tight window of a few days after receiving a new order for ipilimumab to provide educational services and follow-up. As the Pharmacy Practice Editor of the Journal of Hematology Oncology Pharmacy, I urge those not experienced with this novel agent to accept any offer of education or assistance regarding its use. Despite the associated risks involved, this new therapy offers benefits beyond the standard myelosuppressive agents or monoclonal antibody drugs that we have become accustomed to in the past decade and a half, when these therapies proliferated on the oncology scene. It is certainly not my wish to deter clinicians from using this drug, but it does involve many occasions for errors, including the aggressive use of corticosteroids as the primary response to almost any toxicity— which is counterintuitive for many clinicians. Getting the appropriate education about the use of this drug is therefore crucial for preventing adverse outcomes and potentially denying other patients the opportunity for this therapeutic option. Although cost has become a major issue, nothing costs as much as a therapy that is not used successfully or safely. The FDA has been criticized for having approved the fewest number of new drugs in decades, but the approval of ipilimumab offers a novel agent with promising therapeutic outcomes in an area of oncology that has had few worthwhile choices. ■ References 1. Elsevier/Gold Standard Clinical Pharmacology website. Aldesleukin FDA approval date for MM. www.clinicalpharmacology-ip.com/Forms/Mono graph/ monograph.aspx?cpnum=12&sec=mondesc. Accessed May 5, 2011. [Accessible through paid subscription.] 2. American Cancer Society. Cancer facts and figures, 2010. www.cancer.org/acs/groups/content/@nho/ documents/document/acspc-024113.pdf. Accessed May 21, 2011. 3. National Cancer Institute. General information about melanoma. www.cancer.gov/cancertopics/ pdq/treatment/melanoma/HealthProfessional/page 1#Reference1.1. Accessed May 19, 2011. 4. US Food and Drug Administration. Ipilimumab. March 25, 2011. www.fda.gov/AboutFDA/Centers Offices/CDER/ucm248478.htm. Accessed May 23, 2011. 5. Bristol-Myers Squibb. Yervoy (ipilimumab) website. Pivotal phase 3 study. Yervoy (ipilimumab) is the first and only approved therapy to demonstrate an overall survival benefit. www.yervoy.com/hcp/phase-3study/efficacy-study-safety.aspx. Accessed June 2, 2011.

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CONTINUING EDUCATION

Cost Implications for Novel Therapies and Strategies in the Treatment of NSCLC: Perspectives and Clinical Updates from ASCO 2011 Program

regiSTered Pharmacy deSignaTion

Initial Release Date: August 19, 2011 • Expiration Date: August 19, 2012. Estimated time to complete activity: 1 hour. SPonSor

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 0468-9999-11-034-H01-P.

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

diScLoSureS

TargeT audience

This activity was developed for physician oncologists and oncology pharmacists. Learning objecTiveS

At the end of this activity, participants will be able to: • Explain the impact of clinical and health economic data presented at the 2011 ASCO meeting on the care of patients with non–small-cell lung cancer (NSCLC) • Describe how value-based cancer care is evolving in the changing US healthcare system • Examine how all stakeholders can implement value-based care in the treatment of NSCLC commerciaL SuPPorT acknowLedgmenT

This activity is supported by an educational grant from Genentech. inSTrucTionS for crediT

There is no fee for this activity. To receive credit, participants must read this CME/CE activity in its entirety and complete the posttest and evaluation. The posttest and evaluation can be completed online at www.mlicme.org/p11054.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. For questions regarding the accreditation of this activity, please contact Medical Learning Institute, Inc., at 609-333-1693 or cgusack@mlicme.org. PhySician crediT deSignaTion

The University of Cincinnati designates this enduring material for a maximum of 1 AMA PRA Category 1 Credit™. The University of Cincinnati is 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 this activity.

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 offlabel discussions. All identified conflicts of interest are thoroughly vetted by University of Cincinnati and 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. The associates of University of Cincinnati, Medical Learning Institute, Inc., and Center of Excellence Media, LLC, do not have any financial relationships or relationships to products or devices with any commercial interest related to the content of this CME/CE activity for any amount during the past 12 months. The planners and managers reported the following financial relationships or relationships to products or devices they or their spouse/life partner have with commercial interests related to the content of this CME/CE activity. Name of Planner or Manager

Company

Reported Financial Relationship

Teresa Haile, RPh, MBA

Reviewer for MLI

Has nothing to disclose

faculty disclousures

Ira Klein, MD, has nothing to disclose. Caroline Helwick, medical writer, has nothing to disclose. She intends to discuss investigational medications for NSCLC. diScLaimer

The information provided in this CME/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.

