VBCC May 2013 VOL 4 NO 4

MAY 2013 VOL 4 NO 4

INTEGRATING ONCOLOGISTS, PAYERS, AND THE ENTIRE CANCER CARE TEAM www.ValueBasedCancerCare.com

AVBCC Third Conference: Stakeholders Unite Around Common Challenges Influencing the patient-impact factor

By Caroline Helwick

For Florida Congress­woman with a History of Cancer, Genetic Patent Case Is Personal

By Caroline Helwick

Debbie Wasserman Schultz

Hollywood, FL—For the first time, the Annual Conference of the Association for Value-Based Cancer Care (AVBCC) was addressed by a member of Congress. At this year’s conference, Congresswoman Debbie Wasserman Schultz, who represents

Florida’s 23rd District (which encompasses Hollywood), shared her personal experience with cancer and took the opportunity to discuss the impact of exclusive licensing of genes and their related laboratory tests on paContinued on page 9

The Changing Oncology Landscape: Evolution or Revolution?

By Audrey Andrews

Hollywood, FL—Stakeholders from across the field of oncology gathered at the Third Annual Conference of the Association for Value-Based Cancer Care (AVBCC) to network and to explore ways to adapt to a rapidly changing landscape.

Continued on page 8

Ibrutinib Shows Rapid, Dramatic Responses in Patients with CLL FDA designates it a “breakthrough therapy”

©2013 Engage Healthcare Communications, LLC

Hollywood, FL—Panelists at the 2013 National Comprehensive Cancer Net­ work (NCCN) annual conference view the oncology world as rapidly changing, and the impact of this, for better or for worse, will be felt by healthcare providers, payers, and patients alike.

“Certainly, this landscape is shifting beneath our feet,” said Clifford Goodman, PhD, Senior Vice President and Principal, the Lewin Group, a healthcare consulting firm in Falls

Church, VA, who moderated this panel discussion. “There are tectonic forces, and these are unsteady times,” Dr Goodman said.

The Coverage Conundrum The US population is not getting any healthier, despite broadening access to care and efforts to eliminate disparities, the panelists agreed. This is largely because the socioeconomic Continued on page 29

inside

By Charles Bankhead Washington, DC—More than 50% of patients with difficult-to-treat chronic lymphocytic leukemia (CLL) had tumor shrinkage during 6 months of treatment with ibrutinib, results of a phase 2 clinical trial showed.

Treatment with ibrutinib—which is currently under review by the US Food and Drug Administration (FDA)—led to a 1-year progression-free survival rate of 94%. Ibrutinib, a Bruton’s tyrosine kinase inhibitor, reduced spleen

Roy A. Beveridge, MD

volume and tumor spread to bone, reported Adrian Wiestner, MD, PhD, Investigator, Laboratory of Lymphoid Malignancies, National Institutes of Health, Bethesda, MD, at the American Association for Cancer Research (AACR) 2013 annual meeting.

Dramatic responses have occurred quickly in some patients.

“Some patients have had more than a 90% reduction in lymph node disease

Continued on page 32

IN THE LITERATURE . . . . . . . . . . .

Patients unwilling to consider costs in treatment choices

4

NCCN CONFERENCE . . . . . . . . . . 29 NCCN updated its clinical practice guidelines

VALUE PROPOSITIONS . . . . . . . . .

First guidelines for molecular diagnostics in lung cancer

6

AACR ANNUAL MEETING . . . . . . . 34 New mantle-cell regimen leads to remarkable response rate

FDA UPDATE . . . . . . . . . . . . . . . . . 16 Lymphoseek approved for breast cancer and melanoma

PROSTATE CANCER . . . . . . . . . . . 40 AUA revises PSA screening guidelines

PERSONALIZED MEDICINE . . . . . 44 High HER2 expression improves ECONOMICS OF CANCER CARE .24 outcomes with T-DM1 in breast Neoadjuvant chemotherapy reduces costs for older patients with ovarian cancer cancer patients

In the newly metastatic CRPC patient who is asymptomatic or minimally symptomatic

STARTS THE FIGHT

AND HELPS HIS IMMUNE SYSTEM * SUSTAIN IT 1

• Targets and attacks prostate cancer cells • Statistically significant overall survival advantage1,2 • Sustained* immune response *A sustained immune response was seen out to 26 weeks in the pivotal study (the last time point measured).1 INDICATION: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

IMPORTANT SAFETY INFORMATION: PROVENGE is intended solely for autologous use and is not routinely tested for transmissible infectious diseases.

In controlled clinical trials, serious adverse events reported in the PROVENGE group included acute infusion reactions (occurring within 1 day of infusion) and cerebrovascular events. Severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

The most common adverse events (incidence ≥15%) reported in the PROVENGE group were chills, fatigue, fever, back pain, nausea, joint ache, and headache.

For more information on PROVENGE, please see Brief Summary of Prescribing Information on adjacent pages. www.PROVENGEHCP.com

PROVENGE® (sipuleucel-T) Suspension for Intravenous Infusion

Rx Only

BRIEF SUMMARY — See full Prescribing Information for complete product information

INDICATIONS AND USAGE: PROVENGE® (sipuleucel-T) is an autologous cellular immunotherapy indicated for the treatment of asymptomatic or minimally symptomatic metastatic castrate resistant (hormone refractory) prostate cancer.

DOSAGE AND ADMINISTRATION • For Autologous Use Only.

• The recommended course of therapy for PROVENGE is 3 complete doses, given at approximately 2-week intervals.

• Premedicate patients with oral acetaminophen and an antihistamine such as diphenhydramine.

• Before infusion, confirm that the patient’s identity matches the patient identifiers on the infusion bag.

• Do Not Initiate Infusion of Expired Product.

• Infuse PROVENGE intravenously over a period of approximately 60 minutes.

Do Not Use a Cell Filter.

• Interrupt or slow infusion as necessary for acute infusion reactions, depending on the severity of the reaction.

(See Dosage and Administration [2] of full Prescribing Information.)

CONTRAINDICATIONS: None.

WARNINGS AND PRECAUTIONS • PROVENGE is intended solely for autologous use.

• Acute infusion reactions (reported within 1 day of infusion) included, but were not limited to, fever, chills, respiratory events (dyspnea, hypoxia, and bronchospasm), nausea, vomiting, fatigue, hypertension, and tachycardia. In controlled clinical trials, 71.2% of patients in the PROVENGE group developed an acute infusion reaction.

In controlled clinical trials, severe (Grade 3) acute infusion reactions were reported in 3.5% of patients in the PROVENGE group. Reactions included chills, fever, fatigue, asthenia, dyspnea, hypoxia, bronchospasm, dizziness, headache, hypertension, muscle ache, nausea, and vomiting. The incidence of severe events was greater following the second infusion (2.1% vs 0.8% following the first infusion), and decreased to 1.3% following the third infusion. Some (1.2%) patients in the PROVENGE group were hospitalized within 1 day of infusion for management of acute infusion reactions.

No Grade 4 or 5 acute infusion reactions were reported in patients in the PROVENGE group.

Closely monitor patients with cardiac or pulmonary conditions. In the event of an acute infusion reaction, the infusion rate may be decreased, or the infusion stopped, depending on the severity of the reaction. Appropriate medical therapy should be administered as needed.

• Handling Precautions for Control of Infectious Disease. PROVENGE is not routinely tested for transmissible infectious diseases. Therefore, patient leukapheresis material and PROVENGE may carry the risk of transmitting infectious diseases to health care professionals handling the product. Universal precautions should be followed.

• Concomitant Chemotherapy or Immunosuppressive Therapy. Use of either chemotherapy or immunosuppressive agents (such as systemic corticosteroids) given concurrently with the leukapheresis procedure or PROVENGE has not been studied. PROVENGE is designed to stimulate the immune system, and concurrent use of immunosuppressive agents may alter the efficacy and/or safety of PROVENGE. Therefore, patients should be carefully evaluated to determine whether it is medically appropriate to reduce or discontinue immunosuppressive agents prior to treatment with PROVENGE. • Product Safety Testing. PROVENGE is released for infusion based on the microbial and sterility results from several tests: microbial contamination determination by Gram stain, endotoxin content, and in-process sterility with a 2-day incubation to determine absence of microbial growth. The final (7-day incubation) sterility test results are not available at the time of infusion. If the sterility results become positive for microbial contamination after PROVENGE has been approved for infusion, Dendreon will notify the treating physician. Dendreon will attempt to identify the microorganism, perform antibiotic sensitivity testing on recovered microorganisms, and communicate the results to the treating physician. Dendreon may request additional information from the physician in order to determine the source of contamination.

(See Warnings and Precautions [5] of full Prescribing Information.)

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

PROF35855_Provenge_VBCC_DR.indd 2

The safety evaluation of PROVENGE is based on 601 prostate cancer patients in the PROVENGE group who underwent at least 1 leukapheresis procedure in four randomized, controlled clinical trials. The control was non-activated autologous peripheral blood mononuclear cells.

The most common adverse events, reported in patients in the PROVENGE group at a rate ≥15%, were chills, fatigue, fever, back pain, nausea, joint ache, and headache. Severe (Grade 3) and life-threatening (Grade 4) adverse events were reported in 23.6% and 4.0% of patients in the PROVENGE group compared with 25.1% and 3.3% of patients in the control group. Fatal (Grade 5) adverse events were reported in 3.3% of patients in the PROVENGE group compared with 3.6% of patients in the control group.

Serious adverse events were reported in 24.0% of patients in the PROVENGE group and 25.1% of patients in the control group. Serious adverse events in the PROVENGE group included acute infusion reactions (see Warnings and Precautions), cerebrovascular events, and single case reports of eosinophilia, rhabdomyolysis, myasthenia gravis, myositis, and tumor flare.

PROVENGE was discontinued in 1.5% of patients in Study 1 (PROVENGE group n=341; Control group n=171) due to adverse events. Some patients who required central venous catheters for treatment with PROVENGE developed infections, including sepsis. A small number of these patients discontinued treatment as a result. Monitoring for infectious sequelae in patients with central venous catheters is recommended.

Each dose of PROVENGE requires a standard leukapheresis procedure approximately 3 days prior to the infusion. Adverse events that were reported ≤1 day following a leukapheresis procedure in ≥5% of patients in controlled clinical trials included citrate toxicity (14.2%), oral paresthesia (12.6%), paresthesia (11.4%), and fatigue (8.3%).

Table 1 provides the frequency and severity of adverse events reported in ≥5% of patients in the PROVENGE group of randomized, controlled trials of men with prostate cancer.

The population included 485 patients with metastatic castrate resistant prostate cancer and 116 patients with non-metastatic androgen dependent prostate cancer who were scheduled to receive 3 infusions of PROVENGE at approximately 2-week intervals. The population was age 40 to 91 years (median 70 years), and 90.6% of patients were Caucasian.

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Any Adverse Event Chills Fatigue Fever Back pain Nausea Joint ache Headache Citrate toxicity Paresthesia Vomiting Anemia Constipation Pain Paresthesia oral Pain in extremity Dizziness Muscle ache Asthenia Diarrhea Influenza-like illness Musculoskeletal pain Dyspnea Edema peripheral Hot flush Hematuria Muscle spasms

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

591 (98.3) 319 (53.1) 247 (41.1) 188 (31.3) 178 (29.6) 129 (21.5) 118 (19.6) 109 (18.1) 89 (14.8) 85 (14.1) 80 (13.3) 75 (12.5) 74 (12.3) 74 (12.3) 74 (12.3) 73 (12.1) 71 (11.8) 71 (11.8) 65 (10.8) 60 (10.0) 58 (9.7) 54 (9.0) 52 (8.7) 50 (8.3) 49 (8.2) 46 (7.7) 46 (7.7)

186 (30.9) 13 (2.2) 6 (1.0) 6 (1.0) 18 (3.0) 3 (0.5) 11 (1.8) 4 (0.7) 0 (0.0) 1 (0.2) 2 (0.3) 11 (1.8) 1 (0.2) 7 (1.2) 0 (0.0) 5 (0.8) 2 (0.3) 3 (0.5) 6 (1.0) 1 (0.2) 0 (0.0) 3 (0.5) 11 (1.8) 1 (0.2) 2 (0.3) 6 (1.0) 2 (0.3)

291 (96.0) 33 (10.9) 105 (34.7) 29 (9.6) 87 (28.7) 45 (14.9) 62 (20.5) 20 (6.6) 43 (14.2) 43 (14.2) 23 (7.6) 34 (11.2) 40 (13.2) 20 (6.6) 43 (14.2) 40 (13.2) 34 (11.2) 17 (5.6) 20 (6.6) 34 (11.2) 11 (3.6) 31 (10.2) 14 (4.6) 31 (10.2) 29 (9.6) 18 (5.9) 17 (5.6)

Grade 3-5 n (%) 97 (32.0) 0 (0.0) 4 (1.3) 3 (1.0) 9 (3.0) 0 (0.0) 5 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 7 (2.3) 3 (1.0) 3 (1.0) 0 (0.0) 1 (0.3) 0 (0.0) 0 (0.0) 2 (0.7) 3 (1.0) 0 (0.0) 3 (1.0) 3 (1.0) 1 (0.3) 1 (0.3) 3 (1.0) 0 (0.0)

(Table 1 continued on next page.)

3/12/13 4:00 PM

In the Literature Charting the Landscape of Driver Mutations in Acute Myeloid Leukemia

The role of acute myeloid leukemia (AML) mutations in the pathogenesis of the disease has not been fully understood, and many genomic mutations in AML remain unknown. A team of researchers has recently analyzed large databases of genetic muta-

tions and has selected 200 adult cases of de novo AML for their new study, using a variety of methods of genomic sequencing (The Cancer Genome Atlas Research Network. N Engl J Med. 2013 May 1. [Epub ahead of print]).

Results show that AML genes are associated with the fewest mutations of all types of adult cancers, with an average of only 13 mutations. Of these, 5

Table 1 Incidence of Adverse Events Occurring in ≥5% of Patients Randomized to PROVENGE PROVENGE (N = 601)

Hypertension Anorexia Bone pain Upper respiratory tract infection Insomnia Musculoskeletal chest pain Cough Neck pain Weight decreased Urinary tract infection Rash Sweating Tremor

Control* (N = 303)

All Grades n (%)

Grade 3-5 n (%)

All Grades n (%)

Grade 3-5 n (%)

45 (7.5) 39 (6.5) 38 (6.3) 38 (6.3)

3 (0.5) 1 (0.2) 4 (0.7) 0 (0.0)

14 (4.6) 33 (10.9) 22 (7.3) 18 (5.9)

0 (0.0) 3 (1.0) 3 (1.0) 0 (0.0)

37 (6.2) 36 (6.0)

0 (0.0) 2 (0.3)

22 (7.3) 23 (7.6)

1 (0.3) 2 (0.7)

35 (5.8) 34 (5.7) 34 (5.7) 33 (5.5) 31 (5.2) 30 (5.0) 30 (5.0)

0 (0.0) 3 (0.5) 2 (0.3) 1 (0.2) 0 (0.0) 1 (0.2) 0 (0.0)

17 (5.6) 14 (4.6) 24 (7.9) 18 (5.9) 10 (3.3) 3 (1.0) 9 (3.0)

0 (0.0) 2 (0.7) 1 (0.3) 2 (0.7) 0 (0.0) 0 (0.0) 0 (0.0)

*Control was non-activated autologous peripheral blood mononuclear cells.

Cerebrovascular Events. In controlled clinical trials, cerebrovascular events, including hemorrhagic and ischemic strokes, were reported in 3.5% of patients in the PROVENGE group compared with 2.6% of patients in the control group.

(See Adverse Reactions [6] of full Prescribing Information.)

To report SUSPECTED ADVERSE REACTIONS, contact Dendreon Corporation at 1-877-336-3736 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch.

Dendreon Corporation Seattle, Washington 98101

REFERENCES: 1. PROVENGE [package insert]. Dendreon Corporation; June 2011.

2. Kantoff PW, Higano CS, Shore ND, et al; for the IMPACT Study Investigators. Sipuleucel-T immunotherapy for castration-resistant prostate cancer. N Engl J Med. 2010;363:411-422.

©2013 Dendreon Corporation.

All rights reserved. January 2013.

Printed in the U.S.A. Dendreon, the Dendreon logo, and PROVENGE are registered trademarks of Dendreon Corporation.

P-A-01.13-002.00

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Value-Based Cancer Care

mutations on average are in genes that recur in AML in the various phenotypes. A total of 23 genes were significantly associated with AML mutations, and 237 genes were mutated in ≥2 samples. The majority of the samples had ≥1 nonsynonymous mutations in 1 of 9 gene types that are believed to be associated with the pathogenesis of AML; these include transcription-factor fu-

sions, the gene encoding nucleophosmin (NPM1), tumor-suppressor genes, DNA-methylation–related genes, signaling genes, chromatin-modifying genes, myeloid transcription-factor genes, cohesin-complex genes, and spliceosome-complex genes. The classification of the mutated genes into 9 categories reveals strong biologic relationships that will likely have impor­ tant clinical implications.

The team identified at least 1 potential driver mutation in nearly every sample of AML subtype that was investigated, indicating that the complex genetic interaction is linked to the pathogenesis of this malignancy in each patient. The large database will be used to further study the nature of AML and to develop new targeted therapies for this patient population.

Only 57% of Specialty Societies Consider Costs in Clinical Recommendations

Concerns for the cost implications of clinical decision-making by providers and health plans have increased significantly in the recent past, as well as the advice to consider cost in addition to efficacy as a part of the treatment paradigm. However, little research has been conducted to evaluate whether this concern has been reflected in the development of official clinical guidance issued by various medical groups and societies. A new study has reviewed the role of costs in clinical guidance statements issued by 30 of the largest specialty societies in the United States between 2008 and 2012 (Schwartz JA, et al. JAMA Intern Med. 2013 May 6. [Epub ahead of print]).

The investigators focused on 3 specific questions, including (1) whether costs are being included as part of the considerations in the development of a clinical guidance by any of these 30 societies, (2) the mechanism or methodology by which any cost considerations are incorporated into the recommendations, and (3) the manner that cost issues are being used to support the clinical practice recommendations.

Of the 30 specialty physician socie­ties included in this study, only 17 (57%) organizations explicitly consider cost issues in their guidance recommendations; 4 (13%) implicitly relate to costs in their methodological statements; 3 (10%) intentionally do not include costs as part of their rationale for their recommendations; and 6 (20%) do not make any reference to cost in any way that suggests whether the lack of consideration of cost is done intentionally.

Among the 17 societies that do consider cost in their clinical guidance explicitly, 9 (53%) incorporate a system Continued on page 28

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In This Issue Publishing Staff Senior Vice President/Group Publisher Nicholas Englezos nick@engagehc.com Vice President/Director of Sales & Marketing Joe Chanley joe@greenhillhc.com Publisher Cristopher Pires cris@engagehc.com Editorial Director Dalia Buffery dalia@engagehc.com Associate Editor Lara J. Lorton Editorial Assistants Jennifer Brandt Cara Guglielmon Production Manager Melissa Lawlor The Lynx Group President/CEO Brian Tyburski Chief Operating Officer Pam Rattananont Ferris Vice President of Finance Andrea Kelly Associate Editorial Director, Projects Division Terri Moore Director, Quality Control Barbara Marino Director, Production & Manufacturing Alaina Pede Director, Creative & Design Robyn Jacobs Creative & Design Assistant Lora LaRocca Director, Digital Media Anthony Romano Web Content Managers David Maldonado Anthony Travean Digital Programmer Michael Amundsen Senior Project Manager Andrea Boylston Project Coordinators Deanna Martinez Jackie Luma Business Manager Blanche Marchitto Executive Administrator Rachael Baranoski Office Coordinator Robert Sorensen Engage Healthcare Communications, LLC 1249 South River Road - Ste 202A Cranbury, NJ 08512 phone: 732-992-1880 fax: 732-992-1881

Value-Based Cancer Care, ISSN 2153-4888 (print); ISSN 2153-4896 (online), is published 9 times a year by Engage Healthcare Communica­tions, LLC, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Copyright © 2013 by Engage Healthcare Communications, LLC. All rights reserved.

Value-Based Cancer Care is a registered trademark of Engage Health­care Communi­cations, LLC. No part of this publication may be reproduced or transmitted in any form or by any means now or hereafter known, electronic or mechanical, including photocopy, recording, or any informational storage and retrieval system, without written permission from the publisher. Printed in the United States of America.

The ideas and opinions expressed in Value-Based Cancer Care do not necessarily reflect those of the editorial board, the editors, or the publisher. Publication of an advertisement or other product mentioned in Value-Based Cancer Care should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturers about any features or limitations of products mentioned. Neither the editors nor the publisher assume any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material mentioned in this publication.

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IN THE LITERATURE

PATIENT ENGAGEMENT

Specialty societies don’t include costs in clinical guidelines Patients unwilling to let costs influence treatment choices More….

Health IT facilitates patient engagement

VALUE PROPOSITIONS First guidelines for molecular diagnostics in lung cancer More….

3rd CONFERENCE Payers’ perspectives on transforming care WellPoint’s perspective on value-based cancer care Aetna’s value-based process improvement More….

ECONOMICS OF CANCER CARE Palliative care cost-effective for ovarian cancer More….

HEALTH POLICY Concerns over CMS’s proposed limits to FDG-PETs More….

OVARIAN CANCER Novel immunotherapy for ovarian cancer More….

PROSTATE CANCER AUA revises PSA screening guidelines More….

PERSONALIZED MEDICINE Gene expression and head and neck cancer therapy More….

VBCC Editorial Board Editor-in-Chief Craig Deligdish, MD Hematologist/Oncologist Oncology Resource Networks Orlando, FL Al B. Benson III, MD, FACP, FASCO Professor of Medicine Associate Director for Clinical Investigations Robert H. Lurie Comprehensive Cancer Center of Northwestern University, Chicago, IL Scott Breidbart, MD Chief Medical Officer Empire BlueCross BlueShield, New York, NY

Mark J. Krasna, MD Corporate Medical Director of Oncology Jersey Shore University Medical Center Neptune, NJ

Denise K. Pierce DK Pierce & Associates Zionsville, IN Jatin J. Shah, MD M.D. Anderson Cancer Center Houston, TX

Mary Kruczynski Director of Policy Analysis Community Oncology Alliance Washington, DC

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

Jennifer Malin, MD, PhD Medical Director, Oncology and Care Management, WellPoint, Inc

Bruce A. Cutter, MD, MMM Cutter HealthCare Consulting Spokane, WA

John L. Marshall, MD Chief, Hematology and Oncology and Director, Otto J. Ruesch Center for the Cure of Gastrointestinal Cancers, Lombardi Comprehensive Cancer Center, Georgetown University Medical Center Washington, DC

Peter G. Ellis, MD University of Pittsburgh School of Medicine and UPMC Cancer Centers, Pittsburgh, PA

Matthew Mitchell, PharmD, MBA Manager, Pharmacy Services SelectHealth, Salt Lake City, UT

Arlene A. Forastiere, MD Senior Vice President Medical Affairs, eviti, Inc, Philadelphia, PA

Marcus Neubauer, MD Medical Director, Oncology Services, McKesson Specialty Health, The Woodlands, TX

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

Lee Newcomer, MD, MHA UnitedHealthcare Group Minnetonka, MN

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

Lynn Nishida, RPh Director, Clinical Services Catamaran Center of Excellence Northwest Region, Portland, OR

Kevin B. Knopf, MD, MPH Medical Oncology, California Pacific Medical Center, Sutter Health Care San Francisco, CA Michael Kolodziej, MD National Medical Director, Oncology Solutions Aetna, Hartford, CT

Brian K. Solow, MD, FAAFP Chief Medical Officer Prescription Solutions/OptumRx Irvine, CA John D. Sprandio, MD, FACP Chief Physician, Consultants in Medical Oncology and Hematology Chief of Oncology, Delaware County Memorial Hospital, Drexel Hill, PA Timothy Tyler, PharmD, FCSHP Director of Pharmacy Services Comprehensive Cancer Center Desert Regional Medical Center, CA G. Rhys Williams, ScD, MS Amgen, Thousand Oaks, CA Winston Wong, PharmD CareFirst BlueCross BlueShield Baltimore, MD

Ted Okon, BS, MBA Executive Director Community Oncology Alliance, Washington, DC Ed Pezalla, MD, MPH National Medical Director of Pharmacy Policy and Strategy, Aetna, Hartford, CT

Yu-Ning Wong, MD, MSCE Fox Chase Cancer Center Philadelphia, PA Burt Zweigenhaft, BS Chief Executive Officer, OncoMed Great Neck, NY

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.

Contact Information: For subscription information please contact: Telephone: 732-992-1538 Fax: 732-992-1881, circulation@valuebasedcancercare.com 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: 732-992-1536 • Fax: 732-992-1881.

Postmaster: Correspondence regarding subscriptions or change of address should be directed to CIRCULATION DIRECTOR, Value-Based Cancer Care, 1249 South River Road, Suite 202A, Cranbury, NJ 08512. Fax: 732-992-1881. Yearly subscription rates: 1 year: $99.00 USD; 2 years: $149.00 USD; 3 years: $199.00 USD.

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5

VALUE PROPOSITIONS First Guidelines Issued for Molecular Diagnostics Use in Patients with Lung Cancer

After a decade of developing molecular diagnostics for lung cancer, 3 organizations have issued the first guidelines for testing for the EGFR mutation and ALK rearrangement in patients with lung cancer, the number one cancer-related killer worldwide, providing a valuable new tool to fully utilize the benefits of targeted therapies for this patient population.

The guidelines have been developed by the College of American Pathologists (CAP), the International Association for the Study of Lung Cancer (IASLC), and the Association for Molecular Pathology. The guidelines, titled “Molecular Testing Guideline for Selection of Lung Cancer Patients for EGFR and ALK Tyrosine Kinase Inhibitors,” establish the first recommendations for the use of EGFR and ALK testing to guide targeted therapies in patients with lung cancer.

“The key recommendation of the guideline, and perhaps most impor­ tant to lung cancer patients, is that all patients with advanced lung adenocarcinoma should be tested for EGFR and ALK abnormalities, that would qualify them for tyrosine kinase inhibitor therapy, regardless of their clinical variables, such as smoking history, gender, or ethnicity,” said Marc Ladanyi, MD, of the Molecular Diagnostics Service at Memorial Sloan-Kettering Cancer Center in New York, and an IASLC member.

The guidelines highlight the role of personalized medicine for this patient population and provide answers to clinical questions, such as who should be tested, when, and what genes should be tested routinely in patients with lung cancer.

Up to 20% of patients with lung cancer “will test positive for one of the two biomarkers,” said Philip T. Cagle, MD, FCAP, Medical Director of Pulmonary Pathology, Department of Pathology and Genomic Medicine, The Methodist Hospital, Houston, TX, and a CAP member. “It is critical to identify these patients because they stand to benefit more from new targeted drugs than from conventional chemotherapy, and with fewer side effects.”

According to Dr Ladanyi, “The guideline is an important step in making sure that patients benefit from the new molecular understanding of lung cancer.” The guidelines were published on April 3, 2013. International Association for the Study of Lung Cancer Press Release; April 8, 2013

New Genomic Classification of Endometrial Cancers Will Soon Guide Therapy

Endometrial cancer is the fourth most common malignancy among American women. The National Cancer Institute estimates that close to 50,000 women will be diagnosed with endometrial cancer in 2013; for a majority of women with aggressive, high-grade tumors, the 5-year survival rate is approximately 16%.

A new analysis of nearly 400 endometrial tumors can now help to distinguish the important types of endometrial tumors and the frequency of mutations that could enhance treatment decisions. Led by researchers from The Cancer Genome Atlas (TCGA), this new study revealed 4 novel subtypes of endometrial tumors, as well as genomic similarities between endometrial cancer and breast, ovarian, and colorectal cancers.

“More genomic similarities are emerging between disparate tumor types,” said National Institutes of Health Director Francis S. Collins, MD, PhD. “Teasing out heretofore unknown genomic markers or mutations in various cancers is again proving the value of TCGA.” According to this study, approximately 25% of high-grade endometrial tumors have mutations in TP53, a tumor-suppressor gene, and many copy alterations.

“Some tumors with the same characterization by pathologists may have very different molecular features. That’s where these findings will

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be directly implemented in additional research, and also in the context of clinical trials,” said co-lead investigator Douglas A. Levine, MD, Head of the Gynecology Research Laboratory at Memorial Sloan-Kettering Cancer Center, New York.

“Finding genomic similarities among types of breast, ovarian, endometrial and colorectal tumors once again reveals that cancer, although very complex, may have themes extending beyond tissue type that can be exploited for therapeutic benefit,” said Eric D. Green, MD, PhD, Director of the National Human Genome Research Institute. “These similar genomic features demonstrate hitherto unknown commonalities among these cancers.” National Institutes of Health Press Release; May 1, 2013

Powerful Algorithms Help Decipher the Genetics of Cancer

Using data-sifting algorithms developed by computer scientists at Brown University, researchers are beginning to untangle the complex genetics of cancer. In a new study published in the New England Journal of Medicine (see article, page 4), investigators have outlined the most complete genetic profile of acute myeloid leukemia (AML). This research is expected to lead to new treatments for AML based on the unique genetics of each patient. The use of the new algorithms was key to “making sense of the giant datasets” required for this study, which is part of The Cancer Genome Atlas project that aims to map out the entire genome of cancer cells. “Genes don’t usually act on their own, but instead act together in pathways or networks,” said Ben J. Raphael, PhD, of the Department of Computer Science and Center for Computational Molecular Biology at Brown University. “Cancer-causing mutations often target these networks or pathways.” By analyzing the large amount of cancer data, “we hope that the algorithms produce actionable information that is clinically important.” Brown University Press Release; May 1, 2013

First Recipients of Bridge Grants to Support Hematologic Research Announced

The American Society of Hematology (ASH) announced the first recipients of its new program, ASH Bridge Grants, that is designed to provide hematologists with research funding to mitigate the reduction in research support from the National Institutes of Health (NIH) as a result of the recent cuts to federal funding, including a $1.6-billion cut in 2013 and additional cuts that will take place during the next several years as a result of sequestration.

To help address this crisis, ASH committed $9 million to create the grant program to support its members and to sustain their hematology research.

“While the establishment of this program represents an unprecedented financial commitment on the part of ASH, we recognize that it provides nowhere near what is needed to replace the NIH funding that has been cut for hematology research,” said ASH President Janis L. Abkowitz, MD. “What we really need is for Congress to understand that medical research is a national priority, which is why it was so important for ASH to support today’s rally at the highest level.”

The bridge grants awarded in April 2013 will support 17 basic, clinical, and translational hematology researchers whose NIH grant applications were deemed excellent by the NIH but that were not funded because of the budget cutbacks. ASH will award at least 30 bridge grants annually for the next 3 years to promote hematologic research. American Society of Hematology Press Release; April 8, 2013

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3rd Conference

AVBCC Third Conference: Stakeholders Unite...

Influencing the Patient-Impact Factor The focus of the meeting this year was on “Influencing the PatientImpact Factor.” In 18 general sessions and several roundtable forums, cancer care providers, payers, patient advocates, and manufacturers participated in discussions on the hottest topics in value-based cancer care—new payment models, emerging delivery systems (ie, oncology medical homes and accountable care organizations), novel strategies for value-based purchasing, patient assistance programs, patient adherence, survivorship and cancer rehabilitation, health insurance exchanges, biosimilars, and much more.

“From our inception, AVBCC has tried to be… an inclusive group that is the harmonization of the oncology ecosystem. We want to put together an agenda that is inclusive, that offers all viewpoints, and that facilitates achievable change—not just ‘talked about’ change.”

—Burt Zweigenhaft, BS

The unique value of the AVBCC meeting is the inclusiveness and diversity of viewpoints that are being presented, according to program co-chairs Gary M. Owens, MD, President of Gary Owens Associates, Glen Mills, PA; Burt Zweigenhaft, BS, President and Chief Executive Officer of OncoMed, Great Neck, NY; and Craig K. Deligdish, MD, Hematol­ogist/

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Oncologist, Oncology Resource Networks, Orlando, FL. “Who would have thought that 3 years ago, in a small 1-day meeting in Philadelphia, that this conference would evolve into this type of construct, bringing together various oncology stakeholders in discussions that now span 3 days plus a preconference session?” said Mr Zweigenhaft.

“From our inception, AVBCC has tried not to be a self-serving myopic group, but an inclusive group that is the harmonization of the oncology ecosystem.

We want to put together an agenda that is inclusive, that offers all viewpoints, and that facilitates achievable change—not just ‘talked about’ change.”

The discussion of value in cancer care has to focus on measurable results that will lead to positive changes, according to Mr Zweigenhaft. “We have to get measurable results, show the utility of the activity that is driving change. We think the reimbursement system today is broken,” he said.

A Year of “Firsts” Providing insight were individuals who are at the forefront of these changes. The faculty represented commercial and government insurers, managed market payers, employer co­ alitions, cancer centers and hospital systems, patient advocacy groups, and oncology organizations, including the American Society of Clinical Oncology (ASCO), the National Comprehensive Cancer Center, and the Community Oncology Alliance.

As an indication of the growing significance of AVBCC, this year’s conference was addressed by ASCO President Sandra M. Swain, MD, FACP (see article, page 10), and Congresswoman Debbie Wasserman Schultz, Chair of the Democratic National Committee and a breast cancer survivor, who discussed the challenges facing patients with cancer (see article, page 9).

Dr Owens pointed out that the 2013

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“This is the first time we have had a Congressperson address the group, the first time we have used roundtables to facilitate up-close and intimate conversations with experts, and the first time we have taken a deep dive into cancer patient issues, including compliance and advanced directives.”

—Gary M. Owens, MD AVBCC conference was one of “firsts.”

He noted, “This is the first time we have had a Congressperson address the group, the first time we have used roundtables to facilitate up-close and intimate conversations with experts, and the first time we have taken a deep dive into cancer patient issues, including compliance and advanced directives.”

Transitions in Cancer Care Dr Deligdish added that the conference is particularly timely. “In the last several years there has been a tremendous focus on cancer care in the United States, on advances in diagnosis and treatment, and also on cost.

Especially in the last 6 months, the discourse has been a focus on the cost of care, the value of care, and the changes that need to be made….The Association for Value-Based Cancer Care has been at the forefront of this conversation,” he said.

Dr Deligdish reminded attendees of the exciting developments in precision medicine, noting, “We know that can-

Continued from cover

cer care starts at the gene level. With genetic sequencing and other biomarker testing, our technology is now radically better than it was even 5 years ago....Developing targeted therapies has accelerated dramatically as a result of our understanding of molecular diagnostics.”

With all the recent changes in oncology, Dr Deligdish emphasized, “The challenge going forward is to better standardize our care and increase the value we deliver…and understand how to do that in the context of pathways that need to be flexible.”

“Especially in the last 6 months, the discourse has been a focus on the cost of care, the value of care, and the changes that need to be made….The Association for Value-Based Cancer Care has been at the forefront of this conversation.”

—Craig K. Deligdish, MD

Defining Value in Cancer Care In a preconference session, the AVBCC Steering Committee con­ vened 7 roundtables to define valuebased cancer care from the perspectives of various oncology stakeholders, including treatment pathways, reimbursement, regulatory/policy, patient advocacy, community oncology practices, hospital care, and managed care organizations.

A full coverage of the Steering Committee’s definitions and discussion will be presented in a future issue of Value-Based Cancer Care. n

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For Florida Congresswoman with a History of Cancer... tient outcomes. Ms Schultz is on the side of the consumer patient—because she is one.

Difficult Choices after a Cancer Diagnosis At the age of 41, Ms Schultz was diagnosed with early breast cancer. Her treatment options were fairly straightforward—lumpectomy and radiotherapy. “That would have been the end of it, had a nurse educator not asked for my health history,” she said.

However, her family history of breast cancer and being an Ashkenazi Jew were red flags for carrying the BRCA mutation (ie, the “breast cancer gene”). “My nurse educator suggested BRCA testing, and this process pre-

was fortunate to be at the stage in life when I had married and had children.

But change my age to 25, and my decision would have been even more significant.”

Thus began Ms Schultz’s journey from a breast cancer diagnosis and survival to her fight against patent protection for genes and the tests that identify them.

She explained that what she most wanted at that time was simply a second opinion. “When I asked about the reliability of this test, I was told it is 100%. Well, knowing that nothing in life is 100%, I knew I would feel better if I could confirm the results. But that was impossible under the current situation.”

“I underwent 7 major surgeries: a double mastectomy and oophorectomy from the administration of a single test at age 41. I was fortunate to be at the stage in life when I had married and had children. But change my age to 25, and my decision would have been even more significant.”

—Debbie Wasserman Schultz

sented a new set of challenges and questions for which no woman could be prepared,” Ms Schultz told AVBCC conference attendees.

“My test showed that I clearly had the BRCA mutation, which conveys an 85% lifetime risk of breast cancer and a 60% risk of ovarian cancer. But I could do nothing to obtain a confirmatory test,” she said. “I underwent 7 major surgeries: a double mastectomy and oophorectomy from the administration of a single test at age 41. I

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The Genetic Patent Controversy Myriad Genetics, Inc, currently holds the patent on the BRCA1 and BRCA2 genes, and an exclusive license for the laboratory assay for these mutations. By patenting the genes, Myriad has exclusive control over diagnostic testing and further research for the BRCA genes.

“Currently, there is no way for a woman questioning her genetic risk to get a second opinion, and for many women, the test results are inconclu-

sive,” she said. These genes “hold the key to survival” and guide women in their decision to undergo body-altering surgery, Ms Schultz emphasized.

On May 12, 2009, the American Civil Liberties Union (ACLU) and the Public Patent Foundation filed a lawsuit charging that patents on the BRCA1 and BRCA2 genes, along with patents for several methods of diagnostic screening for the genes, are unconstitutional and invalid. A federal judge ruled that 7 patents were indeed invalid, but this decision was later overruled by an appeals court. Now, the Supreme Court is re-examining the claim regarding the patentability of human genes.

The ACLU argued the case before the US Supreme Court on April 15, 2013. Myriad argued that once a gene is isolated, and therefore distinguishable from other genes, it can be patented. Petitioners argued that patenting those genes violated the Patent Act, because they were products of nature.

They also argued that the patents limit scientific progress. A decision is expected this summer.

The suit, Association for Molecular Pathology v. Myriad, is backed by researchers, genetic counselors, cancer survivors, breast cancer and women’s health groups, and scientific associations representing 150,000 geneticists, pathologists, and laboratory professionals.

“No woman should have to go through this process without the confidence of a second opinion, with so much at stake,” Ms Schultz argued. “It is important to give everyone as much certainty as possible when life hangs in the balance.”

Extending to the wider field of the commercialization of genetics, she noted that assays are available for many disorders; however, in 80% of cases, the test can only be performed by 1 laboratory because of patent exclusivity.

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“No woman should have to go through this process without the confidence of a second opinion, with so much at stake. It is important to give everyone as much certainty as possible when life hangs in the balance.”

—Debbie Wasserman Schultz

Commenting on her commitment to this issue, Ms Schultz said, “I knew that, with my personal story, I had to do something about this.”

Praise for AVBCC’s Focus on Value At the podium, Congresswoman Schultz also took the opportunity to applaud AVBCC for its continuing focus on “bending the cost curve for patients and families, which has also been a focus of Congress in the last few years.”

“You’ve dedicated your organization to providing affordable, quality care. I appreciate your dedication to America’s health and well-being, and I look forward to your results,” she added. n

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ASCO Urging Oncologists to Consider Value in Patient Care

By Caroline Helwick

Hollywood, FL—At the Third Annual Conference of the Association for ValueBased Cancer Care, Sandra M. Swain, MD, FACP, President of the American Society of Clinical Oncology (ASCO) and Medical Director of Washington Cancer Institute in Washington, DC, described efforts by ASCO to enhance the quality and cost-effectiveness of the cancer care its members provide.

ASCO’s Focus on Quality and Cost Speaking for ASCO’s membership, Dr Swain said, “Oncologists have always wanted to provide the best care for their patients, but the discussion about value and quality is not something that we had in medical school.”

ASCO has carved out approaches to address the needs for quality and value in oncology, by creating a task force, communication tools, and performance measures. “We are showing oncologists that we are being proactive about the cost of care,” Dr Swain said.

She outlined the following ways in which ASCO is demonstrating value through performance measurement: • Implementation of ASCO’s Quality Oncology Practice Initiative (QOPI) as a national platform • Transparent, flexible, and meaningful measures • Specialty society leadership can enhance provider buy-in • Outreach to payer community, including Centers for Medicare & Medicaid Services • ASCO led development of multispecialty consensus on criteria for quality-focused registries—hope is that these can satisfy physician quality reporting system requirements.

ASCO recognizes that providers should not shy away from discussing

costs with patients. In 2007, ASCO established the Cost of Cancer Care Task Force to develop strategies related to cost. In 2009, ASCO expanded this to their Guidance Statement on

“We are committed to providing tools to physicians to discuss cost with patients.

It is important, with all the turbulence in the healthcare field, for them to understand healthcare plans.”

—Sandra M. Swain, MD, FACP

Cost, which maintained that “communicating with patients about cost is a key component of high-quality care.”

This was followed up with a booklet for patients, Managing the Cost of Cancer Care, that was written to help guide these conversations.

“We are committed to providing tools to physicians to discuss cost with patients. It is important, with all the turbulence in the healthcare field, for them to understand healthcare plans,” she pointed out.

Currently, a pilot “treatment regimen tool” for physicians is nearing completion; this assesses the benefit, toxicity, and cost across regimens and will serve as support for patient– physician decision-making. Physician education about cost of care is also provided through ASCO University webinars. In 2010, ASCO issued a

Table Stewardship of Limited Resources Question the following clinical practices before doing them:

1. Use of chemotherapy for patients with advanced cancers who are unlikely to benefit and who would gain more from a focus on palliative care and symptom management

2. For early breast cancer, use of advanced imaging technologies (ie, CT, PET, and radionuclide bone scans) in cancer staging 3. For early prostate cancer, use of advanced imaging technologies (ie, CT, PET, and radionuclide bone scans) in cancer staging

4. Routine use of advanced imaging and blood biomarker tests for women treated with curative therapy for breast cancer and who have no symptoms of recurrence 5. Use of white-cell stimulating factors for patients who are at low risk for febrile neutropenia CT indicates computed tomography; PET, positron emission tomography.

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guidance statement on advanced cancer, which encourages earlier conversations about patient options and preferences for end-of-life care. In a joint effort with C-Change, an organization comprised of key cancer leaders, ASCO is promoting greater uptake of palliative care and hospice.

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Choosing Wisely Program ASCO is particularly proud of its new Choosing Wisely program, which guides physicians in the “stewardship of limited resources,” Dr Swain noted.

The Choosing Wisely program developed by the ASCO Cost of Cancer Care Task Force asks physicians to question 5 common practices that are not typically cost-effective, as outlined in the Table. The next 6 questions will be unveiled later this year.

Quality Oncology Practice Initiative ASCO’s QOPI is an oncologist-led, practice-based quality improvement program aimed at promoting excellence in cancer care by helping practices create a culture of self-examination and improvement. The oncologists perform chart reviews of their practices, comparing their performance on 150 quality core measures to national or regional aggregates. To date, 167 practices have become QOPI-certified.

ASCO hopes to unveil a digital version of QOPI by the end of this year.

CancerLINQ Most of the evidence basis for cancer treatment is generated from clinical trials, but only approximately 3% of patients with cancer enroll in trials. Therefore, real-life results are often different from those seen in clinical trials.

A new database called CancerLINQ (Learning Intelligence Network for Quality) will collect and analyze cancer care data from patient visits to create a knowledge base that can be

accessed in real time by clinicians, researchers, and patients. “We want to generate data based on these 95%.

Every patient will become a knowledge donor,” Dr Swain stated (Figure).

“Oncologists who access CancerLINQ will receive the right decision support at the point of care, to help them select treatments for individual patients,” she added.

A pilot program of patients with breast cancer confirmed the program’s feasibility. In the prototype, more than 100,000 anonymous patient records have been supplied by participating practices, yielding millions of data points (eg, on patient characteristics, treatments, and outcomes) that will ultimately be aggregated into a usable format. This should be particularly helpful in the case of patients who have rare tumors or who have unusual histologies.

Applied to oncology, a rapid learning system through CancerLINQ “will revolutionize the way oncology practices measure and improve the quality of the care,” Dr Swain maintained.

Figure ASCO CancerLinQ

The treatment experience of 95% of people with cancer is isolated in their individual medical records.

CancerLinQ will collect data, analyze it, create knowledge, and then provide real-time access for doctors, researchers, and patients.

A New Value Task Force “Most efforts are currently around cost, but we know it’s also about toxicity, quality of life, and so forth,” Dr Swain noted. ASCO’s board has recently created a Value Task Force to define a value-based framework for cancer care.

A working group will explore a cate­gorical model with weighted value components, including efficacy, toxicity, cost, and patient preference.

The plan is to include a wide range of stakeholders to develop and to disseminate the program.

“We plan to look at this issue during the next year and to eventually be able to measure the value that gives the best quality of life,” Dr Swain concluded. n

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Managed Markets: Payers’ Perspectives on Transforming Care Delivery

By Caroline Helwick

Hollywood, FL—At the Third Annual Conference of the Association for Value-Based Cancer Care, James Lang, PharmD, Vice President of Pharmacy Services at BlueCross BlueShield of Michigan (BCBSM), shared his company’s approach to new managed market challenges.

Dr Lang noted that for each step across the managed market landscape, BCBSM built a “rigorous, intricate infrastructure.” The company has had incentive programs in place for more than a decade, having rolled out its

first Collaborative Quality Initiative in 1997 (Figure 1).

In 2004, based on the chronic care model, BCBS implemented its Physician Group Incentive Program (PGIP). The program rewards physicians for improved performance and efficiency and offers shared savings.

“For providers, participation in the PGIP can mean 10% to 20% of the E&M [evaluation and management] code. It’s a substantial part of their reimbursement,” Dr Lang noted.

This was followed by the pa-

Figure 1 PGIP Catalyzing Health System Transformation in Partnership with Providers

• Transform care processes to effectively manage chronic conditions • Build registry and reporting capabilities to manage populations of patients • Achieve savings in specified areas • Reward physicians for improved performance and efficiency • Share savings

• Build PCMH infrastructure • Strengthen doctor–patient relationship • Support primary care physicians and their teams’ ability to effectively manage care • Coordinate care across the continuum for a defined patient population • Establish linkages with community services

• Support establishment of systems of care that assume responsibility and accountability for managing a defined population of patients across all locations of care

1997 Implement first Collaborative Quality Initiative

Expand PGIP Implement to include PCMH and specialists quality/use involved in initiatives chronic care

Continue to increase number of initiatives

Continue to add new specialties to PGIP

Extend providerdelivered care management with links to BlueCross BlueShield of Michigan for customer reporting statewide

ACOs indicates accountable care organizations; PCMH, patient-centered medical home; PGIP, Physician Group Incentive Program.

Figure 2 Channel Management Specialty drug spending

New cross-functional distribution channel management abilities: • Benefit design

Medical

Pharmacy

• Claim editing Outpatient

Specialty vendor

Inpatient

Mail-order vendor

• Physician Group Incentive Program

Physicians

Retail

• Utilization management programs

-Prior authorization

-Off-label review

-Pipeline monitoring

Durable medical equipment

• Expansion of vendor management • Reimbursement enhancements to take advantage of the most cost-effective care setting

• Provider services

-Electronic prescribing

-Medication adherence

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Home infusion Hemophilia provider

tient-centered medical home (PCMH) program, a model of “primary care transformation.” The newest component of this is the PCMH “neighborhood concept,” which links to other specialties beyond oncology and includes medical management as a requirement. The company’s PCMH is the largest medical home in the country, encompassing 3000 physicians and impacting 2 million members.

Most recently, under an organized system-of-care model, BCBSM added its accountable care organizations, which currently total 38. Hospital incentive contracts are now “bringing hospitals along on this same journey,” Dr Lang said.

Three years ago, provider-delivered care management was implemented, and it now encompasses 400 practices, which are largely primary care. It is an extension of the Michigan Primary Care Transformation program, which is a collaborative effort with Medicare.

Physicians receive trained nurse managers and can identify patients within their practices who warrant greater attention from these “embedded care managers.”

Physician organizations report a positive impact on clinical indicators, but “it’s been a bit of a struggle, as practices do have to reengineer themselves,” Dr Lang acknowledged.

Oncology practices will be added in 2014.

Channel Management The escalating cost of drugs led BCBSM to rethink the delivery of pharmacy services. Over the past 5 years, drugs administered under the medical benefit have been shifting from physicians’ offices to more costly outpatient facilities.

In 2008, the aggregate spending on drugs in the medical benefit (ie, outpatient setting) was $150 million; by 2012, this spending approached $300 million—a 20% rate of growth. Drug spending under the specialty pharmacy benefit rose from $250 million to $350 million, an 8% increase. By contrast, under the physician buy-andbill model, drug spending increased only 1.5%, remaining essentially stable at around $325 million.

“This trend caused me to reorganize how we deliver our services in pharmacy,” Dr Lang said. The result was a cross-functional “channel management” form of distribution, as outlined in Figure 2.

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“For providers, participation in the PGIP can mean 10% to 20% of the E&M [evaluation and management] code. It’s a substantial part of their reimbursement.”

—James Lang, PharmD

Specialty Drug Management Techniques Dr Lang outlined BCBSM’s approach to managing specialty pharmacy. Among the techniques it implements are prior authorization, formulary tiers, off-label limitations, preferred specialty pharmacy, physician specialty treatment dashboard and data set, oncology pathways, pipeline monitoring, and more.

In 2014, the company will also start implementing National Drug Code level pricing and National Drug Code level quantity required, ambulatory infusion benefits, channel efficiency reporting to physicians, global per-member per-month targets (which are currently in place), and specific specialty drug per-member per-month targets.

“We will have the ability to split J code professional claims. We will know what drug is being prescribed,” he said.

The challenges with specialty drug management will remain the obstacles of state and federal mandates, difficult provider contracts, the potential for fraud, problems with manufacturer copay cards, and physician buy-andbill issues, Dr Lang added. n

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WellPoint’s Perspective on Value-Based Cancer Care for Today and Tomorrow

By Caroline Helwick

Hollywood, FL—“The overarching issue that brings us to the AVBCC Annual Conference is that rising healthcare costs are unsustainable,” said Jennifer Malin, MD, PhD, Medical

“In 5 years, premiums and out-of-pocket costs for a family are projected to equal half the median household income. Our challenge is to come to terms with this and continue to innovate in ways that ensure patients have high-quality care.”

Director of Oncology at WellPoint, Inc, who spoke at the Third Annual Conference of the Association for Value-Based Cancer Care from the perspective of managed markets.