Cost Implications for Novel Therapies and Strategies in the Treatment of NSCLC: Perspectives and Clinical Updates from ASCO 2011 By Caroline Helwick, Independent Medical Writer

resentations from the 2011 Annual Meeting of the American Society of Clinical Oncology (ASCO) provide an ideal forum for payers grappling with reimbursement issues and benefit design for patients with non–smallcell lung cancer (NSCLC) and for pharmacists who must understand emerging treatments. This article summarizes key clinical studies and expert discussions that describe current trends in the management of this increasingly complex and mutation-driven tumor and their cost implications. The shifting landscape in NSCLC management highlights the

need to align providers’ and payers’ strategies to enhance high-quality, value-based patient care. maintenance Therapy extends Progression-free Survival by a Slim margin Two randomized phase 3 clinical trials showed a progression-free survival (PFS) benefit for maintenance therapy with pemetrexed and gefitinib in patients with advanced NSCLC. The magnitude of the benefit, however, was modest—a gain of just 1.3 to 2.2 months in remission time, with no gain in overall survival (OS). These studies fail to answer an

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important question: is maintenance therapy superior to second-line treatment initiated once the disease progresses? The maintenance strategy is based on 2 observations: limited benefit from 4 courses of chemotherapy and improved outcomes with second-line chemotherapy after disease progression. Maintenance therapy can involve continued treatment with the same drug, as with pemetrexed in the PARAMOUNT trial,1 or “switch” maintenance, as in the INFORM study, which initiated gefitinib after platinum-based induction.2 The PARAMOUNT trial enrolled 939

patients with advanced nonsquamous NSCLC after they received 4 standard courses of treatment with pemetrexed and cisplatin.1 Of these, 539 patients achieved stable disease and were randomly assigned to maintenance therapy with pemetrexed or to placebo (and best supportive care). Maintenance pemetrexed resulted in a 38% reduction in the risk of disease progression.1 Median PFS in this group was 4.1 months versus 2.8 months for patients receiving placebo (P = .006), and disease control (ie, response plus stable disease) was attained in 71.8% and 59.6%, respectively, but maintenance Continued on page 43

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Figure 1 Use of Erlotinib versus Platinum-Based Chemotherapy in EGFRmut NSCLC Overall use in patients (calculated), %

therapy did not confer a quality-of-life benefit.1 New findings from the PARAMOUNT trial “suggest that patients can still continue to benefit from the use of the same drug rather than ‘use up’ an alternative early in the course of treatment,” said lead investigator Luis Paz-Ares, MD, PhD, Seville University Hospital, Spain. “We believe the magnitude of benefit is clinically significant and may support the use of pemetrexed as maintenance therapy. This could change the standard of care for these patients, at least in terms of maintenance.” Similarly, in the phase 3 clinical study INFORM, maintenance therapy with gefitinib (after 4 cycles of platinum-based chemotherapy) was associated with significantly superior PFS compared with placebo among 296 Chinese patients, but no difference in OS was observed.2 At a median follow-up of 16.8 months, median PFS was 4.8 months with gefitinib maintenance versus 2.6 months with placebo (P <.001), representing a 58% reduction in the risk of disease progression. Approximately one third of patients carried mutations of the epidermal growth factor receptor (EGFR), and they derived the best outcomes from gefitinib.2 Despite both studies meeting their primary end points, study discussant Martin J. Edelman, MD, of the University of Maryland Greenbaum Cancer Center, Baltimore, commented that “maintenance therapy in NSCLC is an ever-contentious issue,” suggesting that “these studies raise more questions than answers.” He pointed out that PFS “does not necessarily predict overall survival,” and that when differences in PFS are small, quality-of-life (QOL) analyses can help define benefit. “But the quality-of-life data from maintenance studies is actually somewhat disappointing.…No differences have been demonstrated, which indicates that maintenance is not necessarily costfree in terms of toxicity,” said Dr Edelman. The PARAMOUNT study demonstrated no improvement in QOL for maintenance therapy with pemetrexed.1 Along with increased toxicity with continued treatment, the cost of treatment also becomes a factor. “We really need a cost-effective analysis in this era of follow-up strategies, of frequent visits and of scanning, with [a study of] early institution of secondline therapy, versus the maintenance approach,” he said. What has been learned from PARAMOUNT, said Dr Edelman, is that “the drugs work in patients who