“In 5 years, premiums and out-ofpocket costs for a family are projected to equal half the median household income,” she noted. “Our challenge is to come to terms with this and continue to innovate in ways that ensure patients have high-quality care.”

A System Out of Alignment New technologies, such as intensity-modulated radiation therapy for prostate cancer, are rapidly adopted, and although they are expensive, their benefit over conventional therapies is often unproven. Ironically, lower-cost therapies that produce equal or better outcomes are adopted more slowly.

In a recent study of radiotherapy for breast cancer, 62% of the patients preferred hypofractionated whole-breast irradiation, which requires fewer treatments than other modalities, but 56% of the radiation oncologists surveyed admitted to never using this approach (Hoopes DJ, et al. Int J Radiat Oncol Biol Phys. 2012;82:674-681). “This is not patient-centered care,” Dr Malin maintained.

Based on WellPoint data, although money is freely spent on technology and drugs in cancer care, with the majority going to chemotherapy (25%)

Figure Technology and Drugs Account for Most of the Cost in Cancer Care 4% 3% n Chemotherapy

11% 25%

n Diagnostic imaging n Surgery 18%

n Hospitalization n Other outpatient 15%

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n Pharmacy n Physician visits

16% 8% Source: WellPoint, Inc, data on file.

and radiation oncology (15%), only 3% of healthcare dollars are spent on physician visits (Figure). “This represents a system that is out of alignment,” she commented. Margins on chemotherapy largely support the average oncology practices, but patient-centered care should be incentivized through direct payments, according to Dr Malin.

Multiple regimens are approved for most tumor types, and although their —Jennifer Malin, MD, PhD toxicities may vary, the differences in outcomes with these regimens are often clinically insignificant. A poignant example comes from Table 1 Variation in Outcomes Across First-Line Regimens for NSCLC a comparison of 6 Comparison of outcomes with 6 platinum-based doublet regimens regimens for the treatment of non– Survival after small-cell lung canEstimated Deaths while platinum-based cer (Table 1). The mesurvival, Serious taking a Chemotherapy chemotherapy, dian overall survival months AEs, % prescription, % cycles, N months ranged from approxPrescription A 10.4 18 0.5 5 6.7 imately 10 months Prescription B 13.1 35 4 5 9.4 with the oldest regimens to 13 months Prescription C 13.4 44 5 5 9.7 with the newer ones.

Prescription D 13.4 30 2 6 8.9 Although patients 7 5 8.1 Prescription E 11.8 35a “probably would not split hairs over this” Prescription F 12.6 35+? ?

4 9.6 survival difference, • What is more important to the individual with cancer—overall survival or quality time Dr Malin suggestwhen not receiving chemotherapy, not in hospital? ed, toxicity might be •Which regimen would you choose if you were that individual? more important to a many patients. The Not reported; assumed to be the same as Prescription A, because hospitalization rates were rates of serious addifferent in randomized trials that compared them. verse events also had AEs indicates adverse events; NSCLC, non–small-cell lung cancer. significant differSources: Sandler A, et al. N Engl J Med. 2006;355:2542-2550; Scagliotti GV, et al. J Clin Oncol. ences per regimen, 2008;26:3543-3551; Reck M, et al. Ann Oncol. 2010;21:1804-1809. ranging from 18% to

12

n Radiation oncology

more than 44% and deaths while receiving treatment ranged from 0.5% to 7%.

The cost differential was also significant. “When you omit the oldest regimen, with the lowest survival, there is over a 7-fold variation in cost, for what I would argue are slight differences in outcomes. Where is the value here?”

Dr Malin questioned (Table 2, page 20).

Improving Value in the Near- and Long-Term To help deal with big differences in costs relative to small differences in outcomes, WellPoint is implementing a new evidence-based decision support tool aimed at streamlining approval for episodes of care. It is a “road map” that supports value-based cancer care—ie, care that is appropriate and consistent with patient preferences—and discourages the use of regimens that are more expensive but offer no additional value.

To improve value in the near-term, WellPoint supports innovation in community practices by increasing chemotherapy administration fees and instituting tiered reimbursement for chemotherapy, and by instituting preauthorization of episode of care and reimbursement that will be tied to the overall adherence to pathways.

The increasing focus on a medical home is a long-term way for improving value, with an emphasis on treatment planning and care coordination, payment linked to performance based Continued on page 20

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POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy. Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

NOW APPROVED Introducing an oral medication for patients with refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and bortezomib

WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial.

Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis POMALYST is only available under a restricted distribution program, POMALYST REMS™.

Please see brief summary of full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS, and Important Safety Information on following pages.

To find out more information about POMALYST, go to www.pomalyst.com or use your smartphone to scan this code.

POMALYST® (pomalidomide) is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Important Safety Information WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment • Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment POMALYST is only available through a restricted distribution program called POMALYST REMS™.

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors

CONTRAINDICATIONS: Pregnancy • POMALYST can cause fetal harm and is contraindicated in females who are pregnant. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus • Pomalidomide is a thalidomide analogue and is teratogenic in both rats and rabbits when administered during the period of organogenesis

WARNINGS AND PRECAUTIONS Embryo-Fetal Toxicity

• Females of Reproductive Potential: Must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Must commit either to abstain continuously from heterosexual sexual intercourse or to use 2 methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Must obtain 2 negative pregnancy tests prior to initiating therapy • Males: Pomalidomide is present in the semen of patients receiving the drug. Males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Males must not donate sperm • Blood Donation: Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST

POMALYST REMS Program Because of the embryo-fetal risk, POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Prescribers and pharmacists must be certified with the program; patients must sign an agreement form and comply with the requirements. Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

Venous Thromboembolism: Patients receiving POMALYST have developed venous thromboembolic events reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or antithrombotic treatment. The rate of DVT or PE was 3%. Consider anticoagulation prophylaxis after an assessment of each patient’s underlying risk factors.

Hematologic Toxicity: Neutropenia of any grade was reported in 50% of patients and was the most frequently reported Grade 3/4 adverse event, followed by anemia and thrombocytopenia. Monitor patients for hematologic toxicities, especially neutropenia, with complete blood counts weekly for the first 8 weeks and monthly thereafter. Treatment is continued or modified for Grade 3 or 4 hematologic toxicities based upon clinical and laboratory findings. Dosing interruptions and/or modifications are recommended to manage neutropenia and thrombocytopenia.

Hypersensitivity Reactions: Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide

were excluded from studies and may be at higher risk of hypersensitivity.

Dizziness and Confusional State: 18% of patients experienced dizziness and 12% of patients experienced a confusional state;

1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice.

WARNINGS AND PRECAUTIONS (continued) Neuropathy: 18% of patients experienced neuropathy (approximately 9% peripheral neuropathy). There were no cases of grade 3 or higher neuropathy adverse reactions reported.

Risk of Second Primary Malignancies: Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

ADVERSE REACTIONS In the clinical trial of 219 patients who received POMALYST alone (n=107) or POMALYST + low-dose dexamethasone (low-dose dex) (n=112), all patients had at least one treatment-emergent adverse reaction.

• In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common adverse reactions (≥30%) included fatigue and asthenia (55%, 63%), neutropenia (52%, 47%), anemia (38%, 39%), constipation (36%, 35%), nausea (36%, 22%), diarrhea (34%, 33%), dyspnea (34%, 45%), upper respiratory tract infection (32%, 25%), back pain (32%, 30%), and pyrexia (19%, 30%) • 90% of patients treated with POMALYST alone and 88% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent NCI CTC Grade 3 or 4 adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common Grade 3/4 adverse reactions (≥15%) included neutropenia (47%, 38%), anemia (22%, 21%), thrombocytopenia (22%, 19%), and pneumonia (16%, 23%). For other Grade 3 or 4 toxicities besides neutropenia and thrombocytopenia, hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion • 67% of patients treated with POMALYST and 62% of patients treated with POMALYST + low-dose dex had at least one treatment-emergent serious adverse reaction • In the POMALYST alone versus POMALYST + low dose dexamethasone arms, respectively, most common serious adverse reactions (≥5%) were pneumonia (14%, 19%), renal failure (8%, 6%), dyspnea (5%, 6%), sepsis (6%, 3%), pyrexia (3%, 5%) dehydration (5%, 3%), hypercalcemia (5%, 2%), urinary tract infection (0%, 5%), and febrile neutropenia (5%, 1%)

DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp). Coadministration of POMALYST with drugs that are strong inhibitors or inducers of CYP1A2, CYP3A, or P-gp should be avoided. Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide.

USE IN SPECIFIC POPULATIONS Pregnancy: If pregnancy does occur during treatment, immediately discontinue the drug and refer patient to an obstetrician/

gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436.

Nursing Mothers: It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, 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: Safety and effectiveness of POMALYST in patients under the age of 18 have not been established.

Geriatric Use: No dosage adjustment is required for POMALYST based on age. Patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia.

Renal and Hepatic Impairment: Pomalidomide is metabolized in the liver. Pomalidomide and its metabolites are primarily

excreted by the kidneys. The influence of renal and hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Avoid POMALYST in patients with a serum creatinine >3.0 mg/dL. Avoid POMALYST in patients with serum bilirubin >2.0 mg/dL and AST/ALT >3.0 x ULN. Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS. POMALYST® is a registered trademark of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation. ©2013 Celgene Corporation 02/13 US-POM120044a

FDA Update FDA Approves Lymphoseek for Breast Cancer and Melanoma

The US Food and Drug Admini­s­ tration (FDA) approved the technetium Tc 99m tilmanocept ([Tc 99m], Lymphoseek Injection; Navidea Biopharmaceuticals)—a novel radioactive receptor-targeted tracer for intraoperative lymphatic mapping—

for use in patients with breast cancer or melanoma who are undergoing surgery to remove tumor-draining nodes. Tc 99m is an imaging drug that helps locate lymph nodes; it is not a cancer imaging drug.

Lymph nodes filter lymphatic fluid that flows from the body’s tissues.

This fluid may contain cancer cells, especially if the fluid drains a part

of the body containing a tumor.

Surgically removing and examining the lymph nodes that drain a tumor in patients with node-negative breast cancer or melanoma can help determine if a cancer has spread.

“Removal and pathological examination of lymph nodes draining a primary tumor is an important diagnostic evaluation for some patients

with breast cancer or melanoma,” said Shaw Chen, MD, Deputy Director of the Office of Drug Evaluation IV in the FDA’s Center for Drug Evaluation and Research. “To use Lymphoseek, doctors inject the drug into the tumor area and later, using a handheld radiation detector, find lymph nodes that have taken up Lymphoseek’s radioactivity.”

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This brief summary does not include all the information needed to use POMALYST® safely and effectively. See full prescribing information for POMALYST. WARNING: EMBRYO-FETAL TOXICITY and VENOUS THROMBOEMBOLISM Embryo-Fetal Toxicity • POMALYST is contraindicated in pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death. In females of reproductive potential, obtain 2 negative pregnancy tests before starting POMALYST treatment.

• Females of reproductive potential must use 2 forms of contraception or continuously abstain from heterosexual sex during and for 4 weeks after stopping POMALYST treatment [see Contraindications (4), Warnings and Precautions (5.1), and Use in Specific Populations (8.1, 8.6)].

POMALYST is only available through a restricted distribution program called POMALYST REMS [see Warnings and Precautions (5.2)].

Venous Thromboembolism • Deep Venous Thrombosis (DVT) and Pulmonary Embolism (PE) occur in patients with multiple myeloma treated with POMALYST. Prophylactic anti-thrombotic measures were employed in the clinical trial. Consider prophylactic measures after assessing an individual patient’s underlying risk factors [see Warnings and Precautions (5.3)].

1 INDICATIONS AND USAGE 1.1 Multiple Myeloma: POMALYST is indicated for patients with multiple myeloma who have received at least two prior therapies including lenalidomide and bortezomib and have demonstrated disease progression on or within 60 days of completion of the last therapy.

Approval is based on response rate [see Clinical Studies (14.1)]. Clinical benefit, such as improvement in survival or symptoms, has not been verified.

Neutropenia • ANC* < 500 per mcL or Febrile neutropenia (fever more than or equal to 38.5°C and ANC < 1,000 per mcL)

Interrupt POMALYST treatment, follow CBC weekly.

• ANC return to more than or equal to Resume POMALYST at 3 mg daily.

500 per mcL • For each subsequent drop < 500 per Interrupt POMALYST treatment mcL • Return to more than or equal to 500 Resume POMALYST at 1 mg less per mcL than the previous dose Thrombocytopenia • Platelets < 25,000 per mcL

Interrupt POMALYST treatment, follow CBC weekly

• Platelets return to > 50,000 per mcL Resume POMALYST treatment at 3 mg daily • For each subsequent drop < 25,000 Interrupt POMALYST treatment per mcL • Return to more than or equal to 50,000 per mcL

Resume POMALYST at 1 mg less than previous dose.

*Note: ANC = Absolute Neutrophil Count For other Grade 3 or 4 toxicities hold treatment and restart treatment at 1 mg less than the previous dose when toxicity has resolved to less than or equal to Grade 2 at the physician’s discretion. To initiate a new cycle of POMALYST, the neutrophil count must be at least 500 per mcL, the platelet count must be at least 50,000 per mcL. If toxicities occur after dose reductions to 1 mg, then discontinue POMALYST. 4 CONTRAINDICATIONS Pregnancy POMALYST can cause fetal harm when administered to a pregnant female [see Warnings and Precautions (5.1) and Use in Specific Populations (8.1)]. POMALYST is contraindicated in females

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5 WARNINGS AND PRECAUTIONS 5.1 Embryo-Fetal Toxicity POMALYST is a thalidomide analogue and is contraindicated for use during pregnancy.

Thalidomide is a known human teratogen that causes severe birth defects or embryo-fetal death [see Use in Specific Populations (8.1)]. POMALYST is only available through the POMALYST REMS program [see Warnings and Precautions (5.2)]. Females of Reproductive Potential Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control, beginning 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy. Two negative pregnancy tests must be obtained prior to initiating therapy. The first test should be performed within 10-14 days and the second test within 24 hours prior to prescribing POMALYST therapy and then weekly during the first month, then monthly thereafter in women with regular menstrual cycles or every 2 weeks in women with irregular menstrual cycles [see Use in Specific Populations (8.6)]. Males Pomalidomide is present in the semen of patients receiving the drug.

Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm [see Use in Specific Populations (8.6)]. Blood Donation Patients must not donate blood during treatment with POMALYST and for 1 month following discontinuation of the drug because the blood might be given to a pregnant female patient whose fetus must not be exposed to POMALYST. 5.2 POMALYST REMS ™ Program Because of the embryo-fetal risk [see Warnings and Precautions (5.1)], POMALYST is available only through a restricted program under a Risk Evaluation and Mitigation Strategy (REMS) called “POMALYST REMS.” Required components of the POMALYST REMS program include the following: • Prescribers must be certified with the POMALYST REMS program by enrolling and complying with the REMS requirements.

• Patients must sign a Patient-Prescriber agreement form and comply with the REMS requirements. In particular, female patients of reproductive potential who are not pregnant must comply with the pregnancy testing and contraception requirements [see Use in Specific Populations (8.6)] and males must comply with contraception requirements [see Use in Specific Populations (8.6)].

• Pharmacies must be certified with the POMALYST REMS program, must only dispense to patients who are authorized to receive POMALYST and comply with REMS requirements.

Further information about the POMALYST REMS program is available at [celgeneriskmanagement.com] or by telephone at 1-888-423-5436.

5.3 Venous Thromboembolism Patients receiving POMALYST have developed venous thromboembolic events (Venous Thromboembolism [VTEs]) reported as serious adverse reactions. In the trial, all patients were required to receive prophylaxis or anti-thrombotic treatment; 81% used aspirin, 16% warfarin, 21% heparin, and 3% clopidogrel. The rate of deep vein thrombosis or pulmonary embolism was 3%. Consider anti-coagulation prophylaxis after an assessment of each patient’s underlying risk factors. 5.4 Hematologic Toxicity Neutropenia was the most frequently reported Grade 3/4 adverse event (AE), followed by anemia and thrombocytopenia. Neutropenia of any grade was reported in 50% of patients in the trial. The rate of Grade 3/4 neutropenia was 43%. The rate of febrile neutropenia was 3%. Monitor patients for hematologic toxicities, especially neutropenia. Monitor complete blood counts weekly for the first 8 weeks and monthly thereafter. Patients may require dose interruption and/or modification [see Dosage and Administration (2.2)]. 5.5 Hypersensitivity Reactions Patients with a prior history of serious hypersensitivity associated with thalidomide or lenalidomide were excluded from studies and may be at higher risk of hypersensitivity. 5.6 Dizziness and Confusional State In the trial, 18% of patients experienced dizziness and 12% of patients experienced a confusional state; 1% of patients experienced grade 3/4 dizziness, and 3% of patients experienced grade 3/4 confusional state. Instruct patients to avoid situations where dizziness or confusion may be a problem and not to take other medications that may cause dizziness or confusion without adequate medical advice. 5.7 Neuropathy In the trial, 18% of patients experienced neuropathy, with approximately 9% of the patients experiencing peripheral neuropathy. There were no cases of grade 3 or higher neuropathy adverse reactions reported.

5.8 Risk of Second Primary Malignancies Cases of acute myelogenous leukemia have been reported in patients receiving POMALYST as an investigational therapy outside of multiple myeloma.

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2 DOSAGE AND ADMINISTRATION 2.1 Multiple Myeloma: Females of reproductive potential must have negative pregnancy testing and use contraception methods before initiating POMALYST [see Warnings and Precautions (5.1) and Use in Specific Populations (8.6)]. The recommended starting dose of POMALYST is 4 mg once daily orally on Days 1-21 of repeated 28-day cycles until disease progression. POMALYST may be given in combination with dexamethasone [see Clinical Studies (14.1)]. POMALYST may be taken with water. Inform patients not to break, chew or open the capsules. POMALYST should be taken without food (at least 2 hours before or 2 hours after a meal).

2.2 Dose Adjustments for Toxicity: Table 1: Dose Modification Instructions for POMALYST for Hematologic Toxicities Toxicity Dose Modification

who are pregnant. Pomalidomide is a thalidomide analogue, and is teratogenic in both rats and rabbits when administered during the period of organogenesis.

If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus.

FDA Update Lymphoseek is the first new drug used for lymph node mapping to be approved by the FDA in more than 30 years.

The approval of Tc 99m was based on 2 clinical trials of 332 patients with melanoma or with breast cancer. All patients were injected with Tc 99m and blue dye, another drug used to help locate lymph nodes. Surgeons

subsequently removed suspected lymph nodes for pathologic examination. Results showed that Tc 99m and blue dye had localized most lymph nodes, although a notable number of nodes were localized only by Tc 99m.

The most common side effects with Tc 99m reported in clinical trials were pain or irritation at the injection site.

(March 13, 2013)

Ibrutinib Gets 3 Breakthrough Therapy Designations

In February 2013, the FDA granted Breakthrough Designation for ibrutinib (Johnson & Johnson) as monotherapy for the treatment of patients with 1 of 2 conditions—refractory or relapsed mantle-cell lymphoma or Waldenström’s macroglobulinemia—

both of which are B-cell malignancies. In April 2013, the FDA granted ibrutinib a third Breakthrough Designation for the treatment of patients with chronic lymphocytic leukemia or small lymphocytic lymphoma with chromosome 17p deletion.

(April 8, 2013) Continued on page 18

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6 ADVERSE REACTIONS The following adverse reactions are described in detail in other labeling sections: • Fetal Risk [see Boxed Warnings, Warnings and Precautions (5.1, 5.2)] • Venous Thromboembolism [see Boxed Warnings, Warnings and Precautions (5.3)] • Hematologic Toxicity [see Warnings and Precautions (5.4)] • Hypersensitivity Reactions [see Warnings and Precautions (5.5)] • Dizziness and Confusional State [see Warnings and Precautions (5.6)] • Neuropathy [see Warnings and Precautions (5.7)] • Risk of Second Primary Malignancies [see Warnings and Precautions (5.8)] 6.1 Clinical Trials Experience in Multiple Myeloma 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. In clinical trial 1, data were evaluated from 219 patients (safety population) who received treatment with POMALYST + Low Dose Dexamethasone (Low dose Dex) (112 patients) or POMALYST alone (107 patients). Median number of treatment cycles was 5. Sixty three percent of patients in the study had a dose interruption of either drug due to adverse reactions. Thirty seven percent of patients in the study had a dose reduction of either drug due to adverse reactions. The discontinuation rate due to treatment-related adverse reaction was 3%. Tables 2, 3 and 4 summarize all treatment-emergent adverse reactions reported for POMALYST + Low dose Dex and POMALYST alone groups regardless of attribution of relatedness to pomalidomide. In the absence of a randomized comparator arm, it is often not possible to distinguish adverse events that are drug-related and those that reflect the patient’s underlying disease.

Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm Trial 1 POMALYSTa

System Organ Class/Preferred Term Number(%) of Patients With at Least One Treatment Emergent Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

107 (100)

112 (100)

59 (55)

70 (63)

Pyrexia

20 (19)

34 (30)

Edema peripheral

25 (23)

18 (16)

Chills

10 (9)

12 (11)

Pain

6 (6)

5 (5)

Blood and lymphatic system disorders Neutropenia

56 (52)

53 (47)

Anemia

41 (38)

44 (39)

Thrombocytopenia

27 (25)

26 (23)

Leukopenia

12 (11)

20 (18)

4 (4)

17 (15)

38 (36)

39 (35)

Gastrointestinal disorders Constipation Diarrhea

36 (34)

37 (33)

Nausea

38 (36)

25 (22)

Vomiting

15 (14)

15 (13)

Infections and infestations Pneumonia

25 (23)

32 (29)

Upper respiratory tract infection

34 (32)

28 (25)

8 (8)

18 (16)

Urinary tract infection

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POMALYST + Low dose Dex (N=112)

n (%)

n (%)

Back pain

34 (32)

34 (30)

Musculoskeletal chest pain

23 (22)

22 (20)

Muscle spasms

20 (19)

21 (19)

System Organ Class/Preferred Term Musculoskeletal and connective tissue disorders

Arthralgia

17 (16)

17 (15)

Musculoskeletal pain

12 (11)

17 (15)

Pain in extremity

5 (5)

16 (14)

Muscular weakness

13 (12)

13 (12)

Bone pain

13 (12)

5 (5)

Dyspnea

36 (34)

50 (45)

Cough

15 (14)

23 (21)

Epistaxis

16 (15)

12 (11)

Respiratory, thoracic and mediastinal disorders

Metabolism and nutritional disorders Decreased appetite

23 (22)

20 ( 18)

Hyperglycemia

13 ( 12)

17 ( 15)

Hyponatremia

11 ( 10)

14 ( 13)

Hypercalcemia

22 ( 21)

13 (12)

Hypocalcemia

6 (6)

13 ( 12)

Hypokalemia

11 ( 10)

12 ( 11)

6 ( 6)

18 ( 16)

23 ( 22)

18 ( 16)

Skin and subcutaneous tissue disorders Hyperhidrosis

Fatigue and asthenia

Lymphopenia

Trial 1 POMALYSTa

Rash Night sweats

5 ( 5)

14 ( 13)

Dry skin

10 ( 9)

12 ( 11)

Pruritus

16 ( 15)

12 ( 11)

Dizziness

21 ( 20)

19 ( 17)

Tremor

10 ( 9)

14 ( 13)

Headache

14 ( 13)

9 ( 8)

Neuropathy peripheral

11 ( 10)

8 ( 7)

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Table 2: Adverse Reactions Reported in 10% of Patients in Any Treatment Arm

Nervous system disorders

Investigations Blood creatinine increased

16 ( 15)

12 ( 11)

Weight increased

1 ( 1)

12 ( 11)

Weight decreased

15 ( 14)

9 ( 8)

Psychiatric disorders Insomnia

7 ( 7)

16 ( 14)

Confusional state

11 ( 10)

15 ( 13)

Anxiety

12 ( 11)

8 ( 7)

16 ( 15)

11 ( 10)

Renal and urinary disorders Renal failure aPOMALYST

alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period

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FDA Update Palbociclib Receives Breakthrough Therapy Designation

The FDA has granted a Break­ through Therapy designation for the investigational drug palbociclib (PD0332991; Pfizer)—an oral, selective inhibitor of cyclin-dependent kinases (CDKs) 4 and 6—for the potential treatment of patients with breast can-

cer. CDKs 4 and 6 are related kinases that enable tumor-cell progression, which enhances cell division and DNA replication. Inhibition of CDKs 4 and 6 with palbociclib has been shown to inhibit tumor-cell growth and DNA replication.

The designation of a Breakthrough Therapy is intended to expedite the FDA review of new medications for

life-threatening conditions when preliminary evidence suggests significant improvement with a specific medication compared with currently available therapies.

The Breakthrough Therapy designation was based on data from several phase 2 clinical trials of patients with breast cancer.

Interim results were presented at T:7”

Table 3: Grade 3/4 Adverse Reactions Reported in ≥5% of Patients in Any Treatment Arm

the 2012 San Antonio Breast Cancer Symposium, showing that women with breast cancer who received palbociclib plus letrozole demonstrated a significant improvement in progression-free survival compared with women who received letrozole alone—26.1 months versus 7.5 months, respectively. (April 10, 2013)

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1

Trial 1 POMALYSTa

System Organ Class/Preferred Term [a] Number(%) of Patients With at Least One Treatment Emergent NCI CTC Grade 3 or 4 Adverse Reaction

(N = 107)

POMALYST + Low dose Dex (N=112)

n (%)

n (%)

96 ( 90)

99 ( 88)

Neutropenia

50 ( 47)

43 ( 38)

Anemia

24 ( 22)

23 ( 21)

Thrombocytopenia

24 ( 22)

21 ( 19)

Leukopenia

6 ( 6)

11 ( 10)

Lymphopenia

2 ( 2)

8 ( 7)

Infections and infestations 26 (23)

2 ( 2)

9 ( 8)

Sepsis

6 ( 6)

3 ( 3)

10 ( 9)

1 ( 1)

12 ( 11)

14 ( 13)

6 ( 6)

3 ( 3)

7 ( 7)

14 ( 13)

13 ( 12)

10 ( 9)

6 ( 6)

4 ( 4)

10 ( 9)

7 ( 6)

Metabolism and nutritional disorders General disorders and administration site conditions Fatigue and asthenia Investigations Blood creatinine increased Respiratory, thoracic and mediastinal disorders Dyspnea Musculoskeletal and connective tissue disorders Back pain Muscular weakness Renal and urinary disorders Renal failure a

POMALYST alone arm includes all patients randomized to the pomalidomide alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Table 4: Serious Adverse Reactions Reported in 2 or more Patients Trial 1 POMALYSTa (N = 107)

POMALYST + Low dose Dex (N=112)

System Organ Class/Preferred Term

n (%)

n (%)

Number(%) of Patients With at Least One Treatment Emergent Serious Adverse Reaction

72 ( 67)

69 ( 62)

Pneumonia

15 (14)

21 (19)

Urinary tract infection

0 ( 0)

6 ( 5)

Sepsis

6 ( 6)

3 ( 3)

5 (5)

7 (6)

Pyrexia

3 (3)

5 (5)

General physical health deterioration

0 (0)

2 (2)

Atrial fibrillation

2 (2)

3 (3)

Cardiac failure congestive

0 (0)

3 (3)

Infections and infestations

Respiratory, Thoracic and mediastinal disorders Dyspnea General disorders and administration site conditions

Cardiac Disorders

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n (%)

n (%)

9 (8)

7 (6)

1 (1)

3 (3)

5 (5)

1 (1)

Dehydration

5 (5)

3 (3)

Hypercalcemia

5 (5)

2 (2)

4 (4)

2 (2)

System Organ Class/Preferred Term Renal and urinary disorders Renal failure Gastrointestinal disorders Blood and Lymphatic system disorders Febrile neutropenia Metabolism and nutrition disorders

Musculoskeletal and connective tissue disorders Back pain

[a] POMALYST alone arm includes all patients randomized to the POMALYST alone arm who took study drug; 61 of the 107 patients had dexamethasone added during the treatment period.

Other Adverse Reactions Other adverse reactions of POMALYST in patients with multiple myeloma, not described above, and considered important: Ear and Labyrinth Disorders: Vertigo; Hepatobiliary Disorders: Hyperbilirubinemia; Infections and Infestations: Pneumocystis jiroveci pneumonia, Respiratory syncytial virus infection, Neutropenic sepsis; Investigations: Alanine aminotransferase increased; Metabolism and Nutritional Disorders: Hyperkalemia; Renal and Urinary Disorders: Urinary retention; Reproductive System and Breast Disorders: Pelvic Pain; Respiratory, Thoracic and Mediastinal Disorders: Interstitial Lung Disease 7 DRUG INTERACTIONS No formal drug interaction studies have been conducted with POMALYST. Pomalidomide is primarily metabolized by CYP1A2 and CYP3A. Pomalidomide is also a substrate for P-glycoprotein (P-gp).

7.1 Drugs That May Increase Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inhibitors: Co-administration of POMALYST with drugs that are strong inhibitors of CYP1A2, CYP3A (e.g. ketoconazole) or P-gp could increase exposure and should be avoided. 7.2 Drugs That May Decrease Pomalidomide Plasma Concentrations: CYP3A, CYP1A2 or P-gp inducers: Co-administration of POMALYST with drugs that are strong inducers of CYP1A2, CYP3A (e.g. rifampin) or P-gp could decrease exposure and should be avoided.

Smoking: Cigarette smoking may reduce pomalidomide exposure due to CYP1A2 induction. Patients should be advised that smoking may reduce the efficacy of pomalidomide. Dexamethasone: Co-administration of multiple doses of 4 mg POMALYST with 20 mg to 40 mg dexamethasone (a weak inducer of CYP3A) to patients with multiple myeloma had no effect on the pharmacokinetics of pomalidomide compared with pomalidomide administered alone.

8 USE IN SPECIFIC POPULATIONS 8.1 Pregnancy Pregnancy Category X [see Boxed Warnings and Contraindications (4)] Risk Summary POMALYST can cause embryo-fetal harm when administered to a pregnant female and is contraindicated during pregnancy. POMALYST is a thalidomide analogue. Thalidomide is a human teratogen, inducing a high frequency of severe and life-threatening birth defects such as amelia (absence of limbs), phocomelia (short limbs), hypoplasticity of the bones, absence of bones, external ear abnormalities (including anotia, micropinna, small or absent external auditory canals), facial palsy, eye abnormalities (anophthalmos, microphthalmos), and congenital heart defects. Alimentary tract, urinary tract, and genital malformations have also been documented and mortality at or shortly after birth has been reported in about 40% of infants. Pomalidomide was teratogenic in both rats and rabbits when administered during the period of organogenesis. If this drug is used during pregnancy or if the patient becomes pregnant while taking this drug, the patient should be apprised of the potential hazard to a fetus. If pregnancy does occur during treatment, immediately discontinue the drug. Under these conditions, refer patient to an obstetrician/ gynecologist experienced in reproductive toxicity for further evaluation and counseling. Report any suspected fetal exposure to POMALYST to the FDA via the MedWatch program at 1-800-332-1088 and also to Celgene Corporation at 1-888-423-5436. Animal Data Pomalidomide was teratogenic in both rats and rabbits in the embryofetal developmental studies, when administered during the period of organogenesis. In rats, pomalidomide was administered orally to pregnant animals at doses of 25 to 1000 mg per kg per day. Malformations of absence of urinary bladder, absence of thyroid gland, and fusion and Cosmos Communications K

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Urinary tract infection

Hypercalcemia

POMALYST + Low dose Dex (N=112)

constipation

Blood and lymphatic system disorders

Pneumonia

POMALYSTa (N = 107)

FDA Update Confusion with Kadcyla’s Generic Name Linked to Medication Errors

The FDA warned healthcare professionals about potential medication errors resulting from confusion with the nonproprietary name for the recently approved breast cancer drug ado-trastuzumab emtansine (Kadcyla; also known as T-DM1).

The FDA noted that in various online publications and in different medical electronic systems the drug is sometimes referred to incorrectly as trastuzumab, which is the active ingredient in the older breast cancer drug Herceptin, which had a different dosing and a different treatment schedule.

The FDA-approved nonproprietary

name for Kadcyla is “ado-trastuzu­ mab emtansine” but the prefix “ado-” is often dropped, which may lead to the confusion with trastuzumab (ie, Herceptin) the FDA notes that it is therefore important to keep the prefix with the nonproprietary name when referring to Kadcyla, when prescribing the medication, and in electronic medical records (EMRs) or any online

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diaphragm or cervical cap. Contraception must begin 4 weeks prior to initiating treatment with POMALYST, during therapy, during dose interruptions and continuing for 4 weeks following discontinuation of POMALYST therapy.

Reliable contraception is indicated even where there has been a history of infertility, unless due to hysterectomy. Females of reproductive potential should be referred to a qualified provider of contraceptive methods, if needed. Females of reproductive potential must have 2 negative pregnancy tests before initiating POMALYST. The first test should be performed within 10-14 days, and the second test within 24 hours prior to prescribing POMALYST. Once treatment has started and during dose interruptions, pregnancy testing for females of reproductive potential should occur weekly during the first 4 weeks of use, then pregnancy testing should be repeated every 4 weeks in females with regular menstrual cycles. If menstrual cycles are irregular, the pregnancy testing should occur every 2 weeks. Pregnancy testing and counseling should be performed if a patient misses her period or if there is any abnormality in her menstrual bleeding. POMALYST treatment must be discontinued during this evaluation. Males Pomalidomide is present in the semen of males who take POMALYST. Therefore, males must always use a latex or synthetic condom during any sexual contact with females of reproductive potential while taking POMALYST and for up to 28 days after discontinuing POMALYST, even if they have undergone a successful vasectomy. Male patients taking POMALYST must not donate sperm. 8.7 Renal Impairment Pomalidomide and its metabolites are primarily excreted by the kidneys [see Clinical Pharmacology (12.3)]. The influence of renal impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum creatinine greater than 3.0 mg/dL were excluded in clinical studies. Avoid POMALYST in patients with a serum creatinine greater than 3.0 mg/dL. 8.8 Hepatic Impairment Pomalidomide is metabolized in the liver [see Clinical Pharmacology (12.3)].

The influence of hepatic impairment on the safety, efficacy, and pharmacokinetics of pomalidomide has not been evaluated. Patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x upper limit normal (ULN) were excluded in clinical studies. Avoid POMALYST in patients with serum bilirubin greater than 2.0 mg/dL and AST/ALT greater than 3.0 x ULN. Manufactured for: Celgene Corporation Summit, NJ 07901 POMALYST®, REVLIMID® and THALOMID® are registered trademarks of Celgene Corporation.

POMALYST REMS™ is a trademark of Celgene Corporation.

U.S. Pat. Nos. 5,635,517; 6,045,501; 6,315,720; 6,316,471; 6,476,052; 6,561,976; 6,561,977; 6,755,784; 6,908,432; 8,158,653; 8,198,262; 8,204,763; 8,315,886 ©2005-2013Celgene Corporation, All Rights Reserved.

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misalignment of lumbar and thoracic vertebral elements (vertebral, central and/or neural arches) were observed at all dose levels. There was no maternal toxicity observed in this study. The lowest dose in rats resulted in an exposure (AUC) approximately 85-fold of the human exposure at the recommended dose of 4 mg per day. Other embryofetal toxicities included increased resorptions leading to decreased number of viable fetuses. In rabbits, pomalidomide was administered orally to pregnant animals at doses of 10 to 250 mg per kg per day. Increased cardiac malformations such as interventricular septal defect were seen at all doses with significant increases at 250 mg per kg per day. Additional malformations observed at 250 mg per kg per day included anomalies in limbs (flexed and/or rotated fore- and/or hindlimbs, unattached or absent digit) and associated skeletal malformations (not ossified metacarpal, misaligned phalanx and metacarpal, absent digit, not ossified phalanx, and short not ossified or bent tibia), moderate dilation of the lateral ventricle in the brain, abnormal placement of the right subclavian artery, absent intermediate lobe in the lungs, low-set kidney, altered liver morphology, incompletely or not ossified pelvis, an increased average for supernumerary thoracic ribs and a reduced average for ossified tarsals. No maternal toxicity was observed at the low dose (10 mg per kg per day) that resulted in cardiac anomalies in fetuses; this dose resulted in an exposure (AUC) approximately equal to that reported in humans at the recommended dose of 4 mg per day. Additional embryofetal toxicity included increased resorption. 8.3 Nursing mothers It is not known if pomalidomide is excreted in human milk. Pomalidomide was excreted in the milk of lactating rats. Because many drugs are excreted in human milk and because of the potential for adverse reactions in nursing infants from POMALYST, a decision should be made whether to discontinue nursing or to discontinue the drug, taking into account the importance of the drug to the mother. 8.4 Pediatric use Safety and effectiveness of POMALYST in patients below the age of 18 have not been established. 8.5 Geriatric use No dosage adjustment is required for POMALYST based on age. Of the total number of patients in clinical studies of POMALYST, 41 percent were 65 and over, while 12 percent were 75 and over.

No overall differences in effectiveness were observed between these patients and younger patients. In this study, patients greater than or equal to 65 years of age were more likely than patients less than or equal to 65 years of age to experience pneumonia. 8.6 Females of Reproductive Potential and Males POMALYST can cause fetal harm when administered during pregnancy [see Use in Specific Populations (8.1)]. Females of reproductive potential must avoid pregnancy while taking POMALYST and for at least 4 weeks after completing therapy. Females Females of reproductive potential must commit either to abstain continuously from heterosexual sexual intercourse or to use two methods of reliable birth control simultaneously (one highly effective form of contraception – tubal ligation, IUD, hormonal (birth control pills, injections, hormonal patches, vaginal rings or implants) or partner’s vasectomy and one additional effective contraceptive method – male latex or synthetic condom,

or other publications. The FDA notes that some third-party publications, compendia references, health information systems (ie, EMR systems and other systems used for pharmacy prescription processing, wholesaler ordering, and pharmacy ordering), and various websites are incorrectly using “trastuzumab emtansine” and omitting the “ado-” prefix.

Although no medication errors related to confusion between Kadcyla and Herceptin have been reported since the approval of Kadcyla on February 22, 2013, such errors did occur during the clinical trials that evaluated the safety and efficacy of the drug before its approval, according to the FDA. The agency advises health plans, pharmacists, and prescribers to implement strategies to warn against and look for any confusion between the 2 drugs in electronic systems, and when needed, to correct the error.

Furthermore, the FDA insists that ado-trastuzumab emtansine should not be substituted for or used with trastuzumab. The recommended dose of Kadcyla is 3.6 mg/kg, administered by intravenous infusion every 3 weeks for a total of 21 days. This drug should not be prescribed at higher doses. By contrast, the recommended dose of Herceptin is significantly higher, up to 8 mg/kg per loading dose, followed by a maintenance dose of 6 mg/kg every 3 weeks. These drugs may not be used concomitantly. (May 6, 2013) n

FDA’s Social Media Guidance for Drugs and Devices a High Priority

One of the FDA’s highest priorities at the moment is providing guidance on drugs and medical devices to drug and device companies on their use of social media, according to Tom Abrams, head of the FDA’s Office of Prescription Drug Promotion.

The FDA hopes to meet its designated deadline of July 2014 for issuing that guidance. In the interim, the FDA has scheduled a virtual conference to advise drug- and device-makers on how to take advantage of social media, including Facebook, Twitter, and YouTube, for disseminating their news and breakthroughs via online marketing within the FDA regulatory limits.

The virtual conference will spell out what companies can and cannot do regarding the marketing of their drugs and devices in social media— the latest channel for influencing policymakers, patients, payers, and healthcare providers.

www.ValueBasedCancerCare.com

19

3rd Conference

Aetna’s Value-Based Process Improvement for the Survival of Community Oncology

By Caroline Helwick

Hollywood, FL—Community oncology will not survive in the absence of novel management strategies and process improvements, according to Michael Kolodziej, MD, FACP, National Medical Director of Oncology Solutions,

“The patient-centered medical home is a way of dealing with these differences in a way that will improve the outcome of patients. ” —Michael Kolodziej, MD, FACP

who offered his insights at the Third Annual Conference of the Association for Value-Based Cancer Care.

The Institute of Medicine has suggested that approximately 30% of healthcare spending, or $750 billion annually, is “a waste,” he said (Figure 1). “This is doing things that don’t benefit patients, and it’s lousy care delivery.”

Aetna spends 30.8% ($1.5 billion) of its dollars on medical therapies, 23.3% ($1.1 billion) on inpatient care, 22.4% ($1.1 billion) on radiology, and 9.4% ($483 million) on specialty physicians; these are the top drivers in cancer care at Aetna. Therefore, processes must be implemented that could curb these costs, Dr Kolodziej emphasized.

Evidence-Based Medicine in Every Corner If integrated into delivery systems, Aetna’s “mantra” of evidence-based medicine would help avoid waste, he proposed. Aetna’s value-based processes focus on evidence-based medicine and include the following prin­ ciples: • Drive efficient use of evidence-based medicine: this involves platforms that provide content and workflows, integration of evidence-based medicine into the Aetna and provider systems, and simpler adminis-

Figure 1 The Healthcare System Produces $750 Billion in Annual Waste Approximately 30% of health spending is waste Prevention failures Unnecessary services

Fraud

7% 10%

27% US healthcare system waste Excess administrative costs

25%

14%

Inflated prices

17% Inefficient care delivery

Source: Institute of Medicine; 2009 data.

trative processes for providers • Avoid the waste and misuse of medical services: this involves better provider alignment, more narrow and tiered networks, and better decision support strategies • Leverage and integrate current and future medical and pharmacy cancer-care initiatives: this involves seamless, end-to-end cancer experiences for Aetna members and providers.

Dr Kolodziej and colleagues conducted one of the few studies, if not the only one, to demonstrate that evi-

dence-based medicine is cost-saving (Neubauer MA, et al. J Oncol Pract.

2010;6:12-18). Patients with non–smallcell lung cancer from 8 practices within the US Oncology Network were analyzed. The overall outpatient costs were found to be 35% lower for on-pathway versus off-pathway patients, whereas survival was unchanged.

The study should that treating patients according to pathways was cost-effective across a plausible range of willingness-to-pay thresholds.

Continued on page 22

WellPoint’s Perspective on Value-Based Cancer Care... on pathways, disease management, and early palliative care.

The delivery of such patient-centered care will require practice re-engineering, Dr Malin added, which includes: • Information technology infrastructure and decision support • Protocols for nurse-led symptom management • Tools to guide patient-centered decision-making, assessment of symptoms, and need for palliative care • Change in culture regarding palliative care • Quality and outcome measurements • Collaborative approach to quality improvement.

“The key is ongoing innovation for practices to make these kinds of changes, and the challenge is to make this scalable,” Dr Malin pointed out.

20

Although various models have the attention of practice leaders, knowl-

Value-Based Cancer Care

edge is still scarce about implementing them in practice.

Table 2 Little Variation in Outcomes, but Marked Variation in Cost

Treatment regimen

Prescription A: carboplatin plus paclitaxel

Survival after platinum-based chemotherapy, months

Estimated cost of 4 cycles, $

6.7

9.4

7982

9.7

34,596

Prescription D: carboplatin, paclitaxel, plus bevacizumab

8.9

28,156

8.1

24,574

Prescription F: cisplatin, pemetrexed, plus bevacizumab

9.6

51,890

Prescription B: gemcitabine plus cisplatin

Prescription C: gemcitabine, cisplatin, plus bevacizumab

Prescription E: cisplatin plus pemetrexed

I

MAY 2013

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Continued from page 12

Innovation to Reduce Variation in Cost As an example of innovation, Dr Malin described a program in which a plan member is informed about less-expensive alternatives. For example, during preauthorization for an imaging test, the patient is informed if a comparable facility offers the test at less cost, which may mean lower outof-pocket costs for that patient. If the patient elects to have imaging done at the lower-cost facility, he or she will be assisted in making a new appointment.

New tools will help patients understand relative quality and cost, and this should enhance patient engagement in value. “The average cancer patient spends about $2500 in the first year in out-of-pocket costs, so he or she has skin in the game,” Dr Malin noted. n

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No. 4

AVBCC wishes to acknowledge the organizations listed below that graciously gave their support on behalf of AVBCCâ&#x20AC;&#x2122;s Third Annual Conference, held May 3-5, 2013, in Hollywood, Florida.

Platinum Sponsor & Corporate Member

Gold Sponsor

Silver Sponsor & Corporate Member

Corporate Members/Preconference Supporters

May 7-9, 2014

4TH ANNUAL CONFERENCE

Loews Hollywood Hotel Los Angeles, CA AVBCC_KsizeTU

3rd Conference

Aetna’s Value-Based Process Improvement...

Pathways must take into account, however, that different patient subsets have various requirements, Dr Kolodziej added. “HER2-positive breast cancer in a 40-year-old person is different from that in a 70-year-old person. The drugs may be the same, but the resources consumed by these patients are different. Until we get our hands around this concept, we will struggle,” he said. “The patient-cen-

tered medical home is a way of dealing with these differences in a way that will improve the outcome of patients.”

Preparing Systems for Novel Payment Models An Innovent/Aetna pilot program is studying patients enrolled in the Innovent Oncology Program to evaluate the impact of a cancer management program on patients receiving chemo-

Figure 2 Oncology Medical Home Solution We have the capabilities to equip oncologists with the tools to transition to a medical home Oncology Medical Home Solution

Source: Aetna, Inc.

“We will develop tools to assist the practice in executing these strategies and transitioning to a medical home.” therapy for 1 or 2 years who were seen

by Texas Oncology physicians between May 2010 and May 2012. The study is evaluating drug costs, emergency department visits, inpatient admissions, and costs.

A key component of this pilot program is a proactive approach by oncology nurses. Early results show a 12% overall cost-savings in patients with breast, lung, and colon cancers as a result of a reduction in emergency department visits and inpatient days per member. The use of nurses who are trained in end-of-life counseling also enhances timely enrollment to hospice, the data showed. “We have de facto proof of process. If you could execute this strategy, it would work,” Dr Kolodziej maintained.

He acknowledged that the average practice could have difficulty implementing this type of approach.

However, Dr Kolodziej said, Aetna is seeking to help oncology practices transition to the new models of val-

Figure 3 Creating a More Collaborative Network of Caregivers iNexx Result

iNexx gives you the power to connect and to create the care delivery system that you want

Referral Order Virtual care team reconciliation

Source: Aetna, Inc; 2012.

22

Value-Based Cancer Care

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maY 2013

Continued from page 20

ue-based care, such as the medical home and accountable care organizations (ACOs). “We will develop tools to assist the practice in executing these strategies and transitioning to a medical home,” he said (Figure 2).

“We can also look to leverage Aetna accountable care solutions to serve oncology practices seeking shared savings through the accountable care organization model,” Dr Kolodziej said.

Aetna will leverage accountable care solutions to facilitate relationships between enabled oncology practices.

Aetna prepares hospital systems to become ACOs through an analytical, intellectual process that results in the creation of a value-based plan, he added.

The Current System Must Change Change must come to the “current state of affairs,” in which the oncologist and his or her office is “stuck in a 20th century communication and data exchange environment” in which collaboration with other healthcare providers is often tedious, costly, and difficult to obtain, Dr Kolodziej maintained.

A fully digital healthcare delivery system, in contrast, makes true collaboration with a network of caregivers possible and fully satisfies meaningful use. For example, the iNexx payer app, Aetna Connect, greatly simplifies the ability of providers to manage their communications with Aetna by consolidating everything through a single point of communication. This brings the right administrative and clinical processes to the physician’s practice, making it easier for practices to conduct their business, he said (Figure 3).

Success, Dr Kolodziej concluded, “will require multiple steps,” that will include: • Transformation of clinical practice • Evolution of the hospital into an integrated delivery system • Adoption of performance measurements and process improvement • Modernization of the health information platform, focused on payer, provider, and patient integration • Reformation of the reimbursement platform • Partnership.

To improve cancer care and remove the enormous waste in the system, all stakeholders must work together as an integrated system, with the common goal of enhancing patient care by embracing new technologies and improved, evidence-based processes. n

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No. 4

2013 WORLD CUTANEOUS MALIGNANCIES CONGRESS

• Melanoma • Basal Cell Carcinoma • Cutaneous T-Cell Lymphoma • Squamous Cell Carcinoma • Merkel Cell Carcinoma

TM

July 26-28, 2013

Hyatt Regency La Jolla • San Diego, California PROGRAM OVERVIEW

CONFERENCE CO-CHAIRS

A 2-day congress dedicated to informing, educating, and fostering the exchange of clinically relevant information in the field of cutaneous malignancies on topics in melanoma, basal cell carcinoma, cutaneous T-cell lymphoma, squamous cell carcinoma, and Merkel cell carcinoma, including: • Epidemiology and genetic/environmental factors • Molecular biology and cytogenetics related to the pathogenesis of cutaneous malignancies • Risk stratification based on patient and tumor characteristics • Principles of cancer prevention of melanoma and basal cell carcinoma • Current treatment guidelines • Emerging treatment options for personalized therapy • Future strategies in management based on translational data from current clinical trials and basic research

LEARNING OBJECTIVES Upon completion of this activity, the participant will be able to: • Review the molecular biology and pathogenesis of cutaneous malignancies as they relate to the treatment of cutaneous T-cell lymphoma, basal cell carcinoma, Merkel cell tumors, and malignant melanoma • Compare risk stratification of patients with cutaneous malignancies, and how to tailor treatment based on patient and tumor characteristics • Summarize a personalized treatment strategy that incorporates current standards of care and emerging treatment options for therapy of patients with cutaneous malignancies

TARGET AUDIENCE This activity was developed for medical and surgical oncologists, dermatologists, radiation oncologists, and pathologists actively involved in the treatment of cutaneous malignancies. Advanced practice oncology or dermatololgy nurses, oncology pharmacists, and researchers interested in the molecular biology and management of cutaneous malignancies are also encouraged to participate.

DESIGNATION OF CREDIT STATEMENTS SPONSORS This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

COMMERCIAL SUPPORT ACKNOWLEDGMENT Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

Sanjiv S. Agarwala, MD Professor of Medicine Temple University School of Medicine Chief, Oncology & Hematology St. Luke’s Cancer Center Bethlehem, Pennsylvania

REGISTERED NURSE DESIGNATION Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.0 contact hours.