Outside the US

50 40 30 20 10 0 Erlotinib: current

Chemo: current

Erlotinib: future

Chemo: future

EGFRmut indicates epithelial growth factor receptor mutation; Chemo, chemotherapy; NSCLC, non– small-cell lung cancer. Source: MDoutlook, powered by The Arcas Group, LLC. Used with permission.

derive benefit from first-line chemotherapy. To date, there is no evidence that early introduction of therapy will improve survival compared with introducing second-line therapy at disease progression.” First-Line Erlotinib Superior to Chemotherapy Erlotinib, given as first-line treatment to patients with advanced NSCLC and EGFR mutations, substantially prolonged remissions in the phase 3 clinical trial EURTAC (European Randomized Trial of Tarceva vs Chemotherapy).3 “EGFR tyrosine kinase–activating mutations are present in 10% to 26% of NSCLC tumors and are associated with increased response to erlotinib and gefitinib. But little is known about the efficacy and safety profile of erlotinib compared with chemotherapy in EGFR-mutant Caucasian patients,” said Rafeal Rosell, MD, of the Catalan Institute of Oncology, Barcelona, Spain, who presented the findings.3 The interim updated analysis of 173 patients in the EURTAC trial showed significant efficacy for single-agent erlotinib over a standard platinumbased doublet in the up-front setting. Erlotinib reduced the risk for disease progression or death by 63%, nearly doubling the median PFS, which was 9.7 months versus 5.2 months with chemotherapy (P <.001). Objective response rates were 58% with erlotinib and 15% with chemotherapy.3 The death rate was also reduced by 20%, but this finding was not significant (P = .417),3 presumably because of high crossover from chemotherapy to an EGFR inhibitor, and because the OS data are not mature. Erlotinib was bet-

ter tolerated than chemotherapy, Dr Rosell reported. New Class of Agents May Change Treatment for 5% of Patients with NSCLC The novel agent crizotinib, which targets the EML4-ALK mutation that is found in about 5% of patients with NSCLC, is positioned to become an integral part of treatment for this NSCLC subgroup. The oral agent crizotinib is first in a class known as anaplastic lymphoma kinase (ALK) inhibitors; it targets tumors harboring rearrangements of the ALK gene, which is involved in growth and survival of lung tumors. Ross Camidge, MD, PhD, of the University of Colorado, Denver, remarked in an interview, “Knowing that ALK-positive patients respond to crizotinib—you can take this to the bank.” He said that the data show a “consistency of message” and form the basis for confirmatory registration studies that will compare crizotinib with chemotherapy. These will “nail down where the drug fits in the treatment paradigm for what is essentially a new disease—ALK-positive lung cancer,” he said. Crizotinib nearly doubled OS among ALK-positive patients with NSCLC in an update of a phase 1 study reported at ASCO 2011 by Alice T. Shaw, MD, PhD, of Massachusetts General Hospital, Boston.4 The study involved 82 heavily pretreated patients with the ALK fusion gene who received crizotinib after tumor progression. The objective response rate was 57%, the disease control rate was 87%, and more than 90% of the tumors regressed in the ALK-positive group

who received crizotinib. The survival rate was 74% at 1 year and 54% at 2 years. Median OS has not yet been reached, because more than half of the 82 subjects are still alive. Side effects with crizotinib were generally mild and transient, although unusual visual effects were common.4 By comparison, the OS rate among ALK-positive control patients receiving standard chemotherapy was 44% at 1 year and 12% at 2 years; median OS was 6 months. The median OS was similar for ALK-positive patients who received chemotherapy and for patients lacking the ALK rearrangement, Dr Shaw reported.4 In a separate presentation, Dr Camidge reported on a combined analysis of these 82 patients plus the first 19 ALK-positive patients who received crizotinib.5 After a median follow-up of 11 months, median PFS was 10 months and OS has not been reached; 79% of the patients remain alive, yielding a survival probability of 90% at 6 months and 81% at 1 year, Dr Camidge said.5 Accelerated approval for crizotinib in ALK-positive NSCLC has been sought from the US Food and Drug Administration in conjunction with the ongoing confirmatory phase 3 program.

Crizotinib nearly doubled OS among ALK-positive patients with NSCLC in a phase 1 study reported at ASCO 2011.