REGISTERED PHARMACY DESIGNATION The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.0 contact hours (1.2 CEUs) of continuing pharmacy education credit. The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION EARLY BIRD REGISTRATION NOW OPEN! $175.00 UNTIL APRIL 30, 2013

www.CutaneousMalignancies.com

Professor Dr. Med. Axel Hauschild Professor, Department of Dermatology University of Kiel Kiel, Germany

AGENDA* FRIDAY, JULY 26, 2013 3:00 pm – 7:00 pm

Registration

5:30 pm – 7:30 pm

Welcome Reception/Exhibits

SATURDAY, JULY 27, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Welcome to the Second Annual World Cutaneous Malignancies Congress — Setting the Stage for the Meeting - Sanjiv S. Agarwala, MD

8:30 am – 11:45 am General Session I: A Clinician’s Primer on the Molecular Biology of Cutaneous Malignancies • Keynote Lecture Understanding the Basic Biology and Clinical Implications of the Hedgehog Pathway • Keynote Lecture Pathogenesis of Merkel Cell Carcinoma: An Infectious Etiology? - Paul Nghiem, MD, PhD 12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 4:30 pm

General Session II: Current Treatment Guidelines in Cutaneous Malignancies • Case Studies Optimal, Value-Based Therapy of Cutaneous Malignancies: The Expert’s Perspective on How I Treat My Patients • Panel Discussion Management Controversies and Accepted Guidelines for the Personalized Management of Cutaneous Malignancies • Keynote Lecture New Combinations in Melanoma: A Role for MEK + BRAF and Anti–PD-1

4:30 pm – 6:30 pm

Meet the Experts/Networking/Exhibits

PHYSICIAN CREDIT DESIGNATION The Medical Learning Institute Inc designates this live activity for a maximum of 12.0 AMA PRA Category 1 Credits ™. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Steven J. O’Day, MD Hematology/Oncology Director of Clinical Research Director of Los Angeles Skin Cancer Institute at Beverly Hills Cancer Center Clinical Associate Professor of Medicine USC Keck School of Medicine Los Angeles, California

SUNDAY, JULY 28, 2013 7:00 am – 8:00 am

Breakfast Symposium/Product Theater/Exhibits

8:00 am – 8:15 am

BREAK

8:15 am – 8:30 am

Review of Saturday’s Presentations and Preview of Today’s Sessions

8:30 am – 11:45 am General Session III: Review of Emerging Treatment Options for Cutaneous Malignancies General Session IV: Challenges for the Cutaneous Malignancies Clinician • Panel Discussion How Can the Healthcare Team Work Best Together to Deliver Value-Based Care in Cutaneous Malignancies?

12:00 pm – 1:00 pm Lunch Symposium/Product Theater/Exhibits 1:00 pm – 1:15 pm

BREAK

1:15 pm – 2:45 pm

General Session V: “Hot Data” — What I Learned at Recent Meetings: Focus on Cutaneous Malignancies

2:45 pm – 3:00 pm

Closing Remarks - Steven J. O’Day, MD

*Agenda is subject to change.

For complete agenda please visit www.CutaneousMalignancies.com

Economics of Cancer Care

Palliative Care Cost-Effective for Platinum-Resistant Ovarian Cancer

By Charles Bankhead

Los Angeles, CA—Early palliative care proved to be cost-effective and cost-saving versus routine end-of-life care for patients with recurrent platinum-resistant ovarian cancer, according to a decision-model analysis.

Based on a 6-month time horizon, the model projected a savings of $1275 per patient versus routine care. In a 1-way sensitivity analysis, palliative care remained within an incremental cost-effectiveness ratio (ICER) of $50,000 per quality-adjusted life-year (QALY), until the cost of the intervention exceeded $2400—approximately $2000 more than the estimated cost.

“When we assumed no clinical benefit of early palliative care other than quality of life, early palliative care remained highly cost-effective, with an incremental cost-effectiveness ratio of $37,440 per quality-adjusted lifeyear,” William J. Lowery, MD, Fellow, Division of Gynecologic Oncology, Department of Obstetrics and Gy­ necology, Duke University, Durham, NC, and colleagues reported at the 2013 Society of Gynecologic Oncology annual meeting.

Sensitivity analyses incorporating a variety of clinical and cost parameters showed no significant changes in the model’s basic findings.

The background for this analysis came from a randomized controlled trial involving patients with meta­ static non–small-cell lung cancer

(NSCLC). Early palliative care was associated with fewer hospital admissions and fewer emergency department visits, as well as reduced administration of chemotherapy in the last 30 days of life (Temel JS, et al. N Engl J Med. 2010;363:733-742).

Applying the underlying principles of the lung cancer study to recurrent ovarian cancer, Dr Lowery and colleagues constructed a decision model to compare the cost of routine end-oflife care (determined by the treating physician) with the cost of routine care plus early palliative care. They defined the intervention as monthly consultation with a palliative care provider to discuss symptoms and the goals of care and to assist with decision-making that is related to proposed treatment.

The primary outcome was the average cost of each treatment strategy.

The investigators used the NSCLC study to develop the decision model for recurrent ovarian cancer. The key assumptions were: • Each patient who was hospitalized was assumed to have a single hospitalization • Patients who visited emergency departments were assumed to have done so once • Liposomal doxorubicin was the chemotherapy regimen for all patients • Patients who received early pallia-

tive care had an initial outpatient visit, followed by 5 monthly visits • The base model did not include quality of life • Survival was equivalent with the 2 strategies.

“When we assumed no clinical benefit of early palliative care other than quality of life, early palliative care remained highly costeffective, with an incremental cost-effectiveness ratio of $37,440 per quality-adjusted life-year.”

—William J. Lowery, MD

Results of the NSCLC trial showed that early palliative care was associated with a 32% odds ratio for hospital admission, a 26% reduction in the odds ratio for emergency department visits, and a 23% reduction in the odds ratio for chemotherapy administration. These outcomes were incorporated into the decision model for recurrent platinum-resistant ovarian cancer.

The costs (including hospital admission, emergency department vis-

its, chemotherapy administration, and palliative care) were obtained from the Agency for Healthcare Research and Quality and the Centers for Medicare & Medicaid Services. The estimated cost of early palliative care was $472 per case.

The model produced a base case with an average cost of $5017 for early palliative care and $6303 for routine care alone, a savings of $1286 per patient. In a sensitivity analysis incorporating quality of life, the strategy of early palliative care remained dominant compared with routine care, Dr Lowery and colleagues reported.

Sensitivity analyses showed that early palliative care would have to cost more than $3000 before the ICER exceeded $100,000 per QALY versus routine care.

Invited discussant Amer Karam, MD, a gynecologic and surgical oncologist, Department of Obstetrics and Gynecology, University of California, Los Angeles Health System, found several aspects of the analysis open to questioning, beginning with the applicability of data derived from a study of metastatic NSCLC to platinumresistant recurrent ovarian cancer.

He also cited limitations related to the thresholds used to define cost-effectiveness and to the assumption that early palliative care would incur no additional costs beyond the $472 over 6 months. n

See also Ovarian Cancer, page 39

Neoadjuvant Chemotherapy Reduces Costs for Older Patients with Ovarian Cancer Los Angeles, CA—Neoadjuvant chemotherapy for older patients with ovarian cancer would save $19 million annually compared with primary de­ bulking surgery, based on a new costmodel assessment.

Per-patient costs were 7.5% lower with neoadjuvant chemotherapy, resulting in a difference of $3048 versus surgery. The savings could range as high as $10,000 per patient, given the variation in charge to cost for drugrelated group (DRG) codes, reported Michelle R. Rowland, MD, PhD, MPH, Department of Obstetrics, Gynecology, and Reproductive Sciences, MageeWomens Hospital of the University of

24

Pittsburgh Medical Center, PA, at the 2013 Society of Gynecologic Oncology annual meeting.

Most of the savings resulted from reduced hospital costs that are primarily attributable to lower projected complication rates in patients who received chemotherapy.

Extrapolating the findings to clinical experience in 2012, “approximately 6350 women age 65 and older will be diagnosed with advanced epithelial ovarian cancer, for an estimated cost-savings of $19 million with neoadjuvant chemotherapy,” Dr Row­land noted.

“Cost-savings may be underestimat-

Value-Based Cancer Care

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maY 2013

ed, as costs of complications are conservative and readmissions are not included in this model. Moreover, assumptions regarding survival may also affect the cost benefit,” she explained.

Results of several studies have suggested that neoadjuvant chemother­ apy and primary debulking surgery lead to similar outcomes as initial treatment for older patients with advanced epithelial ovarian cancer.

Other studies have indicated higher complication rates and lower chemotherapy completion rates for surgically treated patients.

Noting a lack of consensus about the

optimal initial therapy for older patients with ovarian cancer, the investigators performed a cost model comparison of primary debulking surgery and neoadjuvant chemotherapy. The comparison incorporated 2 base treatment strategies: • Primary debulking surgery followed by 6 cycles of chemotherapy with carboplatin plus paclitaxel • Three cycles of the same chemotherapy, followed by interval debulking, and subsequently followed by 3 additional cycles of chemotherapy.

Costs for debulking surgery and add-on procedures, such as bowel reContinued on page 25

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Economics of Cancer Care

Cancer Support Program Documents Savings

By Caroline Helwick

Hollywood, FL—A case management program for terminally ill patients with cancer can reduce cancer-related healthcare costs and extend hospice length of stay, according to an analysis of the Cancer Support Program (CSP) of Optum Health, a health services company, which was presented at the 2013 National Comprehensive Cancer Network® annual conference.

Charlotte Wu, Associate Director of Healthcare Analytics, OptumHealth

at a glance ➤ OptumHealth’s Cancer Support Program shows that case management of terminally ill patients with cancer can reduce costs and improve symptom management ➤ The Cancer Support Program has a patient satisfaction rating of 98%

Care Solutions, Minneapolis, MN, presented a case study comparing participants and nonparticipants of the Optum CSP. The CSP, which was launched in 2006, provides patients, their families, and their caregivers with telephone case management (ie, education, support, referrals) by experienced oncology nurses and social workers who are supported by a physician staff.

“These services are intended to help patients better comply with treatments and more effectively manage symptoms,” Ms Wu said. “As a result, patients are less likely to have cancer-related complications and will experience a better quality of life. Since the inception of the program, patients have reported extremely high satisfaction. The intent of this study was to estimate the financial impact of the CSP.” The researchers analyzed cancerrelated expenditures and hospice utilization near the end of life for 7455 patients who were actively treated for cancer and another 1388 patients who

had already died. Propensity score weighting of 100 variables was used to adjust for baseline differences between the 8843 participants and non-

“These services are intended to help patients better comply with treatments and more effectively manage symptoms. As a result, patients are less likely to have cancer-related complications and will experience a better quality of life.”

—Charlotte Wu

participants. For the survivors, the study period spanned the 6 months after they qualified for the CSP; for the decedents, it was the time after pro-

gram qualification through the date of death.

Cancer-Related Cost-Savings “The savings were primarily driven by a reduction in inpatient admissions,” Ms Wu noted. This included a 5.7% reduction among the survivors in the program and a 16.8% reduction among the patients who had died.

These differences resulted in an average cost-savings of $1128 per patient per month for the survivors and $3999 for the decedents.

In addition, end-of-life hospice use among all deceased CSP participants increased by 0.56 days, or by 42%, Ms Wu reported.

“Extrapolating these results to our population, which has an active treatment cancer rate of 0.4%, these savings amount to about $1.01 per participant per month,” she said.

Ms Wu added, “Since the inception of the Optum Cancer Support Pro­ gram, patients’ satisfaction has remained very high, at 98% satisfied or very satisfied.” n

Neoadjuvant Chemotherapy Reduces Costs for... section, were based on Medicare reimbursement rates. The model took into account the differences in surgical complexity in the 2 treatment arms.

In each treatment arm, the hospital costs were derived from a weighted average of the DRG costs for ovarian cancer, including surgery with no, minor, or major complications, as determined by published data on complication rates of patients aged ≥65 years. The cost of chemotherapy was based on institutional costs, and investigators assumed that 5.7% of patients who were treated with primary de­ bulking surgery would not receive chemotherapy and that 9.5% of the neoadjuvant chemotherapy group would not complete therapy.

The model incorporated the estimated complication rates for both treatment strategies, including complication-free rates of 23.7% with primary surgery and of 35.4% with neoadjuvant chemotherapy.

Both strategies were associated with 1 or more minor complications in 25% of patients, and 1 or more major complications were estimated for 51.3% of surgical patients and for 39.4% of the

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neoadjuvant chemotherapy arm.

The analysis yielded estimated mean costs of $40,498 per patient for primary debulking surgery and $37,450 for neoadjuvant chemotherapy, including the following component costs: • Surgery—$2712 versus $1691 • Chemotherapy—$13,698 versus $14,526 • Hospital stay—$24,087 versus $21,233.

neoadjuvant chemotherapy. “Given an average reported charge-to-cost ratio for the DRG codes included of 3.3, the overall estimated charge savings per patient would be $10,058,” they noted. “The cost-savings conclusion is robust to variation in the model parameter estimates.”

A study published last year underscored the complexities involved in

This model, which “resulted in a cost-savings of $19 million with neoadjuvant chemotherapy would translate to a cost for primary debulking surgery of only $2800 per quality-adjusted life-year saved. Most authorities agree that any treatment that leads to a quality-adjusted life-year cost of less than $75,000 is a good healthcare value.”

—Robert E. Bristow, MD, MBA

Estimating that 6350 American women aged ≥65 years have newly diagnosed advanced epithelial ovarian cancer annually, the investigators found a potential cost-savings of $19 million with an initial strategy of

assessing cost-effectiveness of therapies for advanced ovarian cancer, said Robert E. Bristow, MD, MBA, Director, Division of Gynecologic Oncology, the University of California, Irvine Medical Center.

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Continued from page 24

at a glance ➤ Based on this analysis, neoadjuvant chemotherapy for 6350 older patients with ovarian cancer would save $19 million annually ➤ The mean per-patient savings was $3048 with neoadjuvant chemotherapy versus primary debulking surgery, but could be as high as $10,000 ➤ These savings are based on a reduction in hospital costs, because of fewer projected complications with chemotherapy This model, which “resulted in a costsavings of $19 million with neoadjuvant chemotherapy would translate to a cost for primary debulking surgery of only $2800 per quality-adjusted lifeyear saved,” said Dr Bristow. “Most authorities agree that any treatment that leads to a quality-adjusted life-year cost of less than $75,000 is a good healthcare value.”—CB n

www.ValueBasedCancerCare.com

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Making

PRO gress with patient-reported outcomes How PROs were successfully integrated into the Jakafi® (ruxolitinib) drug development program1 A novel approach to engage clinicians and FDA

TAILORING a PRO tool for myelofibrosis

PROs are an important means to demonstrate treatment benefits in clinical trials.2,3 Use of a PRO instrument can evaluate symptoms best judged by the patient, whether caused by the disease or treatment toxicity. Assessment of symptom burden is important because it can be a major indicator of disease severity, progression or improvement.

Incorporating PROs into a clinical trial program provides a means for evaluating the impact of therapy from the patient’s perspective and helps patients and clinicians make betterinformed decisions.4

Myelofibrosis (MF) is a life-threatening, progressive disease characterized by splenomegaly, debilitating symptoms and cytopenias.5-7 Measures to assess both the splenomegaly and core symptoms of MF were incorporated into the phase III, double-blind placebo-controlled study, COMFORT-I, for Jakafi. Spleen reduction, as measured by imaging (MRI or CT), was the primary and biologic endpoint, and a reduction in total symptom score (TSS), the PRO measure, was a key secondary endpoint.8,9 The TSS encompassed the following symptoms: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain.9 To include PROs in the trial, a novel instrument had to be specifically developed. After patient interviews, advice from clinical experts and extensive input from the FDA, the modified Myelofibrosis Symptom Assessment Form, version 2.0 (modified MFSAF v2.0) was finalized as part of the Special Protocol Assessment prior to the initiation of COMFORT-I. Ultimately, Jakafi was approved by the FDA for the treatment of intermediate or high-risk MF.1,8 This became Incyte’s first approved drug and also the first oncology medicine approved with symptom data in its label since the FDA’s draft guidance on PROs was finalized in 2009.2,4

Indications and Usage Jakafi is indicated for treatment of patients with intermediate or high-risk myelofibrosis, including primary myelofibrosis, post–polycythemia vera myelofibrosis and post–essential thrombocythemia myelofibrosis.

Important Safety Information • Treatment with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia, which are each dose-related effects, with the most frequent being thrombocytopenia and anemia.

A complete blood count must be performed before initiating therapy with Jakafi. Complete blood counts should be monitored as clinically indicated and dosing adjusted as required • The three most frequent non-hematologic adverse reactions were bruising, dizziness and headache • Patients with platelet counts <200 × 109/L at the start of therapy are more likely to develop thrombocytopenia

during treatment. Thrombocytopenia was generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If clinically indicated, platelet transfusions may be administered • Patients developing anemia may require blood transfusions.

Dose modifications of Jakafi for patients developing anemia may also be considered • Neutropenia (ANC <0.5 × 109/L) was generally reversible and was managed by temporarily withholding Jakafi • Patients should be assessed for the risk of developing serious bacterial, mycobacterial, fungal and viral infections.

Active serious infections should have resolved before starting Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection (including herpes zoster) and initiate appropriate treatment promptly • A dose modification is recommended when administering Jakafi with strong CYP3A4 inhibitors or in patients with

JAKAFI endpoints included both biologic and patient-reported outcomes8,9 COMFORT-I: Percent Change in Spleen Volume in Individual Patients From Baseline to Week 24 or Last Observation9,a

COMFORT-I: Percent Change in TSS in Individual Patients From Baseline to Week 24 or Last Observation9,a,b 150

0 -20 -40

35% Reduction

-60 -80

Upper 50th Percentile

Jakafi (n = 155)

Upper 50th Percentile

0 -50

-100

Placebo (n = 153)

Each bar represents an individual patient’s response.

50

WORSENING

20

100

IMPROVEMENT

Change From Baseline (%)

40

WORSENING

60

IMPROVEMENT

Change From Baseline (%)

80

50% Improvement

Upper 50th Percentile

Jakafi (n = 145)

Upper 50th Percentile

Placebo (n = 145)

Each bar represents an individual patient’s response. Worsening of TSS is truncated at 150%.

PROVIDING proof of patient benefit MF is progressive, and spleen size and symptoms can become increasingly burdensome to patients over time.5-7 Jakafi is proven to decrease total symptom score in patients with intermediate or high-risk MF—this is an important consideration when evaluating and treating patients.9 The FDA approval included patients with intermediate-2 risk and high risk, as well as patients with intermediate-1 risk, since intermediate-1 patients may also have symptoms that require treatment. Clinical experience with Jakafi has shown that with the right process, manufacturers can successfully collaborate with regulatory agencies and academic experts to develop relevant and validated PRO instruments that can be incorporated into clinical trials.1,8 The approval of Jakafi marks a significant milestone in which validated PRO instruments can provide symptom data and demonstrate clinical benefit. The experience with Jakafi may provide a model for the future use of PROs in marketing applications.8

renal or hepatic impairment [see Dosage and Administration].

Patients should be closely monitored and the dose titrated based on safety and efficacy • There are no adequate and well-controlled studies of Jakafi in pregnant women. Use of Jakafi during pregnancy is not recommended and should only be used if the potential benefit justifies the potential risk to the fetus • Women taking Jakafi should not breast-feed. Discontinue nursing or discontinue the drug, taking into account the importance of the drug to the mother References: 1. McCallister E, et al. BioCentury. Reprint from December 5, 2011. 2. Haley S. The Pink Sheet. November 21, 2011;73:47. Symptom Measurement in Clinical Trials.

3. US Department of Health and Human Services Guidance for Industry: Patientreported outcome measures: Use in medical product development to support labeling claims. December 2009. 4. Basch E, et al. Issue brief from Conference on Clinical Cancer Research, November 2011. 5. Cervantes F, et al. Blood. 2009;113:2895-2901.

6. Mesa RA, et al. Leuk Res. 2009;33:1199-1203. 7. Verstovsek S, et al. N Engl J Med. 2012;366:799-807. 8. Deisseroth AB, et al. Clin Cancer Res. 2012 Apr 27. (Epub ahead of print). 9. Jakafi Prescribing Information. Incyte Corporation. November 2011.

10. Data on File, Incyte Corporation.

a

As studied in COMFORT-I, a randomized, double-blind, placebo-controlled phase III study with 309 total patients (United States, Canada, Australia). The primary endpoint was the proportion of subjects achieving a ≥35% reduction in spleen volume from baseline to Week 24 as measured by MRI or computed tomography (CT). A secondary endpoint was the proportion of subjects with a ≥50% reduction in TSS from baseline to Week 24 as measured by the daily patient diary, the modified MFSAF v2.0.9,10 b Symptom scores were captured by a daily patient diary recorded for 25 weeks. TSS encompasses debilitating symptoms of MF: abdominal discomfort, pain under left ribs, early satiety, pruritus, night sweats and bone/muscle pain. Symptom scores ranged from 0 to 10 with 0 representing symptoms “absent” and 10 representing “worst imaginable” symptoms. These scores were added to create the daily total score, which has a maximum of 60. At baseline, mean TSS was 18.0 in the Jakafi group and 16.5 in the placebo group.9,10

Please see Brief Summary of Full Prescribing Information on the following page.

Jakafi is a registered trademark of Incyte Corporation. © 2012, Incyte Corporation. All rights reserved.

RUX-1130A 05/12

In the Literature encing their recommendations.

Of the 138 specific recommendaContinued from page 4 tions included in these guidance docto explain the strength of the impact uments that included cost as a comof cost on the recommendation, and ponent of their guidance rationale, the 1INC0078JK0 BS 12P_Layout 11/16/11 9:16 AM Page 1 most frequent (36%) recommendation (47%) societies 1use an inconsistent approach or have not mentioned the advocates the use of a specific treatmechanism by which costs were influ- ment or a medical device as a result of

Only 57% of Specialty Societies Consider Costs...

a similar effectiveness among different options and lower costs associated with that specific device or treatment.

Although slightly more than 50% do consider cost issues in their guidance development and half of them explain the impact of cost on the strength of the recommendation, many special-

Table 2: Worst Hematology Laboratory Abnormalities in the Placebo-controlled Studya Jakafi Placebo (N=155) (N=151) Laboratory All All Grade 4 Grades Grade 3 Grade 4 Parameter Gradesb Grade 3 BRIEF SUMMARY: For Full Prescribing Information, see package insert. (%) (%) (%) (%) (%) (%) INDICATIONS AND USAGE Jakafi is indicated for treatment of patients with intermediate or high-risk Thrombocytopenia 69.7 9.0 3.9 30.5 1.3 0 myelofibrosis, including primary myelofibrosis, post-polycythemia vera myelofibrosis and post-essential Anemia 96.1 34.2 11.0 86.8 15.9 3.3 thrombocythemia myelofibrosis.

Neutropenia 18.7 5.2 1.9 4.0 0.7 1.3 CONTRAINDICATIONS None.

WARNINGS AND PRECAUTIONS Thrombocytopenia, Anemia and Neutropenia Treatment a Presented values are worst Grade values regardless of baseline b National Cancer Institute Common Terminology Criteria for Adverse Events, version 3.0 with Jakafi can cause hematologic adverse reactions, including thrombocytopenia, anemia and neutropenia.

A complete blood count must be performed before initiating therapy with Jakafi [see Dosage and Additional Data from the Placebo-controlled Study 25.2% of patients treated with Jakafi and 7.3% of Administration (2.1) in Full Prescribing Information]. Patients with platelet counts of less than 200 X 109/L patients treated with placebo developed newly occurring or worsening Grade 1 abnormalities in alanine transat the start of therapy are more likely to develop thrombocytopenia during treatment. Thrombocytopenia was aminase (ALT). The incidence of greater than or equal to Grade 2 elevations was 1.9% for Jakafi with 1.3% Grade 3 and no Grade 4 ALT elevations. 17.4% of patients treated with Jakafi and 6.0% of patients treated generally reversible and was usually managed by reducing the dose or temporarily withholding Jakafi. If with placebo developed newly occurring or worsening Grade 1 abnormalities in aspartate transaminase clinically indicated, platelet transfusions may be administered [see Dosage and Administration (2.2) in Full (AST). The incidence of Grade 2 AST elevations was 0.6% for Jakafi with no Grade 3 or 4 AST elevations.