Mutation Testing Poised for Routine Use Based on the results of mutational testing through the new Lung Cancer Mutation Consortium, Ramaswamy Govindan, MD, Washington University, St. Louis, said EGFR testing is ready to be clinically applied in lung cancer and that EML4-ALK (the target of crizotinib) fusion testing is not too far behind. Dr Govindan was the invited discussant of a presentation by Mark G. Kris, MD, of Memorial Sloan-Kettering Cancer Center, New York. The Consortium evaluated 1234 patients with stage IV adenocarcinoma for 10 known mutations using standard multiplexed assays and fluorescence in situ hybridization.6 Driver mutations were identified in 54% of adenocarcinomas—most often KRAS (22%), EGFR (17%), and EML4ALK rearrangement (7%). Less comContinued on page 44

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Cost Implications for Novel Therapies and Strategies...

Oncologists Plan to Use More Targeted Agents Oncologists who treat NSCLC plan to rely more on erlotinib therapy and less on platinum-based chemotherapy in advanced disease, according to results of a survey conducted immediately after ASCO 2011—the MDOutlook ASCO 2011 Quick Poll— facilitated by the Arcas Group.7 The survey showed that approximately 50% of patients with mutations of EGFR now receive erlotinib, and about 45% receive chemotherapy. However, survey respondents anticipated prescribing erlotinib for 65% of their patients in the next year and reducing the use of platinum-based chemotherapy by 15% (Figure 1).7 The oncologists also indicated high interest in crizotinib therapy for patients with the EML4-ALK gene rearrangement. More than 55% of the respondents predicted that they would “always” prescribe crizotinib to this mutation subgroup and 25% said they would “often” prescribe the new drug (Figure 2).7 The respondents also expected to start integrating c-Met inhibitors, especially in the setting of NSCLC resistant to EGFR inhibitors. Novel Agents Show Encouraging Activity New EGFR Inhibitor Comparable with Gefitinib Icotinib, an EGFR inhibitor manufactured in China, was found to be as active and effective as gefitinib in patients with advanced NSCLC and EGFR mutations who had received previous treatment.8 In the noninferiority randomized ICOGEN trial of 395 patients, icotinib was comparable to gefitinib in PFS, OS, and QOL, but it was better tolerated than gefitinib8. The median PFS was 137 days for icotinib versus 102 days for gefitinib, and median OS was 419 days and 467

Figure 2 Frequency of Crizotinib Use in the Treatment of ALK-Positive NSCLC 60 US

Physicians responding, %

mon were alterations in BRAF, PIK3CA, HER2, Met amplification, MEK1, NRAS, and AKT1.6 “While an individual mutation may be rare, having a mutation of some kind that is actionable is very common in adenocarcinoma,” Dr Kris said. Mutation identification allowed EGFRpositive patients to be selected for erlotinib and patients with other mutations to be referred to clinical trials of other targeted agents. The collaborative effort represents the revolutionary changes taking place in the management of lung cancer and the potential for personalized treatment, Dr Kris added.

50 Outside the US

40 30 20 10 0 Always

Often

Sometimes

Rarely

Never

NSCLC indicates non–small-cell lung cancer. Source: MDoutlook, powered by The Arcas Group, LLC. Used with permission.

days, respectively. As expected, patients with EGFR mutations had preferential benefit over those with wild-type EGFR, with responses observed in more than 50% of this group compared with 5% of patients without the mutation.8 Also showing promise was the Met inhibitor MetMAb (an antibody to c-Met) combined with erlotinib in a study of 137 previously treated patients.9 Met gene expression is associated with a worse NSCLC prognosis. Among patients with the Met mutation, the combination (compared with erlotinib alone) extended median PFS to 2.9 months compared with 1.5 months with erlotinib alone (P = .04), and extended median OS to 12.6 months versus 3.8 months (P = .002). A phase 3 trial of this combination will begin later in 2011.9 Second-Generation Hsp90 Inhibitors in the Pipeline Geoffrey Shapiro, MD, PhD, of Dana Farber Cancer Institute, Boston, reported encouraging results for the heat shock protein 90 (Hsp90) inhibitor ganetespib from an openlabel phase 2 trial of 96 patients who received previous treatment for advanced NSCLC. The median PFS was 24.1% by week 16.10 Ganetespib provides potent Hsp90 inhibition and better safety than firstgeneration compounds. The dose-limiting hepatic and ocular toxicity, which has complicated the development of other Hsp90 inhibitors, is absent. “Ganetespib showed promising clinical activity as a single agent, especially in tumors harboring the ALK rearrangement,” Dr Shapiro noted.