Prescribing Information, and Adverse Reactions]. Patients developing anemia may require blood trans- 16.8% of patients treated with Jakafi and 0.7% of patients treated with placebo developed newly occurring or fusions. Dose modifications of Jakafi for patients developing anemia may also be considered. Neutropenia worsening Grade 1 elevations in cholesterol. The incidence of Grade 2 cholesterol elevations was 0.6% for (ANC less than 0.5 X 109/L) was generally reversible and was managed by temporarily withholding Jakafi Jakafi with no Grade 3 or 4 cholesterol elevations. [see Adverse Reactions]. Complete blood counts should be monitored as clinically indicated and dosing DRUG INTERACTIONS Drugs That Inhibit or Induce Cytochrome P450 Enzymes Ruxolitinib adjusted as required [see Dosage and Administration (2.2) in Full Prescribing Information, and Adverse is predominantly metabolized by CYP3A4. Strong CYP3A4 inhibitors: The C max and AUC of ruxolitinib Reactions]. Infections Patients should be assessed for the risk of developing serious bacterial, mycobac- increased 33% and 91%, respectively, with Jakafi administration (10 mg single dose) following ketoconazole terial, fungal and viral infections. Active serious infections should have resolved before starting therapy with 200 mg twice daily for four days, compared to receiving Jakafi alone in healthy subjects. The half-life was also Jakafi. Physicians should carefully observe patients receiving Jakafi for signs and symptoms of infection and prolonged from 3.7 to 6.0 hours with concurrent use of ketoconazole. The change in the pharmacodynamic initiate appropriate treatment promptly. Herpes Zoster Physicians should inform patients about early signs marker, pSTAT3 inhibition, was consistent with the corresponding ruxolitinib AUC following concurrent adminand symptoms of herpes zoster and advise patients to seek treatment as early as possible [see Adverse istration with ketoconazole. When administering Jakafi with strong CYP3A4 inhibitors a dose reduction is Reactions]. recommended [see Dosage and Administration (2.4) in Full Prescribing Information]. Patients should be ADVERSE REACTIONS Clinical Trials Experience Because clinical trials are conducted under closely monitored and the dose titrated based on safety and efficacy. Mild or moderate CYP3A4 inhibitors: widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly There was an 8% and 27% increase in the Cmax and AUC of ruxolitinib, respectively, with Jakafi administration compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The (10 mg single dose) following erythromycin, a moderate CYP3A4 inhibitor, at 500 mg twice daily for 4 days, safety of Jakafi was assessed in 617 patients in six clinical studies with a median duration of follow-up of 10.9 compared to receiving Jakafi alone in healthy subjects. The change in the pharmacodynamic marker, pSTAT3 months, including 301 patients with myelofibrosis in two Phase 3 studies. In these two Phase 3 studies, inhibition was consistent with the corresponding exposure information. No dose adjustment is recommended patients had a median duration of exposure to Jakafi of 9.5 months (range 0.5 to 17 months), with 88.7% of when Jakafi is coadministered with mild or moderate CYP3A4 inhibitors (eg, erythromycin). CYP3A4 patients treated for more than 6 months and 24.6% treated for more than 12 months. One hundred and inducers: The Cmax and AUC of ruxolitinib decreased 32% and 61%, respectively, with Jakafi administration eleven (111) patients started treatment at 15 mg twice daily and 190 patients started at 20 mg twice daily. In (50 mg single dose) following rifampin 600 mg once daily for 10 days, compared to receiving Jakafi alone in a double-blind, randomized, placebo-controlled study of Jakafi, 155 patients were treated with Jakafi. The healthy subjects. In addition, the relative exposure to ruxolitinib’s active metabolites increased approximately most frequent adverse drug reactions were thrombocytopenia and anemia [see Table 2]. Thrombocytopenia, 100%. This increase may partially explain the reported disproportionate 10% reduction in the pharmacoanemia and neutropenia are dose related effects. The three most frequent non-hematologic adverse reactions dynamic marker pSTAT3 inhibition. No dose adjustment is recommended when Jakafi is coadministered with were bruising, dizziness and headache [see Table 1]. Discontinuation for adverse events, regardless of a CYP3A4 inducer. Patients should be closely monitored and the dose titrated based on safety and efficacy. causality, was observed in 11.0% of patients treated with Jakafi and 10.6% of patients treated with placebo. USE IN SPECIFIC POPULATIONS Pregnancy Pregnancy Category C: There are no adequate Following interruption or discontinuation of Jakafi, symptoms of myelofibrosis generally return to and well-controlled studies of Jakafi in pregnant women. In embryofetal toxicity studies, treatment with pretreatment levels over a period of approximately 1 week. There have been isolated cases of patients discon- ruxolitinib resulted in an increase in late resorptions and reduced fetal weights at maternally toxic doses. tinuing Jakafi during acute intercurrent illnesses after which the patient’s clinical course continued to worsen; Jakafi should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. however, it has not been established whether discontinuation of therapy contributed to the clinical course in Ruxolitinib was administered orally to pregnant rats or rabbits during the period of organogenesis, at doses these patients. When discontinuing therapy for reasons other than thrombocytopenia, gradual tapering of the of 15, 30 or 60 mg/kg/day in rats and 10, 30 or 60 mg/kg/day in rabbits. There was no evidence of teratodose of Jakafi may be considered [see Dosage and Administration (2.6) in Full Prescribing Information]. genicity. However, decreases of approximately 9% in fetal weights were noted in rats at the highest and maternally toxic dose of 60 mg/kg/day. This dose results in an exposure (AUC) that is approximately 2 times Table 1 presents the most common adverse reactions occurring in patients who received Jakafi in the doublethe clinical exposure at the maximum recommended dose of 25 mg twice daily. In rabbits, lower fetal weights blind, placebo-controlled study during randomized treatment. of approximately 8% and increased late resorptions were noted at the highest and maternally toxic dose of Table 1: Adverse Reactions Occurring in Patients on Jakafi in the Double-blind, Placebo-controlled 60 mg/kg/day. This dose is approximately 7% the clinical exposure at the maximum recommended dose. In Study During Randomized Treatment a pre- and post-natal development study in rats, pregnant animals were dosed with ruxolitinib from implanJakafi Placebo tation through lactation at doses up to 30 mg/kg/day. There were no drug-related adverse findings in pups for (N=155) (N=151) fertility indices or for maternal or embryofetal survival, growth and development parameters at the highest Adverse All All dose evaluated (34% the clinical exposure at the maximum recommended dose of 25 mg twice daily). a Reactions Grades Grade 3 Grade 4 Grades Grade 3 Grade 4 Nursing Mothers It is not known whether ruxolitinib is excreted in human milk. Ruxolitinib and/or its metabolites were excreted in the milk of lactating rats with a concentration that was 13-fold the maternal (%) (%) (%) (%) (%) (%) plasma. Because many drugs are excreted in human milk and because of the potential for serious adverse Bruisingb 23.2 0.6 0 14.6 0 0 reactions in nursing infants from Jakafi, a decision should be made to discontinue nursing or to discontinue Dizzinessc 18.1 0.6 0 7.3 0 0 the drug, taking into account the importance of the drug to the mother. Pediatric Use The safety and effecHeadache 14.8 0 0 5.3 0 0 tiveness of Jakafi in pediatric patients have not been established. Geriatric Use Of the total number of Urinary Tract Infectionsd 9.0 0 0 5.3 0.7 0.7 myelofibrosis patients in clinical studies with Jakafi, 51.9% were 65 years of age and older. No overall differWeight Gaine 7.1 0.6 0 1.3 0.7 0 ences in safety or effectiveness of Jakafi were observed between these patients and younger patients. Renal Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in Flatulence 5.2 0 0 0.7 0 0 healthy subjects [CrCl 72-164 mL/min (N=8)] and in subjects with mild [CrCl 53-83 mL/min (N=8)], Herpes Zosterf 1.9 0 0 0.7 0 0 moderate [CrCl 38-57 mL/min (N=8)], or severe renal impairment [CrCl 15-51 mL/min (N=8)]. Eight (8) a National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE), version 3.0 b includes contusion, ecchymosis, hematoma, injection site hematoma, periorbital hematoma, vessel puncture site additional subjects with end stage renal disease requiring hemodialysis were also enrolled. The pharmacokinetics of ruxolitinib was similar in subjects with various degrees of renal impairment and in those with hematoma, increased tendency to bruise, petechiae, purpura c includes dizziness, postural dizziness, vertigo, balance disorder, Meniere’s Disease, labyrinthitis normal renal function. However, plasma AUC values of ruxolitinib metabolites increased with increasing d includes urinary tract infection, cystitis, urosepsis, urinary tract infection bacterial, kidney infection, pyuria, bacteria severity of renal impairment. This was most marked in the subjects with end stage renal disease requiring urine, bacteria urine identified, nitrite urine present hemodialysis. The change in the pharmacodynamic marker, pSTAT3 inhibition, was consistent with the e includes weight increased, abnormal weight gain corresponding increase in metabolite exposure. Ruxolitinib is not removed by dialysis; however, the removal f includes herpes zoster and post-herpetic neuralgia of some active metabolites by dialysis cannot be ruled out. When administering Jakafi to patients with Description of Selected Adverse Drug Reactions Anemia In the two Phase 3 clinical studies, median moderate (CrCl 30-59 mL/min) or severe renal impairment (CrCl 15-29 mL/min) with a platelet count time to onset of first CTCAE Grade 2 or higher anemia was approximately 6 weeks. One patient (0.3%) between 100 X 109/L and 150 X 109/L and patients with end stage renal disease on dialysis a dose reduction discontinued treatment because of anemia. In patients receiving Jakafi, mean decreases in hemoglobin is recommended [see Dosage and Administration (2.5) in Full Prescribing Information]. Hepatic reached a nadir of approximately 1.5 to 2.0 g/dL below baseline after 8 to 12 weeks of therapy and then Impairment The safety and pharmacokinetics of single dose Jakafi (25 mg) were evaluated in a study in gradually recovered to reach a new steady state that was approximately 1.0 g/dL below baseline. This pattern healthy subjects (N=8) and in subjects with mild [Child-Pugh A (N=8)], moderate [Child-Pugh B (N=8)], or was observed in patients regardless of whether they had received transfusions during therapy. In the severe hepatic impairment [Child-Pugh C (N=8)]. The mean AUC for ruxolitinib was increased by 87%, 28% randomized, placebo-controlled study, 60% of patients treated with Jakafi and 38% of patients receiving and 65%, respectively, in patients with mild, moderate and severe hepatic impairment compared to patients placebo received red blood cell transfusions during randomized treatment. Among transfused patients, the with normal hepatic function. The terminal elimination half-life was prolonged in patients with hepatic median number of units transfused per month was 1.2 in patients treated with Jakafi and 1.7 in placebo impairment compared to healthy controls (4.1-5.0 hours versus 2.8 hours). The change in the pharmacotreated patients. Thrombocytopenia In the two Phase 3 clinical studies, in patients who developed Grade 3 dynamic marker, pSTAT3 inhibition, was consistent with the corresponding increase in ruxolitinib exposure or 4 thrombocytopenia, the median time to onset was approximately 8 weeks. Thrombocytopenia was except in the severe (Child-Pugh C) hepatic impairment cohort where the pharmacodynamic activity was generally reversible with dose reduction or dose interruption. The median time to recovery of platelet counts more prolonged in some subjects than expected based on plasma concentrations of ruxolitinib. When above 50 X 109/L was 14 days. Platelet transfusions were administered to 4.7% of patients receiving Jakafi administering Jakafi to patients with any degree of hepatic impairment and with a platelet count between and to 4.0% of patients receiving control regimens. Discontinuation of treatment because of thrombo- 100 X 109/L and 150 X 109/L, a dose reduction is recommended [see Dosage and Administration (2.5) in cytopenia occurred in 0.7% of patients receiving Jakafi and 0.9% of patients receiving control regimens. Full Prescribing Information].

Patients with a platelet count of 100 X 109/L to 200 X 109/L before starting Jakafi had a higher frequency of Grade 3 or 4 thrombocytopenia compared to patients with a platelet count greater than 200 X 109/L (16.5% Jakafi is a trademark of Incyte Corporation. All rights reserved. versus 7.2%). Neutropenia In the two Phase 3 clinical studies, 1.0% of patients reduced or stopped Jakafi U.S. Patent No. 7,598,257 because of neutropenia. Table 2 provides the frequency and severity of clinical hematology abnormalities © 2011 Incyte Corporation. All rights reserved. reported for patients receiving treatment with Jakafi or placebo in the placebo-controlled study.

Issued: November 2011 RUX-1040

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Value-Based Cancer Care

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MAY 2013

ty societies still do not include any cost considerations in their clinical guidance or are vague and nonspecific about it having any true clinical value. The investigators suggest that “physician specialty societies should demonstrate greater transparency and rigor in their approach to cost considerations in documents meant to influence care decisions.”

Many Patients Unwilling to Let Costs Influence the Treatment They Receive

The issue of cost in clinical decision-making is increasingly becoming necessary in the face of growing healthcare costs, limited resources, and often limited access to care. Involving patients in the cost discussion has been suggested as a way to begin to curb the rising costs of care. A new study investigated the inclination of Americans with health insurance to discuss their willingness to have cost as part of the decision-making in their care (Sommers R, et al. Health Aff [Millwood]. 2013;32:338-346).

The study population included 22 focus groups of Americans with health insurance from 2 geographically distinct metropolitan areas—Santa Monica, CA, and Washington, DC. Al­ though all participants had insurance, they varied by age, race, education, and by income levels. At least 50% had incomes of <300% of the poverty level and 43% had incomes of <$40,000.

“We found that the majority of participants were unwilling to consider cost when deciding between nearly comparable options and generally resisted the less expensive, marginally inferior option,” the authors wrote.

The 4 barriers to participants’ willingness to consider cost in treatment decisions included: • Preference for the best therapeutic option, regardless of cost • Inexperience in making trade-off decisions between health and money • Lack of concern for money spent by society and health insurance • No sense of personal responsibility for the cost of care • Noncooperation because of prioritizing self-interest concerns.

Overall, participants wanted the best care and were not interested in considering limited resources and making trade-offs between their health and money, holding physicians responsible to provide them the best care available, regardless of cost.

Based on their findings, the investigators conclude that “for cost to be an explicitly recognized and discussed factor in clinical decisions, public attitudes about health care costs must first undergo a significant shift.” n

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The Changing Oncology Landscape... gap is widening and healthcare is becoming less affordable. “In 3 years, the person who makes an average US salary will have to spend 50% of it to cover his out-of-pocket expenses and healthcare premium,” Lee N. Newcomer, MD, MHA, Senior Vice President, UnitedHealthcare Group, Minneapolis, MN, pointed out.

John L. Fox, MD, MHA, Senior Medical Director, Priority Health, Grand Rapids, MI, further predicted, “In the future, there will be healthcare exchanges and subsidies for low-income persons, but the middle class may be squeezed. Their out-of-pocket costs could be up to $6000 for an individual or $12,000 for a family. Even Medicare and Medicaid will experience more cost-sharing. This is a new disparity.”

One result of this is a population of persons who bypass preventive care and screening, and thus enter or re-enter the workplace with a higher risk profile or more advanced disease.

Susan A. Higgins, MD, MS, Associate Director, Department of Therapeutic Radiology Residency Training Pro­ gram, Yale Cancer Center, New Haven, CT, added that in her practice at Yale, she is seeing stage IV cervical cancer (a “third-world country disease”) among her underprivileged patients. In contrast, her affluent patients are moving into concierge practices.

Although the Affordable Care Act will “ballast the very bottom,” Dr Higgins said, high copays for everyone else means that “the bottom of the middle class is falling down.”

Roy A. Beveridge, MD, Chief Medical Officer, McKesson Specialty Health, predicted that healthcare reform will increase coverage for previously uninsured persons, “but it is going to create other types of problems for how we care for them.”

Dr Newcomer predicted that reform will broaden access to care, but it will not affect the escalating cost of care.

“Access may not be worth much if people cannot afford the deductible,” he pointed out.

Involving the Patient Greater attention must be paid to early integration of palliative care. Dr Fox suggested that before cancer outcomes can be improved, oncology stakeholders need to determine “which outcomes are most valuable.”

At Priority Health, he said, the outcomes are “those that are most valuable to our patients,” and this is not necessarily longer life expectancy.

The patient’s list of priorities must be front and center of clinical deci-

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sion-making, and any treatment should be consistent with them. “The only way to know this is to ask the patient,” Dr Fox said.

Dr Beveridge saw other obstacles to the successful integration of palliative care or end-of-life care: the lack of manpower to effectively deliver it, and the fact that patients often fail to grasp its meaning. “Patients don’t want to make their caregivers unhappy. We have found in interviews that many will accept a third or fourth line of futile therapy, because they don’t want to let their doctors down. Interestingly, physicians say they are giving futile therapy because they don’t want to let their patients down,” he said.

“In 3 years, the person who makes an average US salary will have to spend 50% of it to cover his out-of-pocket expenses and healthcare premium....Access may not be worth much if people cannot afford the deductible.”

—Lee N. Newcomer, MD, MHA Dr Newcomer called this a “philosophical barrier.” “Americans still think death is an option,” he said. “We have a whole culture that says it is wrong to stop [treatment],” and this impedes a full and open exchange about prognosis.

“When you throw in the family and

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cultural dynamic, you almost need the Department of State as a negotiator,” Dr Beveridge added. “We have found that it is frequently better to have a nurse practitioner or social worker introduce the topic, because we as physicians are not trained to do this, and we don’t do it particularly well.”

Tools to help initiate these discussions are becoming available, including the American Board of Internal Medicine Foundation’s Choosing Wisely initiative, which includes the American Society of Clinical On­ cology’s “Top Five” list of common, costly procedures in oncology that are not supported by evidence and that should be questioned. Some practices in the UnitedHealth Group network are asking patients to complete the Choosing Wisely form on hospital admission. “These practices are achieving much more patient-oriented outcomes, far fewer days in the ICU [intensive care unit], and more deaths at home, because they are having this discussion,” Dr Newcomer reported.

Dr Newcomer said that he recently used the Choosing Wisely tool with his own parents and was surprised at what he learned. “I changed my viewpoint about their end-of-life care. This can be done,” he stated. “It doesn’t require an army of palliative care specialists but a cultural commitment.”

How to Brave the New World: The Evolving Ecosystem The future of cancer care requires a reformed “ecosystem,” in the words of Dr Goodman. This means the integration of components in a multidisciplinary approach and a competitive collaboration to problem solving.

The evolving ecosystem is no longer centered on individual excellence but rather on interoperable performance.

“We were trained to play golf. The game has switched to basketball,” he said. “It’s about interoperability [and] how to work together, so that I can’t be as good as I need to be without Lee

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Newcomer,” said Andrew C. von Eschenbach, MD, President of Samari­ tan Health Initiatives, Montgomery, TX, and Adjunct Professor, M.D. Anderson Cancer Center, Houston, TX.

The outcomes are “those that are most valuable to our patients,” and this is not necessarily longer life expectancy.

—John L. Fox, MD, MHA Dr Goodman noted that Dr von Eschenbach once headed the National Cancer Institute, which included “many competing cancer institutions doing research.” Dr von Eschenbach said that the ideal scenario would not have been “61 separate phenomenal cancer centers, but 61 playing together like a well-orchestrated team.”

“As we look toward a brave new world in oncology, it’s tempting to look at all the high-tech stuff we have for discovering the next cure. But in this roundtable, we saw that in order to get to the next level, we can’t forget that we have disparities in care that drag the system down,” Dr Goodman said. “We need to hold up that part of our at-risk population at the same time we advance the cutting edge with big data and reorganizing the cancer ecosystem. Our current incentives and disincentives are not providing for optimal care.” n

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NCCN Annual Conference

NCCN Updates Its Clinical Practice Guidelines

By Audrey Andrews

Hollywood, FL—Updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines® were presented at the 2013 NCCN annual conference. The updates were minor for most tumor sites, but new guidelines were introduced for penile cancer and for survivorship.

New Guidelines for Penile Cancer The NCCN issued inaugural guidelines for penile cancer, a rare malignancy. The standard of care remains complete tumor excision and eradication of negative margins, but in many patients, less invasive management can be appropriate. For superficial disease, less invasive options can be considered, based on the stage and grade of the tumor. These options include topical treatment with imiquimod 5% (Aldara) or with 5-fluorouracil cream (Efudex), which can produce “excellent outcomes,” according to Philippe E. Spiess, MD, MSc, Genitourinary Oncologist, H. Lee Moffitt Cancer Center, Tampa, FL. For more extensive tumors, radical surgery is the chief recommendation.

Options include wide local excision, laser treatment, radiation therapy, glansectomy, and partial/total penectomy. Penile-preserving surgery maintains function and quality of life in patients with small lesions, where negative margins can be obtained. For bulky disease with positive lymph nodes, neoadjuvant chemotherapy has been proved effective. A nomogram is recommended for predicting metastatic lymph node involvement, because it outperforms the conventional clinical risk categories. The NCCN does not recommend dynamic sentinel-node biopsy, because of its low sensitivity and inadequacy in detecting occult inguinal disease.

New Survivorship Guidelines A growing appreciation of the unmet needs of cancer survivors has led to a new set of guidelines for survivorship. Topics include anxiety and depression, cognitive function, exercise, immunizations and infections, fatigue, pain, sexual function, and sleep disorders.

“The survivorship guidelines are intended as a library of tools for a provider to use when assessing a cancer survivor,” said Crystal S. Denlinger, MD, Co-Site Director, Internal Medicine Residency Program, Fox Chase Cancer Center, Philadelphia, PA. The NCCN recommends physical activity and returning to daily ac-

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tivities, tailored to the individual’s abilities and preferences, as soon as possible after cancer treatment. The general recommendation is at least 150 minutes of moderate-intensity activity weekly, coupled with strength training and stretching. The document includes an assessment pathway and advice for specific populations (eg, for patients with lymphedema); offers examples of light, moderate, and vigorous exercise; and suggests strategies to motivate patients.

Cognitive dysfunction can occur as a complication of cancer treatment.

The guidelines discuss general principles of cognitive dysfunction and provide an evaluation pathway, specific assessments, and practical interventional strategies, but this is still an area that is not well understood and is not backed by strong data.

The guidelines encourage immunizations based on age and medical condition as part of standard practice. Vaccinations against influenza, pneumonia, meningitis, and hepatitis are considered safe for patients with cancer, but live attenuated vaccines are contraindicated or should be used with caution. Principles for zoster vaccination in cancer or transplant survivors are included.

Sexual dysfunction is common for cancer survivors, and clinicians should assess level of sexual activity (past and present), the impact of cancer therapy, sexual concerns, comorbidities, risk factors, and psychosocial factors.

The guidelines include validated tools for assessment: a brief sexual symptom checklist for women and a sexual health inventory for men.

Acute Promyelocytic Leukemia: A Nonchemotherapy Option “For the first time, the NCCN guidelines have taken chemotherapy out of the upfront treatment for acute promyelocytic leukemia [APL],” said Margaret R. O’Donnell, MD, Associate Clinical Director, Department of Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, Duarte, CA. The guidelines for APL were changed as a result of a recent study (Lo-Coco F, et al. Blood. 2012;120:Abstract 6). For patients with low- or intermediate-risk APL, the guidelines now recommend induction with all-transretinoic acid plus arsenic trioxide.

New Agents in Colorectal Cancer Two new agents are now included in the NCCN guidelines for metastat-

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ic colorectal cancer—ziv-aflibercept (Zaltrap) and regorafenib (Stivarga)— although their overall benefit is relatively minor, acknowledged Leonard Saltz, MD, Chief of the Gastrointestinal Oncology Service, and Head of the Colorectal Oncology Section, Memorial Sloan-Kettering Cancer Center, New York. “We had hoped ziv-aflibercept would be the next step forward, but in the registration study, it provided only a 1.5-month overall survival benefit,” Dr Saltz noted.

“For the first time, the NCCN guidelines have taken chemotherapy out of the upfront treatment for acute promyelocytic leukemia.”

—Margaret R. O’Donnell, MD In the updated guidelines, ziv-aflibercept is acceptable when added to the FOLFIRI regimen or to irinotecan, but it should not be used as a single agent, in combination with FOLFIRI after failure of FOLFIRI plus bevacizumab (Avastin), or added to a failed regimen. Bevacizumab was also added as an option after first disease progression, in combination with the FOLFIRI regimen, with irinotecan, with the FOLFOX regimen, or with capecitabine (Xeloda) plus oxaliplatin (Eloxatin).

Regorafenib was added to the guide­lines as a treatment option after first, second, or third disease progression, depending on previous lines of therapy used, based on the 1.4-month survival advantage seen in the CORRECT trial (Grothey A, et al.

Lancet. 2013;381:303-312).

Giant-Cell Tumor of Bone New treatment pathways for giant-cell tumor of bone (GCTB) and chordoma debuted in the updated version of the guidelines for bone cancer.

These are rare neoplasms and most clinicians are unfamiliar with them.

Although GCTB is considered a benign disease, it carries a 2% risk for metastasis.

Intralesional excision with the use of a high-speed burr is advised rather than more extensive surgery that requires skeletal reconstruction.

Although recurrence is not uncommon, the use of adjuvant therapy— thermal or chemical—ameliorates this

risk. In patients with unresectable or recurrent disease, denosumab (Prolia) can help restore the skeletal architecture and allow a joint-conserving procedure or avoidance of surgery altogether.

For localized disease, excision is recommended; if resection carries unacceptable morbidity, or if the tumor is unresectable, treatment options include serial embolization, denosumab, interferon, pegylated interferon, and/or radiotherapy. For metastatic disease, surgery is indicated if feasible. The recommended workup includes history, physical examination, cross-sectional imaging of the primary site, chest imaging, and biopsy, with optional bone scan.

New Agents in Multiple Myeloma “We have wonderful new agents, at least a lot more potent than priorgeneration drugs,” said Kenneth C. Anderson, MD, Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics, Dana-Farber Cancer Institute, and Oncologist, Brigham and Women’s Hospital, Boston. The approval of the second-generation protea­some inhibitor carfilzomib (Kyprolis) led to its recent inclusion in the guidelines in combination with lenalidomide (Revlimid) plus dexamethasone for transplant candidates.

This triplet joins a growing list of regimens that greatly increase response rates, Dr Anderson noted.

For relapsed and/or refractory disease, the updated guidelines also include carfilzomib as a preferred salvage therapy option, as well as the new immunomodulating drug pomalidomide (Pomalyst) plus low-dose dexamethasone. Other recommended regimens now include bortezomib (Velcade) plus vorinostat (Zolinza) and lenalidomide plus bendamustine (Treanda) and dexamethasone.

Updates in Non-Hodgkin Lymphoma The growing use of lenalidomide by patients with non-Hodgkin lymphoma is reflected in the updated guidelines. New to the guidelines for the second-line treatment of stage I to II disease is lenalidomide, with or without rituximab (Rituxan). For chronic lymphocytic leukemia, first-line therapy now includes lenalidomide (continuous or intermittent dosing) as a treatment option, and bendamustine, with or without rituximab. For relapsed Continued on page 31

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Patient Engagement

Health IT Facilitates Patient Engagement Across Many Settings

By Caroline Helwick

New Orleans, LA—“Patient engagement” is a healthcare buzz phrase, and a critical part of this concept is patient connectivity to information technology (IT). GetWellNetwork is a patientfocused IT system that aims to empower the patient to improve outcomes in a variety of disease states.