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Surash S. Ramalingam, MD, of Emory University, Atlanta, commented on the Hsp90 inhibitor pipeline. Despite a strong biologic rationale for these drugs, he said, there have been many hurdles in drug development, primarily involving formulation issues, dose-limiting hepatic toxicity, and less than robust efficacy. The second-generation compounds, including ganetespib, are structurally different and more potent than the first-generation agents and have a favorable safety profile that facilitates their use in combination. “Therefore, there is a resurgence of interest in these compounds,” Dr Ramalingam said. More than a dozen are in various stages of development, of which the most active in solid tumors are ganetespib, retaspimycin, and AUY-922.

Ganetespib provides potent Hsp90 inhibition and better safety than first-generation compounds.

Ganetespib and retaspimycin have produced “robust anticancer effects,” with tumor regression or disease stabilization seen in almost all ALK-positive patients, Dr Ramalingam noted. “Hsp90 inhibitors have entered the therapeutic algorithm for ALK-positive disease,” he concluded. “In the historically disappointing development of Hsp90 inhibitors, it is my belief that we have reached an important and exciting turning point.”

Continued from page 43

Chemoimmunotherapy with Toll-Like Receptors The toll-like receptor (TLR)-2 agonist mycobacterium w (Cadi-05) looked promising in a study presented by Chandra Belani, MD, of Penn State Hershey Cancer Institute, Hershey, PA. Mycobacterium w works best when combined with paclitaxel and cisplatin as chemoimmunotherapy; this regimen was evaluated in 121 patients.11 Chemoimmunotherapy led to higher response rates and disease control rates than chemotherapy alone. The median PFS was 199 days with the combination versus 97 days with chemotherapy alone, representing a 31% risk reduction (P = .052). Although OS was similar at 208 days versus 196 days, respectively, a survival benefit was observed among the subset of patients with squamous-cell carcinoma: median OS was 229 days with chemoimmunotherapy versus 172 days with chemotherapy, representing a 46% risk reduction (P = .031).11 In addition, in the analysis of patients who completed all 4 cycles, median PFS was 253 days with chemoimmunotherapy versus 157 days with chemotherapy, a 57% risk reduction (P = .001), and OS was 299 days versus 233 days, respectively, for a 36% risk reduction (P = .043). For patients with squamous-cell carcinoma who completed 4 cycles, median OS reached 364 days with chemoimmunotherapy versus 254 days with chemotherapy alone, representing a 60% reduction in risk of dying (P = .041), Dr Belani reported.11 “The addition of Cadi-05 to paclitaxel and cisplatin improved OS and PFS in the prespecified subset of patients completing 4 cycles, and its efficacy was better in patients with squamouscell carcinoma than with adenocarcinoma,” Dr Belani concluded. Raffit Hassan, MD, of the National Cancer Institute, said that several immunotherapy approaches for NSCLC were moving forward, including vaccines and TLR agonists, such as mycobacterium w. “Hurdles remain, and no agent has been approved,” Dr Hasson said, “but recent randomized phase 2 trials show hints of activity, leading to phase 3 trials.” The vaccines in phase 3 trials are belagenpumatucel-L (Lucanix), LBLP25 (Stimuvax), and the MAGE-A3 vaccine, which showed OS benefits (or trends) in phase 2 trials. TLR agonists, by contrast, have been disappointing in phase 3 trials, although mycobacterium w is showing Continued on page 45

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promise, he said. “The results of the ongoing phase 3 trials will be important to validate immunotherapy as a valid option in lung cancer,” Dr Hassan concluded. Future of Some Once-Promising Agents Uncertain Several investigational agents, however, turned in disappointing results. One of these is motesanib, which inhibits a number of tumors. When combined with chemotherapy in the randomized, placebo-controlled phase 3 MONET (Motesanib NSCLC Efficacy and Tolerability) 1 clinical study of 1090 patients with advanced nonsquamous NSCLC, motesanib—which was once considered a promising drug for NSCLC—did not improve OS over chemotherapy alone.12 The vascular-disrupting agent vadimezan has also failed to improve efficacy versus chemotherapy alone in a global phase 3 clinical trial of front-line treatment in 1299 patients.13 Aggressive Care at End of Life Still Common, Expensive The practice of overly aggressive care at the end of life has been recognized as a concern. A study presented at last year’s ASCO showed that OS in patients with NSCLC was actually compromised, not improved, by chemotherapy administered in the final months.14 However, the message that aggressive end-of-life care is unwarranted is still falling on deaf ears, ASCO studies suggested. One in 5 Patients Receives Aggressive End-of-Life Care This appears true even at institutions of the National Comprehensive Cancer Network (NCCN). In an analysis of patients with metastatic NSCLC treated at NCCN institutions, almost 20% of patients received aggressive end-of-life chemotherapy or treatment in the intensive care unit (ICU).15 Investigators identified 1092 patients with metastatic NSCLC who received treatment at 8 NCCN institutions between 2007 and 2010. Aggressive end-of-life care was defined as (1) the initiation of a new chemotherapy regimen within 30 days of death, (2) the receipt of chemotherapy within 14 days of death, or (3) any ICU admission within the last 30 days of life. The analysis revealed that15: • 18.9% of patients received aggressive end-of-life chemotherapy or care in an ICU • 10.7% started a new chemotherapy regimen in the last 30 days of life