At the 2013 Healthcare Information and Management Systems Society annual conference, Michael O’Neil, Founder and CEO of GetWellNetwork, spoke with Value-Based Cancer Care

at a glance ➤ Engaging patients in their own care adds value to cancer care ➤ The use of Interactive Patient Care principles has led to a reported average of: • 22% increase in staff responsiveness • 33% increase in well-controlled pain • 22% reduction in heart failure

readmission rate • 6% decrease in length of stay • 22% reduction in falls • $2.5 million in pharmacy revenue

about how patient engagement via health IT can improve clinical outcomes.

The company’s commitment to improve outcomes through patient engagement started with 1 patient and his cancer experience, explained Mr O’Neil, who was diagnosed with non-Hodgkin lymphoma in 1999. “I had a great medical outcome, but not such a great patient experience,” he said.

Mr O’Neil stated that while barraged by “information,” he still felt uninformed and insecure in making sound treatment decisions for his cancer. This gap in patient-centered information led to his idea for Interactive Patient Care, a personalized, intuitive, interactive patient-centered system that is delivered across multiple technology platforms, including mobile devices, computers, and televisions.

In the ongoing shift to a value-based healthcare economy, patient engagement has become even more critical to improving care and to organizational performance. Partnering with patients to strengthen communication and coordination is a key factor in success, Mr O’Neil stressed.

“There are now many IPC [Inter­ active Patient Care] systems that are delivering on this promise,” he noted.

Evidence-based data show that the

use of Interactive Patient Care tools is improving patient satisfac­tion, clinical outcomes, and financial performance.

“Our tools will make sure the patient is locked in together with the providers on the plan of care, so there will be significantly less chance for mishaps and mistakes.”

—Michael O’Neil Interactive Patient Care products have reported, on average, a 22% increase in staff responsiveness, a 33% increase in well-controlled pain, a 22% reduction in heart failure readmission rate, a 6% decrease in length of stay, and a 22% reduction in falls. They have also gained $2.5 million in pharmacy revenue, according to company data.

The Value of Using Patient Tools in Oncology “On the oncology side, we are working with several groups to understand how these tools can help deliver better outcomes in both the inpatient and outpatient settings,” Mr O’Neil said.

The patient’s first introduction is often

the touchscreen that he or she encounters while in the infusion chair.

Collaborations are under way with oncologists at The Institute for Cancer Care at Mercy Medical Center in Baltimore, MD, and at the Mario Lemieux Center for Blood Cancers at the Hillman Cancer Center of the University of Pittsburgh Medical Center Presbyterian Shadyside, PA. “We are in partnership with these centers to develop a library of oncology pathways that will be tumor- and stage-specific,” he said.

“We want to make sure the cancer patient owns his journey,” Mr O’Neil emphasized. “In my experience, I got an incredible amount of new information, but I was not informed, not feeling in control, so trying to make decisions was very anxiety producing.

I personally learned that when the patient is empowered to be involved in the process, it not only feels good, but the patient also gets better. The informed patient is a better patient.”

This system not only “educates,” but can enhance adherence to the care plan, including medication adherence, nutritional recommendations, and adverse event monitoring.

“Our tools will make sure the patient is locked in together with the providers on the plan of care, so there will be significantly less chance for mishaps and mistakes,” he said. n

NCCN Annual Conference

NCCN Updates Its Clinical Practice... and/or refractory disease, lenalidomide, with or without rituximab, is a treatment option.

New TKIs in Thyroid Cancer With the availability of 2 new tyrosine kinase inhibitors (TKIs), “these are exciting times in thyroid cancer,” said Robert I. Haddad, MD, Associate Professor of Medicine, Dana-Farber Cancer Institute, Harvard Medical School, Boston. TKIs now offer an option for patients with disease refractory to radioactive iodine.

In patients with advanced or meta­ static medullary thyroid cancer, cabozantanib (Cometriq) and vandetanib (Caprelsa) have more than

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doubled progression-free survival.

The guidelines now list both drugs as Category 1 treatments for unresectable disease that is symptomatic or asymptomatic and structurally progressive.

Although not approved by the US Food and Drug Administration (FDA) for thyroid cancer, other small-molecule TKIs (eg, sorafenib, sunitinib) can be considered.

New Drugs Exploit Androgen Pathway in Prostate Cancer Two new drugs approved by the FDA for the treatment of prostate cancer take advantage of the persistence of androgen receptor expression, even in patients with castration-re-

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sistant disease. Abiraterone acetate (Zytiga), an androgen synthesis inhibitor, and enzalutamide (Xtandi), an antiandrogen, have changed the treatment landscape, said Philip W. Kantoff, MD, Chief, Division of Solid Tumor Oncology, Dana-Farber Cancer Institute, Boston.

The NCCN guidelines now include abiraterone plus prednisone as a Category 1 recommendation in the pre- and postchemotherapy settings, and enzalutamide as a Category 2A recommendation for docetaxel-naïve patients and a Category 1 recommendation after chemotherapy. “These drugs have a clinically meaningful impact on survival,” Dr Kantoff said.

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Melanoma: Thin Lesions Can Forego SLNB A substantial change to the melanoma guidelines pertains to the indication for sentinel lymph node biopsy (SLNB), which the panel concluded is not warranted for thin (ie, ≤0.75 mm) lesions. SLNB may be considered when conventional risk factors accompany these very thin lesions.

Otherwise, patients with thin lesions should undergo wide excision, patients with lesions 0.76 mm to 1.0 mm should be considered for SLNB, and patients with lesions >1 mm require SLNB. The change has the potential to affect up to 75% of the patients with melanoma in the average practice. n

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AACR Annual Meeting

AACR Issues New Policy on Tobacco Use Cancer centers asked to educate patients on smoking cessation

By Phoebe Starr Washington, DC—Tobacco use among patients with cancer is an important but often overlooked issue that requires intervention by oncology practices. In recognition of the problem and the gap between the need for intervention and the services delivered, the American Association for Cancer Research (AACR) issued a policy on tobacco use at its 2013 annual meeting.

The genesis for the policy came from some surprising and disappointing survey results showing that many oncology practices do not routinely address tobacco use and that many clinical trials do not document tobacco use at baseline and follow-up, although it is a confounding factor.

In fact, tobacco use interferes with the efficacy of chemotherapy and radiation therapy, leads to worsened side effects from these therapies, increases the risk of developing a second cancer, and increases the risk of dying of heart disease. There is a strong rationale for creating infrastructure for delivery of evidence-based interventions to address tobacco use among patients with cancer.

The AACR policy states that only 38% of National Cancer Institute (NCI)-designated cancer centers that responded to a survey document smoking status as a vital sign, and less than 50% of these centers have dedicated personnel for tobacco cessation;

by contrast, 78% of centers have dedicated nutrition personnel.

A different survey showed that whereas 90% of responding oncologists believe that tobacco use affects cancer outcomes and that tobacco cessation should be included as a standard of care, only 40% of these oncologists provide routine assistance for smoking cessation. Only 33% of lung cancer specialists considered themselves adequately trained in smoking cessation.

A recent study of 155 NCI Clinical Trials Cooperative Group Program trials demonstrated that only 29% of registered trials assessed tobacco use during the study. Less than 5% of these trials include follow-up on subsequent tobacco use status.

It is very difficult for people to quit smoking. Studies suggest that although approximately 50% of smokers try to quit, only between 4% and 7% are successful in doing so without evidence-based intervention.

“Although lung cancer first comes to mind as associated with tobacco use, tobacco is implicated in 18 other cancers. A frequent assumption is that once cancer develops, it is fruitless to stop smoking. This is not true,” said Roy S. Herbst, MD, PhD, Chair of the AACR Tobacco and Cancer Sub­ committee that produced the policy statement, and Chief of Medical Oncology, Yale Cancer Center and

Smilow Cancer Hospital at Yale-New Haven, CT. Evidence-based approaches to stop smoking include pharmacotherapy and nicotine chewing gum, as well as the “5A” approach to smoking cessation—ask about smoking status, ad-

“Although lung cancer first comes to mind as associated with tobacco use, tobacco is implicated in 18 other cancers. A frequent assumption is that once cancer develops, it is fruitless to stop smoking. This is not true.”

—Roy S. Herbst, MD, PhD

vise people to quit, assess interest in quitting, assist with pharmacotherapy and counseling, and arrange follow-up. However, many cancer providers rarely advise patients on how to approach quitting.

Concrete Steps The AACR’s policy statement endorses a number of recommendations to remedy this treatment gap. The

statement notes that oncology practices should be responsible for providing assessment and intervention for patients with cancer who continue to smoke and for recent quitters. The recommendations call for: • Repeat documentation of tobacco use in all patients with cancer, so that the confounding effects of smoking on treatment, disease progression, and comorbidities can be tracked in clinical trials, starting at registration and continuing through follow-up • Tobacco use should also be documented in all clinical care settings; universal standardized measurements of tobacco use and of tobacco exposure are required to be able to make cross-center comparisons and to compile a meaningful database • Researchers and healthcare quality and accreditation bodies should incorporate evidence-based criteria • Healthcare systems, payers, and funding bodies should provide reimbursement for tobacco use in­ terventions and should provide incentives for developing and for delivering interventions.

The Affordable Care Act provides for reimbursement for smoking cessation interventions by insurance plans by 2014, but this will vary by state and will be evidence-based. Electronic medical records will also track smoking status. n

Ibrutinib Shows Rapid, Dramatic Responses... after 2 months,” said Dr Wiestner.

Responses to ibrutinib appear to be durable, he added.

The drug demonstrated activity in patients whose tumors arise from the deletion of chromosome 17p (del[17p]), which is associated with poor response to conventional therapies and with poor prognosis.

Unlike other therapies for CLL, ibrutinib targets the enzyme that mediates B-cell signaling that is associated with disease progression. Ibrutinib is being evaluated as a single agent, whereas conventional CLL treatment typically consists of a combination of chemotherapy and immunotherapy.

Dr Wiestner reported findings from a study involving 54 patients with

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CLL, 29 of whom had the del(17p) and 25 patients who did not have

“Some patients have had more than a 90% reduction in lymph node disease after 2 months.”

—Adrian Wiestner, MD, PhD

del(17p). All patients received ibrutinib 420 mg daily for 6 months.

At the end of the treatment period,

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95% of the patients had at least a 50% reduction in lymph node disease, the median absolute lymphocyte count declined by 62%, and all of the patients had a reduction in spleen volume. Among 26 patients who underwent bone marrow biopsy, tumor infiltration was reduced by 82%.

Of 44 patients evaluable for response, more than 50% met international criteria for partial response, and similar rates were seen in patients with del(17p) and in the 25 patients (aged ≥65 years) with no del(17p).

Ibrutinib was well tolerated, according to Dr Wiestner. The most frequent adverse events were grade 1 or 2 diarrhea, rash, arthralgia, cramps, stomatitis, and fatigue. Grade 3 ad-

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verse events occurred in 13% of the patients and consisted mostly of infections and rash. Two patients died of causes unrelated to treatment.

At the time of the AACR meeting, the FDA designated ibrutinib as an oncologic “breakthrough therapy,” for 2 B-cell malignancies—mantle-cell lymphoma and Waldenström’s macroglobulinemia. A breakthrough therapy designation is intended to expedite the development and review of therapies that have shown potential as improvements over existing treatments. A few weeks later, the FDA granted a third breakthrough designation for ibrutinib for the treatment of patients with chronic lymphocytic leukemia. n

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Fourth Annual Navigation and Survivorship Conference Memphis, Tennessee â&#x20AC;˘ The Peabody Memphis

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Sharon Gentry, RN, MSN, AOCN, CBCN Breast Health Navigator Derrick L. Davis Forsyth Regional Cancer Center Winston-Salem, NC

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AACR Annual Meeting

New Mantle-Cell Regimen Leads to “Remarkable” Response Rate

By Charles Bankhead

Washington, DC—A chemotherapy– immunotherapy combination has been shown to be extremely effective in a small clinical trial of previously untreated mantle-cell lymphoma, leading to objective responses in every patient, including complete responses in almost 90%, investigators reported at the 2013 American Association for Cancer Research annual meeting.

All 37 patients had at least partial

responses to treatment with the com­ bination of vorinostat (Zolinza), cladribine (Leustatin), and rituximab (Rituxan). The regimen achieved com-

“This is a safe and effective combination in previously untreated mantle-cell lymphoma.

Myelosuppression is the primary toxicity and is reversible.”

at a glance ➤ The new combination of vorinostat, cladribine, and rituximab achieves durable response rates of close to 90% in mantle-cell lymphoma ➤ All patients in this trial had at least a partial response ➤ The mean progression-free survival has yet to be reached ➤ Myelosuppression is the primary toxicity

nation in previously untreated mantle-cell lymphoma,” said Dr Sharma.

“Myelosuppression is the primary toxicity and is reversible.”

—Kamal Sharma, DO

plete responses in 32 (86%) patients and in 29 of 32 (91%) patients who have completed the planned 6 cycles of therapy.

With follow-up for as long as 34 months (median, 13 months), the median progression-free survival has yet to be reached, reported Kamal Sharma, DO, a hematologist at Penn State Milton S. Hershey Medical Center, State College, PA. “This is a safe and effective combi-

Mantle-cell lymphoma has no generally accepted standard regimen, although the combination of rituximab and cladribine has been cited in the National Comprehensive Cancer Network’s Clinical Practice Guide­lines® for achieving durable responses in a substantial proportion of patients.

In an effort to build on the success of that immunologic–epigenetic combination, Dr Sharma and colleagues

have added the histone deacetylase inhibitor vorinostat to the mix.

The regimen is administered in 28day cycles that continue until completion of at least 6 cycles, disease progression, or development of un­ac­ ceptable toxicity. Of the first 40 patients enrolled in this study, 32 completed 6 cycles of therapy, and treatment is ongoing for 3 others. None of the patients underwent stem-cell transplantation, nor was an attempt made to harvest stem cells, said Dr Sharma.

Hematologic toxicity consisted of neutropenia (all grades) in 32% of patients (including 11% with grade 3 or 4) and thrombocytopenia in 20% (5% with grade 3 or 4). Fatigue has been the most frequent nonhematologic toxicity.

These “remarkable results” require validation, including laboratory studies to determine the underlying mechanisms for the regimen’s activity, which has been dramatic in some patients, commented Kenneth C. Anderson, MD, Chief of the Division of Hematologic Neoplasia, DanaFarber Cancer Institute, Boston. n

False-Positive Lung Cancer Rates Vary Widely by State Washington, DC—Lung cancer falsepositive rates varied 20-fold across the United States, raising questions about the potential impact on organized screening programs, according to data presented at the 2013 American Association for Cancer Research annual meeting.

A review of Medicare-related data showed that approximately 10% of patients who had surgery for diagnosed or suspected lung cancer turned out to have benign disease. However, the rate of false-positive results ranged from 1.3% to 25% across the 50 states.

Moreover, 2% of patients found to have benign disease died during hospitalization.

The wide variation in false-positive rates emerged from a statistical patchwork that revealed no consistent pattern or factors associated with false results, reported Stephen A. Deppen, MS, a PhD candidate in the doctoral program in epidemiology at The Insti­ tute for Medicine and Public Health, Vanderbilt University, Nashville, TN. “If the prevalence [of benign disease] differs by state or region, then a

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national lung cancer screening program may have varying results,” said Mr Deppen.

Interest in lung cancer screening has picked up in the aftermath of the National Lung Screening Trial, which showed that chest computed tomography (CT) scans afforded significant protection against lung cancer mortality compared with chest x-rays.

However, 96% of positive CT scans proved to be false-positive. Moreover, 25% of patients who underwent surgery for suspected lung cancer ultimately were found to have benign disease.

Despite the high rate of false results, the mortality-lowering impact of chest CT has sparked interest in the development of a national lung cancer screening program. A better understanding of the origin and variation in rates of false-positive results could inform decision-making about planning and implementing a screening program.

In an effort to gain more insight into the accuracy of diagnostic imaging for lung cancer diagnosis, Mr Deppen and colleagues queried the Medicare

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Provider Analysis and Review Hos­ pital National Limited Data Set for 2009, the most recent year with complete data.

The data showed that 25,362 patients underwent surgery for known or suspected lung cancer. Sub­se­quently, 2312 (9.1%) patients were found to have benign disease: 8.5% among men and 9.8% among women. The records also

“If the prevalence [of benign disease] differs by state or region, then a national lung cancer screening program may have varying results.”

—Stephen A. Deppen, MS showed that surgery was associated with an in-hospital mortality rate of 2.3%, including a rate of 2.1% among patients with benign disease.

Analysis of the results by geographic region showed that the overall

false-positive rate provided an incomplete—and possibly misleading—picture. False-positive rates ranged from a low of 1.3% in Vermont to a high of 25% in Hawaii. Overall, the median rate was 8.8%, but rates varied significantly across the states (P <.01).

The Medicare data did not permit an evaluation of possible reasons for the wide geographic variation in false-positive rates. Mr Deppen speculated that one possible explanation involves differences in how quickly providers act on a positive image and send patients to surgery. Haste may increase the likelihood of false-positive rates. In addition, chronic fungal infections involving the lungs may lead to images that mistakenly suggest lung cancer.

Investigators have embarked on a multiyear data analysis to see whether the false-positive rate might have varied over time. In addition, Mr Deppen plans to examine information systems data from a geographic perspective to compare rates of false-positive lung cancer diagnoses with regional prevalences of fungal infections.—CB n

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AACR Annual Meeting See also Health Policy, page 36

Positron Emission Tomography Scanning May Identify Stage I NSCLC that Requires Chemotherapy

By Charles Bankhead

Washington, DC—A positive fluorodeoxyglucose-positron emission tomography (FDG-PET) scan distinguished patients with high-risk stage I non–small-cell lung cancer (NSCLC) who may benefit from adjuvant chemotherapy, a retrospective review of a large database showed.

The increased uptake of FDG was associated with a median 5-year survival rate of 67% compared with 80% for patients with stage I NSCLC. Subgroup analysis showed that the survival difference was attributable to patients with high-risk stage IA disease, according to a study presented at the 2013 American Association for Cancer Research annual meeting.

“FDG-PET avidity was negatively associated with survival in resected stage I non–small-cell lung cancer,” said Eric L. Grogan, MD, MPH, Assistant Professor of Thoracic Sur­ gery, Vanderbilt University Medical Center, Nashville, TN. “Observations were similar in academic and community centers, meaning the results appear to be broadly applicable. FDGPET might be useful for determining which patients with pathologic stage IA non–small-cell lung cancer might benefit from adjuvant chemotherapy,” Dr Grogan noted.

Surgery remains the primary treatment modality for stage I NSCLC. Whereas patients with stages II and III disease clearly benefit from adjuvant therapy, the results are mixed but are generally negative for stage I. The evidence suggests that chemo-

therapy may offer some survival advantages for patients with stage IB NSCLC, but the evidence also has consistently shown that adjuvant chemotherapy adds only toxicity to patients with stage IA NSCLC, Dr Grogan continued.

“FDG-PET avidity was negatively associated with survival in resected stage I non–small-cell lung cancer.

Observations were similar in academic and community centers, meaning the results appear to be broadly applicable.”

—Eric L. Grogan, MD, MPH Nonetheless, the survival data for stage I NSCLC suggest the existence of a high-risk subgroup of stage I cancers, namely, stage IA. Overall, pathologic stage I NSCLC has a 5-year median survival rate of 67%, which is substantially lower than in other early-stage cancers, explained Dr Grogan.

A likely contributing factor is the lack of accuracy for clinical staging. Ap­ proxi­mately 30% of patients with clinical stage I disease are found to have nodal involvement at surgery, reclassifying the disease as stage II or III. “There is an urgent need to identify

this subgroup of patients with stage I non–small-cell lung cancer that is at high risk of recurrence,” said Dr Grogan.

FDG-PET avidity has proved to be a marker of poorer survival in NSCLC, but minimal data for the association have involved patients with pathologic stage I disease. In an effort to resolve the uncertainty, investigators reviewed data from an American College of Surgeons Oncology Group study that examined “proteomic” markers in serum for the detection of NSCLC. From 2004 to 2006, patients with known or suspected clinical stage I NSCLC underwent surgical resection at 51 sites in 39 cities. The pathologic results showed that 80% of the lesions were malignant and 20% were benign.

Of the 969 patients who were eligible for this trial, 682 had FDG-PET imaging, including 400 patients with pathologic stage I NSCLC. Each scan was reviewed by experienced independent radiologists, who characterized lesions by standard uptake value and by FDG-PET avidity. The lesions’ avidity was categorized on a scale of 1 (standard uptake value = 0, not cancer) to 4 (standard uptake value ≥5.0, high avidity/likely cancer).

The primary outcome was all-cause mortality, and FDG-PET avidity– defined differences in survival were reflected in Kaplan-Meier survival curves.

Overall, 314 (78%) FDG-PET scans demonstrated avidity. Pathology showed that 275 (69%) patients had stage IA NSCLC and 125 (31%) had

stage IB disease.

Stage IA disease was associated with significantly better 5-year survival compared with stage IB disease (P = .015). In addition, a positive FDG-PET scan predicted worse survival (P = .02).

Subgroup analysis showed that the FDG-PET results were influenced by differences in patients with stage IA disease. FDG-PET avidity predicted significantly worse survival in pathologic stage IA NSCLC (P = .013), but not in pathologic stage IB disease.

Multivariate analysis showed that a positive FDG-PET scan increased the survival hazard ratio (HR) by almost 80% (HR, 1.78; P = .04). Older age (HR, 1.04; P <.01) and lesion size (HR, 1.02; P = .02) were the only other independent predictors of survival.

The interaction between FDG-PET results and pathologic stage showed that a positive scan more than doubled the survival HR in patients with stage IA disease, but had no effect on survival in patients with stage IB NSCLC. Older age was the only other significant factor in the analysis (age, 74 years vs 60 years; HR, 1.61; P <.01).

Despite the reliance on a retrospective analysis of data and the evaluation of an outcome that was not the primary end point, the varied nature of participating centers, radiologists, and PET equipment provided a reasonable facsimile of the diversity found in clinical practice, which should help make the results broadly applicable. n

Genetically Engineered T Cells for Childhood Leukemia

By Phoebe Starr

Washington, DC—Although still in very early-phase testing in humans, the results of 2 small studies in children suggest that reinfusing autologous genetically engineered T cells can reverse acute lymphocytic leukemia (ALL) in children. Both studies were presented at the 2013 American As­ sociation for Cancer Research meeting.

All the children had run out of treatment options and were close to death; 2 had a remarkable recovery after T-cell therapy and remain in complete remission.

The treatment, called anti-CD19 chi-

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meric antigen receptor (CAR) T-cell therapy, entails collecting a patient’s immune T cells and genetically modifying and expanding them in the laboratory, and then reinfusing them back into the patient. The modified T cells attach to the CD19 protein that is expressed by leukemia cells.

The first study included 4 patients who were treated with the anti-CD19 CAR T cells. The 3 children with ALL had previously undergone bone marrow transplantation and their disease had progressed. After treatment, 2 of 3 children with ALL achieved complete

responses; the third child had a transient response that is too early to evaluate. The fourth child, who had B-cell lymphoma, did not respond to the T-cell therapy.

“Childhood ALL is the most common malignancy in pediatric patients.

The majority of children can achieve remission, but this comes with the price of long therapy, toxicity, and cost, with no guarantee of [a] longterm cure,” said Daniel W. Lee III, MD, Clinical Fellow, Center for Cancer Research, National Cancer Institute.

The second study included 5 pediat-

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ric patients with ALL with CAR T-cell therapy; 4 of them achieved complete responses, said lead investigator David M. Barrett, MD, PhD, Clinical Associate in Pediatrics, The Children’s Hospital of Philadelphia, PA. Three complete responses have been durable; the longest response was 12 months, and 1 response was transient. The fifth patient did not respond.

“The main take-away message is that this therapy is effective in pediatric ALL....This therapy has the potential to save lives when chemotherapy cannot,” Dr Barrett said. n

www.ValueBasedCancerCare.com

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Health Policy

CMS’s Proposal to Severely Limit FDG-PET Use for Patients with Cancer Elicits Concern Co-chairs of the National Oncologic PET Registry reject one-size-fits-all policy

See also AACR Meeting, page 35

By Rosemary Frei

U

S oncologists and radiologists are waiting to see whether the Centers for Medicare & Medicaid Services (CMS) will reconsider its proposal to limit the use of and reimbursement for fluorodeoxy­ glucose-positron emission tomography (FDG-PET) scan after initial anti­ cancer therapy to 1 scan in patients with solid tumors (with the exception of patients with prostate cancer, who will not be reimbursed for any FDGPET scans).

“I have no problem with insurance companies imposing limits beyond which a peer-to-peer consultation is required, as long as it’s understood that the number of PET scans that is appropriate varies for different cancers and different stages of treatment.”

—Barry A. Siegel, MD

On March 14, 2013, officials at CMS proposed ending the requirement enacted in 2006 that FDG-PET scans of less common solid tumors should be included in the National Oncologic PET Registry (NOPR). This is in line with what NOPR had asked for in a September 2012 letter to CMS, citing the accrual of sufficient evidence of FDG-PET’s efficacy.