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• 11.8% received chemotherapy during the last 14 days of life • 3.2% were admitted to the ICU in the last 30 days of life • 43% of patients with poor performance status received aggressive endof-life chemotherapy • 34% of patients receiving aggressive chemotherapy were starting their first and only treatment line • 37.5% of patients receiving an EGFR inhibitor as their final treatment were still using the drug 14 days before death • 48% of patients receiving chemotherapy in the last 14 days of life were taking erlotinib. “This is a higher rate than I was hoping for,” said lead author Kathleen Bickel, MD, from the University of Michigan Comprehensive Cancer Center, Ann Arbor. “And this is recent data. It’s not patients treated 10 years ago.”

OS in patients with NSCLC was actually compromised, not improved, by chemotherapy administered in the final months. Early Palliative Care Reduces Intravenous, but Not Oral, Drug Use Early initiation of palliative care resulted in a 2.7-month (30%) survival benefit and QOL improvements in the randomized study by Temel and colleagues that was presented last year at ASCO 2010.14 A secondary analysis examined the reasons for this finding and was presented at ASCO 2011.16 “Palliative care services are traditionally delivered late in the course of disease, when their benefits may be limited. Ideally, they should be integrated throughout the course of illness and in tandem with life-prolonging treatment,” said lead investigator Joseph Greer, PhD, Massachusetts General Hospital Cancer Center, Boston. Within 8 weeks of a metastatic NSCLC diagnosis, 151 patients were assigned to early palliative care integrated with standard oncology care (regular meetings with a palliative care specialist) or to standard care (ad hoc palliative care upon request).16 Although the early palliative care intervention did not result in less use of oral chemotherapy, other benefits were obvious, he reported. Patients in the early palliative care group were significantly less likely to

receive intravenous (IV) chemotherapy, and, although about 70% of patients in each arm entered hospice, the patients who received early palliative care enrolled earlier and spent almost 3 times as many days under hospice care (P = .004).16 IV chemotherapy was administered within 60 days of death to 25% of the palliative care group versus 45% of patients receiving standard care (P = .01); within 30 days of death in 10% versus 25%, respectively (P = .07); and within 14 days of death in 2% and 10% (P = .06). Less use of IV chemotherapy in the early palliative care arm had no detrimental effect on survival.16 The use of oral agents, however, did not differ between the 2 groups. Oral agents were prescribed within 60 days of death to 28% of patients who received early palliative care and 22% of the standard care group; within 30 days in approximately 20% per arm; and within 14 days in 10% per arm.16 The more frequent use of oral drugs might be the result of a “clinical compromise” or may reflect that they can be started while patients are enrolling in hospice, Dr Greer suggested, but the reasons for their frequent use in the palliative care setting must be determined. The bottom line is that early integration of palliative care means that the timing of final chemotherapy will probably be more appropriate and that patients will access hospice services sooner, he said, “which are key measures of quality end-of-life care.” End-of-Life Care More Expensive than Biologics An analysis of the total cost of managing patients with advanced NSCLC yielded a few surprises, showing that the most costly segment was end-oflife care, and targeted agents were responsible for only a modest portion of the active treatment costs.17 Investigators from the University of Texas Health Science Center at San Antonio used the PharMetrics claims database of 5847 patients to characterize the direct cost of treating patients with advanced NSCLC between 2000 and 2009. They divided the study period into a “preperiod” (2000-2002), “transition period” (2003-2005), and “current period” (2006-2009) to account for the move from standard chemotherapy to the introduction of the newer agents pemetrexed, tyrosine kinase inhibitors (TKIs), and biologics.17 The mean costs of various segments of care over the study period were17: • Total cost: $162,134 per patient (for

≥5 months of therapy) • Cost per patient per month (PPPM): $10,284 • Cost related to diagnosis, PPPM: $9162 • Active mean treatment cost, PPPM: $10,141 • End-of-life cost, PPPM: $18,033 PPPM costs were similar in all 3 periods: $8662 in the preperiod, $10,578 the transition period, and $10,141 in the current period. Newer agents accounted for 16% of active treatment, including pemetrexed (5%), TKIs (6%), and biologics (5%). In total, newer agents accounted for just 4% of the overall cost.17 Cost of Treatment Highly Variable Researchers from McKesson Specialty Care Solutions in South San Francisco, CA, evaluated adherence to national treatment guidelines for NSCLC and chemotherapy costs in the adjuvant and first-line metastatic settings among community oncology practices.18

The most costly segment was end-of-life care, and targeted agents were responsible for only a modest portion of the active treatment costs.

A total of 811 adjuvant and 2761 metastatic regimens were administered by 333 practices in 41 states. National guidelines recommended 26 adjuvant and 67 metastatic regimens. The rate of guideline adherence was significantly higher with the metastatic regimen than with the adjuvant regimen. In both treatment settings, carboplatin-containing regimens were given more often than cisplatin-containing regimens.18 Based on Medicare reimbursement rates for 3 months of treatment, the costs varied for the top 5 regimens in the adjuvant and metastatic settings. A standard course of therapy in the adjuvant group ranged from $2803 (for carboplatin and etoposide every 3 weeks) to $7362 (for carboplatin and paclitaxel every 4 weeks).18 Metastatic regimens ranged from $3297 (for carboplatin and paclitaxel every 3 weeks) to $29,322 (for carboplatin, paclitaxel, and bevacizumab every 3 weeks).18 “A large number of unique regiContinued on page 46

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Cost Implications for Novel Therapies and Strategies... mens were administered in the metastatic group, and costs for the top 5 regimens varied considerably,” the investigators observed. ■ References 1. Paz-Ares LG, De Marinis F, Dediu M, et al. PARAMOUNT: phase III study of maintenance pemetrexed (pem) plus best supportive care (BSC) versus placebo plus BSC immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer (NSCLC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 2. Zhang L, Shenglin M, Song X, et al. Efficacy, tolerability and biomarker analyses from a phase III, randomized, placebo-controlled, parallel group study of gefitinib as maintenance therapy in patients with locally advanced or metastatic non-small cell cancer (NSCLC; INFORM; C-TONG 0804). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 3. Rosell R, Gervais R, Vergnenegre A, et al. Erlotinib versus chemotherapy (CT) in advanced non-small cell lung cancer (NSCLC) patients (p) with epidermal growth factor receptor mutations: interim results of the European erlotinib versus chemotherapy (EURTAC) phase III randomized trial. Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011.

4. Shaw AT, Yeap BY, Solomon BJ, et al. Impact of crizotinib on survival in patients with advanced, ALKpositive NSCLC compared with historical controls. Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 5. Camidge DR, Bang Y, Kwak EL, et al. Progressionfree survival (PFS) from a phase I study of crizotinib (PF-02341066) in patients with ALK-positive nonsmall cell lung cancer (NSCLC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 6. Kris MG, Johnson BE, Kwiatkowski DJ, et al. Identification of driver mutations in tumor specimens from 1,000 patients with lung adenocarcinoma: the NCI’s Lung Cancer Mutation Consortium (LCMC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 7. The Arcas Group website. MDOutlook, LLC. 2011 ASCO Annual Meeting: Immediate Impact on Clinical Practices. NSCLC. 2011 ASCO Quick Poll in NSCLC. http://thearcasgroup.com/sub/wp-content/uploads/ 2011/06/arcas_asco2011_nsclc_quickpoll_final.pdf. Accessed July 26, 2011. 8. Sun Y, Shi Y, Zhang L, et al. A randomized, doubleblind phase III study of icotinib versus gefitinib in patients with advanced non-small cell lung cancer previously treated with chemotherapy (ICOGEN). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 9. Spigel DR, Ervin TJ, Ramlau R, et al. Final efficacy results from OAM4558g, a randomized phase II study

evaluating MetMAb or placebo in combination with erlotinib in advanced NSCLC. Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 10. Wong K, Koczywas M, Goldman JW, et al. An open-label phase II study of the Hsp90 inhibitor ganetespib (STA-9090) as monotherapy in patients with advanced non-small cell lung cancer (NSCLC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 11. Belani CP, Desai D, Khamar BM, for the Cadi-05 Investigators Study Group. Open-label, randomized multicenter phase II clinical trial of a toll-like receptor2 (TLR2) agonist mycobacterium w (Cadi-05) in combination with paclitaxel plus cisplatin versus paclitaxel plus cisplatin in advanced non-small cell lung cancer (NSCLC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 12. Scagliotti G, Vynnychenko I, Ichinose Y, et al. An international, randomized, placebo-controlled, double-blind phase III study (MONET1) of motesanib plus carboplatin/paclitaxel (C/P) in patients with advanced nonsquamous non-small cell lung cancer (NSCLC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 13. Lara P, Douillard J, Nakagawa K, et al. Randomized phase III placebo-controlled trial of carboplatin/paclitaxel (C/P) with or without the vascular disrupting agent vadimezan (ASA404) in advanced non-small cell lung cancer (NSCLC). Presented at the 47th Annual American Society of

Continued from page 45 Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 14. Temel JS, Greer J, Gallagher E, et al. Effect of early palliative care (PC) on quality of life (QOL), aggressive care at the end of life (EOL), and survival in stage IV NSCLC patients: results of a phase III randomized trial. Presented at the 46th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 4-8, 2010. 15. Bickel KE, Niland JC, Mamet R, et al. Aggressive end-of-life (EOL) chemotherapy (CT) use in metastatic non-small cell lung cancer (mNSCLC): a National Comprehensive Cancer Network (NCCN) outcomes database analysis. Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 16. Greer JA, Pirl WF, Jackson VA, et al. Effect of early palliative care on chemotherapy utilization and endof-life care in patients with metastatic non-small cell lung cancer (NSCLC). Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 17. Koeller JM, Bell A, Corral M, et al. Total direct and segmented medical cost-of-care for stage IV (adv) non-small cell lung cancer (NSCLC) in a private insurance population. Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011. 18. Wang Z, Aksamit I, Tuscher L, et al. Guideline adherence rates and costs of chemotherapy treatment for NSCLC patients treated in U.S. community oncologist practices. Presented at the 47th Annual American Society of Clinical Oncology Meeting; Chicago, IL; June 3-7, 2011.

COMMENTARY

Addressing Cost and Quality Issues in Novel Treatment Strategies for Non–Small-Cell Lung Cancer: Where Is Our Focused Factory? Ira M. Klein, MD, MBA, FACP Senior Medical Director, Clinical Consulting, Strategy and Analysis National Accounts, Aetna

vidence-based medicine and a focused clinical orientation are key elements to delivering the right care at the right time to the right person. The recent findings reported at the 2011 American Society of Clinical Oncology annual meeting regarding the use of novel therapies and strategies in the treatment of non–small-cell lung cancer make achieving these goals harder than ever. Each year, treatment approaches become more complex and variable, and translating protocols that demonstrate positive outcomes into daily community practice seems more difficult than ever. Beyond the waste and nonbeneficial care for those not well-matched for treatment, we face the additional problem of sizing and comparing treatment efficiencies within a disease state. How would experts in process control and quality improvement from other industries handle this issue? Oncology care in the United States

We are in dire need of decision support and data storage tools that address oncologists’ needs in real time. We also need reporting that helps us all learn what is the most effective and efficient care at an aggregate level.

today reflects 2 dramatic contrasts. Although admirable in its application of molecular biology (the pinnacle of science), oncology care is still very nonsystematic and inconsistent in the way new discoveries and practices are being incorporated into the patient care realm. If data are the drivers of quality improvement, how do we collect and measure that quality information in real-life cancer care? A universal oncol-

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ogy care data repository does not exist today. Without the regular application of agreed upon gold standard National Comprehensive Cancer Network– derived pathways, the typical community oncology practice, even if verbally espousing commitment to best practices, is practicing “mass inspection” for quality rather than building quality into the product in the first place. Academic oncology practices should also not be given a pass on this

issue, because quality is more than a glossy advertising campaign. We are in dire need of decision support and data storage tools that address oncologists’ needs in real time. We also need reporting that helps us all learn what is the most effective and efficient care at an aggregate level. Without this, we will never know who might be better served with maintenance therapy, when to use erlotinib, and how we can apply companion diagnostic testing (to detect mutations in, for example, epithelial growth factor receptor, EML4-ALK, heat shock protein 90, and toll-like receptor 2) to the right patients so that they may benefit from more targeted agents. Finally, the application of aggressive end-of-life care will surely decline when all treating oncologists have more data-linked confidence in the “best care options.” When this happens, we will have our “focused factories,” and the gods of process control will be smiling down upon us. ■

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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_Aug_11_2_Follow ASCO Tabloid 8/11/11 9:38 AM Page 48

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.