However, CMS also suggested in

36

March that reimbursement should be granted only for a single posttreatment FDG-PET scan, to determine whether the initial therapy was effective. It would then be up to regional Medicare administrative contractors to determine whether subsequent scans should be covered.

Officials at NOPR responded in mid-April with a detailed and strongly worded letter showing that posttreatment FDG-PET can significantly change patient management.

They stated that “the imposition of a one-size-fits-all national limit of one scan for subsequent patient management has no clinical or scien­ tific basis” (www.cancerpetregistry. org/pdf/NOPRComment-CAG00184R4-04-11-2013.pdf). CMS will issue its final decision by June 14, 2013.

“Our bottom line is that we really support the notion that PET shouldn’t be used for surveillance, and neither should other forms of advanced imaging, because studies do not support it,” Barry A. Siegel, MD, coauthor of the letter to CMS and Co-Chair of NOPR, Chief of the Division of Nuclear Medicine, Washington University School of Medicine, St Louis, MO, told Value-Based Cancer Care. “There are better ways to accommodate the complexity of modern oncologic practice and the need for PET to evaluate what’s going on at particular times during patients’ treatment, while still avoiding healthy people who come back for a PET scan every 6 months ‘just because.’”

However, Dr Siegel and his colleagues at NOPR believe that it would be preferable for CMS to make clear to physicians that surveillance scanning is not appropriate for low-risk patients, while allowing the unrestricted national coverage of FDG-PET, with Medicare administrative contractors setting reasonable frequency limits as necessary.

“I have no problem with insurance companies imposing limits beyond which a peer-to-peer consultation is required, as long as it’s understood that the number of PET scans that is appropriate varies for different cancers and different stages of treatment,” said Dr Siegel.

A similar stance has been taken by the heads of the Society of Nuclear Medicine and Molecular Imaging, the World Molecular Imaging Society, the

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American College of Radiology, the American Society of Neuroradiology, and the American College of Nuclear Medicine. In a letter submitted to CMS in April 2013, they stated, “The Joint Societies would be pleased to collaborate with CMS to develop protocols that can be implemented to accomplish this end” of ensuring that only nonsurveillance FDG-PET scans are reimbursed.

“The data...strongly indicate that additional scans are being ordered by physicians not for routine surveillance purposes, but to actively manage clinical problems in their patients.”

—Barry A. Siegel, MD —Bruce E. Hillner, MD —Anthony F. Shields, MD, PhD

FDG-PET Coverage in Oncology Since 2009, CMS has allowed more than 1 FDG-PET scan during and after treatment for 10 common cancer types—breast, cervical, colo­­rectal, esophageal, head and neck, non– small-cell lung, non–small-cell ovarian, lymphoma, melanoma, and myeloma. Coverage for all other cancers was allowed if data were collected for NOPR. The average payment for an FDGPET scan, including the technical and professional portions, is approximately $1200.

To demonstrate that more than 1 scan can be beneficial, Dr Siegel, together with NOPR Chair Bruce E. Hillner, MD, Professor and Eminent Scholar, Department of Internal Med­­icine, and Massey Cancer Center Research Member, Virginia Common­ wealth University School of Medicine, Richmond, VA, and Co-Chair Anthony F. Shields, MD, PhD, Professor of Medicine and Oncology, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, analyzed 2006-2011 data from patients in NOPR. Drs Siegel, Hillner, and Shields found that more than 30% of patients

at a glance ➤ CMS has proposed a limit of 1 FDG-PET scan for patients with solid tumors after initial anticancer therapy, with an exemption for patients with prostate cancer ➤ Although they agree that FDG-PET scans should not be used for surveillance, providers argue that these scans are important for treatment decisions after treatment initiation ➤ More than 30% of patients with 1 to 3 scans for restaging or detection had a change in management ➤ Instituting a 1-scan limit would lead to many appeals from physicians for rejected claims ➤ Various radiologic societies have banded together and proposed that only nonsurveillance scans be reimbursed

with 1 to 3 scans for restaging or detection of suspected cancer recurrence had a change in management, along with 28.7% of the few hundred patients with 4 scans. Furthermore, among patients with up to 4 scans for treatment monitoring, approximately 30% had switched or added a medication as a result, and another 14% to 16.9% had their treatment stopped.

The team also pointed out that imposing a 1 posttreatment scan limit could lead to a flood of requests to Medicare administrative contractors from physicians who are appealing rejected claims.

“The data...strongly indicate that additional scans are being ordered by physicians not for routine surveillance purposes, but to actively manage clinical problems in their patients,” the trio concluded. “We encourage CMS to recognize the medical reality that cancer patients have improved outcomes as a result of better and more tailored medications, targeted radiotherapeutic and surgical techniques, in conjunction with treatment monitoring strategies.” n

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SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

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SUNDAY, OCTOBER 6

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

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PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management The official publication of â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

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The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

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PERSONALIZED MMEDICINE IN ONCOLOGY

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

TM

Ovarian Cancer

Novel Immunotherapy Approach Encouraging in Advanced Ovarian Cancer Washington, DC—A 2-step immunotherapy approach holds promise for women with advanced recurrent ovarian cancer, a disease that has limited therapeutic options. The 2 steps entail a personalized dendritic-cell vaccine, followed by adoptive T-cell therapy.

In an early study reported at the 2013 American Association for Cancer Research (AACR) annual meeting, almost 66% of patients derived clinical benefit from the vaccine alone, and the use of both therapies achieved approx-

at a glance ➤ Ovarian cancer typically relapses after responding to initial treatment, and the prognosis is poor ➤ A 2-step immunotherapy that includes a personalized dendritic-cell vaccine followed by adoptive T-cell therapy is promising for women with advanced recurrent ovarian cancer ➤ Of the patients who completed both steps, 7 achieved stable disease and 1 had a complete response ➤ This novel treatment has minor side effects

imately a 75% benefit.

More than 60% of ovarian cancer cases are diagnosed after the disease has spread to the lymph nodes and/or to other distant sites. Ovarian cancer that responds to initial treatment typically relapses, and the prognosis is poor. There is an unmet need for novel, alternative therapies for advanced ovarian cancer.

“This is the first time that a combination immunotherapy approach has been used for patients with ovarian cancer, and we believe the results are leading us toward a completely new way to treat this disease,” stated Lana Kandalaft, PharmD, PhD, MTR, Director of Translational and Clinical Operations, Ovarian Cancer Research Center, University of Pennsylvania Perelman School of Medicine, Philadelphia.

“Our 2-step approach harnesses the immune system to create T cells that are soldiers that go back into the body to fight the cancer,” Dr Kandalaft added.

In the first phase of the study, 31 patients with advanced, recurrent stage III or IV ovarian cancer underwent surgery and chemotherapy.

During surgery, patients’ tumor cells were cryopreserved to create personalized vaccines made by exposing each patient’s dendritic cells to tumor tissue. After chemotherapy, patients

Photo © AACR/Alan Lessig 2013

By Phoebe Starr

“This is the first time that a combination immunotherapy approach has been used for patients with ovarian cancer, and we believe the results are leading us toward a completely new way to treat this disease.”

—Lana Kandalaft, PharmD, PhD, MTR were vaccinated via intranodal injection into the groin several times over a period of approximately 3 months.

Of the 31 patients who entered in the first phase, 20 (61%) had stable disease or better.

Of the 20 patients who responded to

the vaccine, 11 continued to the second phase of adoptive T-cell therapy. T cells that had been primed by the vaccine to attack tumor cells were collected from the patients’ blood and stimulated and expanded in the laboratory; these T cells were then reinfused into the patients. Seven patients treated with adoptive T-cell therapy achieved stable disease and 1 had a complete response, for a clinical benefit rate of approximately 75%.

Dr Kandalaft said that 1 of the patients who had both treatments was cancer-free for 45 months at the time of the AACR meeting.

She pointed out that, as with other vaccines, immunotherapy has a delayed response. At baseline, there were multiple cancer sites and most had progressed by the end of the study.

But by 6 weeks later, lesions were stabilized or were regressing.

“Initially, you may see progression, but this could be due to tumor infiltrate and, later on, these lesions may regress,” Dr Kandalaft said.

The therapy has minor side effects, according to Dr Kandalaft.

Both treatments were given along with bevacizumab (Avastin) to control blood vessel growth. “This is a powerful duo—the vaccine plus bevacizu­ mab. The trial is open to accrual, and we will test other combinatorial strategies,” she stated. n

Deviation from Clinical Guidelines Takes Toll on Ovarian Cancer Survival Referring patients to high-volume provider center can improve outcomes

By Charles Bankhead Los Angeles, CA—Most women with ovarian cancer receive substandard care that significantly reduces their survival odds, based on a new retrospective review of 13,000 patients that was presented at the 2013 Society of Gynecologic Oncology annual meeting.

Treatment that diverged from the current National Comprehensive Cancer Network (NCCN) guidelines increased the 5-year survival hazard by 33% compared with patients who received the recommended care, reported Robert E. Bristow, MD, MBA, FACS, Director, Division of Gyneco­ logic Oncology, Professor, Department

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“We have a lot of work to do. In particular, we have to increase our efforts to ensure that ovarian cancer patients receive the best care possible, and that means getting them to high-volume surgeons and centers.”

—Robert E. Bristow, MD, MBA, FACS of Obstetrics and Gynecology, and the Philip J. DiSaia Chair of Gynecologic Oncology, University of California, Irvine Medical Center.

“Adherence to NCCN guidelines for ovarian cancer is associated with over-

all survival and may be a useful measure of quality cancer care,” noted Dr Bristow. “High-volume providers are significantly more likely to provide NCCN guideline–adherent care, which is associated with improved survival.”

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This new analysis showed that 37% of the patients were treated in accordance with guidelines established by the NCCN. Treatment at high-volume centers (≥20 ovarian cancer cases annually) and by high-volume surgeons (≥10 cases annually) improved the chances that a woman would receive the recommended therapy; even then, the care fell short of NCCN standards 50% of the time.

Noting that fewer than 20% of patients with ovarian cancer received care from high-volume providers, Dr Bristow said, “We have a lot of work to Continued on page 40

www.ValueBasedCancerCare.com

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Prostate Cancer

AUA Revises Its Guidelines for Prostate Cancer PSA Screening

See also page 42

Relaxing its support of general screening, now limited to ages 55-69 years

By Charles Bankhead

San Diego, CA—Prostate cancer screening with prostate-specific antigen (PSA) tests should focus on men aged 55 to 69 years, the group that is the most likely to benefit from screening, according to a new clinical guideline issued by the American Urological Association (AUA) at its 2013 annual meeting. This represents a significant shift from the previous position held by the AUA for strong support of PSA screening for men of all age-groups.

The new AUA position now does not recommend routine PSA screening tests for average-risk men aged 40 to 54 years. The organization recommends against PSA screening for men aged <40 years. Screening for men aged ≥70 years “is not recommended,” nor is screening for men of any age who have a life expectancy of less than 10 to 15 years. The AUA acknowledges that some older men aged ≥70 years and in excellent health may benefit from screening and should be evaluated on an individual basis.

Regardless of age or recommendation, the AUA emphasizes that screening should proceed only after a careful discussion with the patient about potential benefits and risks of screening.

The decision to screen should be a

shared one between physician and patient.

“It’s time to reflect on how we screen men for prostate cancer and take a more selective approach in order to maximize benefit and minimize harms,” said the guideline panel chair H. Ballentine Carter, MD, Professor of

“It’s time to reflect on how we screen men for prostate cancer and take a more selective approach.”

—H. Ballentine Carter, MD Urology at Johns Hopkins University in Baltimore. “Our focus was to help urologists identify those individuals who are most likely to benefit from being tested,” Dr Carter said. “The conclusion we came to, based on the evidence, was that the group more likely to benefit would be men ages 55 to 69, which is where we should be focusing our efforts.”

The recommendation pertaining to men aged 40 to 54 years is likely to be the most controversial aspect of the

guideline, Dr Carter added in a video interview released by the AUA. Patients in that age range have a low risk of prostate cancer and a very long lead time with respect to testing. If they are tested and are found to have prostate cancer, the disease is likely to be in a very early stage, including what many urologists and oncologists have termed “clinically insignificant” or “inconsequential” cancers.

If men in the 40- to 54-year-old agegroup are treated, they will “live with the harms of treatment for a very long time,” he emphasized.

“For all of those reasons, we concluded that these men, while some may benefit [from screening], there is probably more harm than benefit as compared with beginning screening at age 55,” said Dr Carter.

The new guideline replaces an AUA Practice Statement that was issued in 2009. The practice statement supported screening of average-risk men in the 40- to 54-year-old age-group.

However, the statement also addressed risk stratification and prostate cancer management. The guideline has a sole focus on the use of PSA screening tests.

Moreover, the practice statement relied heavily on expert and consensus opinions. The guideline was derived

from a review of published evidence through 2012.

In addition to the age-related recommendations, the guideline offers physicians the option to screen less frequently than annually in appropriately selected men. The decision to screen every other year, or even less frequently, should be preceded by a careful discussion with the patient, and should be guided by the patient’s baseline PSA value.

The US Preventive Services Task Force recommendation against routine screening for men of any age was targeted to primary care physicians, and was strongly objected to by urologists.

By contrast, the AUA guideline emphasizes that the recommendations apply to urologists.

The AUA “is not dismissing the PSA test as the task force has done,” said guideline committee member Philip W. Kantoff, MD, Director, Lank Center for Genitourinary Oncology, DanaFarber Cancer Institute, and Professor of Medicine, Harvard Medical School, Boston. “There should be a more reasonable approach to the use of PSA.” In keeping with AUA policy, the guidelines will be updated as appropriate in response to new information about prostate cancer screening, said Dr Carter. n

Ovarian Cancer

Deviation from Clinical Guidelines... do. In particular, we have to increase our efforts to ensure that ovarian cancer patients receive the best care possible, and that means getting them to high-volume surgeons and centers.”

A critical need exists to establish

at a glance ➤ Not following current NCCN guidelines increased the 5-year survival hazard by 33% compared with those who received recommended care ➤ Among 13,321 patients with ovarian cancer, 37.2% received guideline-adherent care

40

best practices, and then to enforce guidelines to improve care, he added.

The Study Findings This retrospective review of the California Cancer Registry of women with newly diagnosed ovarian cancer between 1999 and 2006 assessed adherence to the NCCN guidelines and the link to survival. All patients underwent a minimum surgical procedure of oophorectomy.

Adherence was defined as the use of stage-appropriate surgical procedures, and the use of chemotherapy adopted by the NCCN. The analysis included 13,321 patients. Overall, 37.2% of patients received guideline-adherent care. High-volume centers accounted for 18.8% of cases, and approximately

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Continued from page 39

16.4% of surgeries were done by high-volume surgeons.

Patients had a significantly better chance of receiving guideline-consistent care at high-volume centers (50.8%) compared with at low-volume centers (34.1%; P <.001). High-volume surgeons treated patients in accordance with the NCCN guidelines significantly more often than low-volume surgeons (47.6% vs 34.5%, respectively; P <.001).

An adjusted analysis showed that low-volume centers and low-volume surgeons were significantly associated with deviation from the NCCN guidelines (odds ratios, 1.83 and 1.19, respectively).

The 5-year survival rate in the study population was 45%. A multivariable

analysis of survival showed that nonadherence to the NCCN guidelines was significantly associated with worse 5-year survival (hazard ratio [HR], 1.34). After adjustment for guideline adherence, low-volume hospitals and low-volume surgeons remained independent predictors of worse survival (HRs, 1.08 and 1.18, respectively).

While exhorting his gynecologic oncology colleagues to advocate aggressively for better ovarian cancer care, Dr Bristow also encouraged patients to be their own advocates and to insist on treatment by high-volume providers.

“If a surgeon performs only 2 ovarian cancer surgeries a year, you don’t want to be one of those 2,” he said. n

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Prostate Cancer

Budget Impact Model: Epigenetic Assay Can Help Avoid Unnecessary Repeated Prostate Biopsies, Reduce Spending

By Wade Aubry, MD; Robert Lieberthal, PhD; Arnold Willis, MD; Grant Bagley, MD, JD; Simon M. Willis III, MS; Andrew Layton, BA This is an abbreviated version of the original article that was recently published in American Health & Drug Benefits. 2013;6(1):15-24.

The full version of this article is available at www.AHDBonline.com.

P

rostate cancer is the most frequently detected cancer in men: 1 of 6 men will be diagnosed with prostate cancer during their lifetime based on Medicare enrollment data.1 In the United States, approximately 19 million men annually are screened by prostate-specific antigen (PSA) testing,2 resulting in approximately 4.7 million abnormal PSA test results (≥4.0 ng/mL)3 and approximately 1.3 million biopsy procedures.4 According to the National Cancer Institute, 241,740 men are diagnosed with prostate cancer annually, and 28,170 prostate cancer–related deaths were reported in 2012.5 Although some forms of prostate cancer are deadly, many forms are low grade and can be managed by active surveillance.

Aggressive variants of prostate cancer can be one of the deadliest cancers in men, and accurate diagnosis and follow-up remain a challenge and come at a considerable cost to the US healthcare system.

The Burden of PSA Screening Despite the recent controversy that was raised by the US Preventive Services Task Force findings on PSA testing, leading to their recommendations to stop routine PSA-based screening,6 the American Urological Asso­ ciation (AUA) continues to recommend the PSA blood test, along with digital

rectal examination (DRE), for screening men at risk for prostate cancer. (The AUA has just revised its screening recommendations. See article on page 40.)

Screening has led to detection of earlier-stage disease, resulting in an increased likelihood for curative treatment. If screening is eliminated, urologists fear an increased incidence of advanced cancers and an increase in healthcare costs to effectively treat these patients.7 Today, urologists typically perform a biopsy for high-risk patients with a rising PSA level and for patients with a PSA level ≥4.0 ng/mL, obtaining approximately 10 to 12 needle-core tissue samples according to the current standard of care.8,9 An abnormal PSA result can often be caused by factors other than cancer, including infection, inflammation, or other benign conditions, such as benign prostatic hyperplasia. This leads to the inclusion of many men with no cancer among those who are being subjected to prostate biopsies (ie, false-positive PSA screening). The rate of cancer detection in men undergoing prostate biopsies is approximately 30%, and approximately 75% of men undergoing biopsies have negative prostate biopsy results.2,3 An elevated PSA and/or abnormal DRE identify men at high risk for prostate cancer, and, as a result, many of these men will undergo a biopsy pro-

Table 1 Men at Risk for a Repeated Prostate Cancer Biopsy Reference New scenario scenario (epigenetic (standard of care) assay)

Variable Men at risk of repeated biopsy, N

2101

2101

Men referred for repeated biopsy or methylation test, %

43

43

Men referred for repeat biopsy or methylation test, N

903

903

3

3

N/A

99.9

Men with ASAP, % Cases with sufficient tissue for methylation test, % Risk stratification based on methylation markers Evaluable cases, N

N/A

875

Cases with positive methylation markers, N

N/A

Cases with negative methylation markers, N

N/A

510

903

365

Total men referred for repeated biopsy, N

ASAP indicates atypical small acinar proliferation; N/A, not applicable.

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cedure. However, because of the nature of random and limited sampling of the prostate, many cancers are undetected by histopathologic review.

Studies by urology and pathology opinion leaders report that initial prostate biopsy histopathology has a 20% to 30% false-negative rate.8,10,11 Given these false-negative rates for histology, many patients with persistently elevated PSA values are at risk for occult cancer. This uncertainty poses a diagnostic dilemma, resulting in many men receiving 2, 3, and sometimes 4 repeated biopsy procedures.12-14 Repeated biopsies expose patients to the discomfort and risk of complications associated with this invasive procedure1; they also generate high medical costs. Approximately $1.86 billion is spent annually on PSA tests alone.2,15 More than $4 billion is spent annually on therapies for prostate cancer, and this amount is expected to increase to $8.7 billion by 2019.16 Molecular Testing With such high costs to the US healthcare system, as well as negative quality-of-life implications to patients, the AUA has called for new biomarkers for the improved diagnosis and treatment of prostate cancer.17 With the growing movement toward personalized medicine, the application of molecular testing to improve cancer detection and the management of patients represents an evolution in oncology.2,18 Epigenetic assays, in particular, have been reported to improve on the accuracy of prostate biopsies and histopathologic review.2,8 In a recent multicenter, blinded study, the epigenetic assay ConfirmMDx for Prostate Cancer was used to detect occult cancer in histopathologically negative prostate biopsies.8 The assay used multiplex methylation-specific polymerase chain reaction to assess the DNA methylation status of the GSTP1, APC, and RASSF1 genes associated with the presence of cancer in residual negative prostate biopsy tissue samples.3,8,10 Using this advanced molecular diagnostic test allows for a higher degree of accuracy that was previously unattainable through prostate biopsy procedures alone.

The results of this new epigenetic assay can guide urologists in decisions

regarding the need to repeat a biopsy in patients with a previously negative biopsy who are still considered at risk for prostate cancer. The test is designed such that its high (90%) negative predictive value accurately distinguishes the patients with negative prostate biopsies from patients who may have occult cancer.8 A Budget Impact Analysis A budget impact model was developed to assess whether the epigenetic assay can also produce financial benefits, beyond the reported clinical and health benefits. The model was designed to quantify the impact on the costs associated with repeated biopsies used for the screening and diagnosis of prostate cancer, and to test the hypothesis that the epigenetic assay produces a beneficial reduction in costs to commercial health plans, while providing guidance for patient management that leads to less invasive and less costly care.

The assumed membership of the hypothetical health plan is 1 million members, half of whom are males, aged 40 to 64 years (similar to those in a commercial health plan; younger and older men were excluded from the analysis). For men at risk of undergoing a repeated biopsy, the model allows for the simulation of the current (reference scenario) and a counterfactual reality (new scenario). In the reference scenario, the model uses current clinical patterns of care to simulate the treatment of men at risk of prostate cancer in the reference scenario; a molecular assay was not utilized for prostate cancer detection. In the new scenario, men at risk for repeated biopsy are evaluated with the epigenetic assay, and those with negative DNA methylation test results are spared a repeat of the biopsy, thereby reducing the number of unnecessary procedures.

In the budget impact model, under the reference scenario, 43% (903) of men at risk for repeat biopsy were referred for repeat biopsy. In the new scenario, testing the high-risk patients with the epigenetic assay significantly reduced the number of repeated biopsies by confirming the histopathologically negative biopsy results for 510 men. The epigenetic assay identified 365 men with positive DNA methyla-

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Prostate Cancer tion results who would be referred for repeated biopsy (Table 1).

The average cost of a prostate biopsy procedure is $1946, which is a conservative estimate, based on decreased interim 2013 Medicare Physician Fee Schedule rates; this does not take into account prophylactic antibiotic, pain, or other concomitant medication costs.

The total expected complication costs per patient for an initial or repeat­ed biopsy were calculated using Surveillance, Epidemiology and End Results (SEER)-Medicare cancer registries’ reported incidence of infectious and noninfectious complications and the associated mean payment for the Medicare Severity Diagnosis Related Groups (MS-DRGs) from the 2012 Centers for Medicare & Medicaid MSDRG payment schedule.

Table 2 shows the calculations for the average cost ($392) of complications per patient undergoing repeated

prostate cancer biopsy. The total weighted cost of a fully burdened biopsy is $1946—the sum of the procedural cost and the cost of complications weighted by incidence. The retail price for the epigenetic assay is $206 per individual core, or $2060 for a 10core biopsy. The model assesses the health plan’s costs compared with billed charges; therefore, the cost of this assay is discounted by 10%, to conservatively reflect payer costs, at $1855.02 per test.

Results The total cost of repeated biopsies avoided is $2,152,276 (1106 biopsies avoided × $1946 per biopsy). The total cost to the health plan in 1 year was calculated to be $2,864,142 in the reference scenario versus $2,333,341 with the epigenetic assay in the new scenario. To calculate the total diagnostic cost per patient in the reference scenario, the

Table 2 Per-Patient Costs Associated with Biopsy Complications DRG payment, $

Infectious complications

Incidence (SEER-Medicare)

Per-patient cost, $

Kidney infection

5594

Urinary tract infection

5594

Prostatitis

Cystitis

5594

Sepsis/bacteremia

16,662

Endocarditis

10,943

Hypotension

5801

Average payment for infectious complications

8058

0.04

322

DRG payment, $

Incidence (SEER-Medicare)

Per-patient cost, $

0.012

70

Noninfectious complications

6220

Gastrointestinal hemorrhage

6559

Hematuria

5366

Acute posthemorrhagic anemia

5660

Urinary symptoms/retention

5594

Average payment for noninfectious complications

5795

Average cost

392

DRG indicates diagnosis-related group; SEER, Surveillance, Epidemiology and End Results.

cost of a prostate biopsy ($1946) was applied and weighted to repeated biopsy distribution rates for the percentage of men who receive first, second, and third repeated biopsies of 43%, 44%, and 43%, respectively.13 For the new scenario, the total diagnostic cost per patient includes the cost of the assay plus the weighted biopsy cost, applied and weighted to 43% of men who have positive results based on the epigenetic assay (based on the sensitivity, specificity, and negative and positive predictive values).8 The total diagnostic cost per patient was $3172 in the reference scenario compared with $2584 in the new scenario, resulting in a savings of $588 per patient managed. This results in a total savings of $530,801 annually to the health plan, or –$0.0442 per member per month (Table 3).

This analysis demonstrates that the net cost to a commercial plan is lower if patients undergoing prostate cancer biopsies are managed using the assay.

Although this involves an additional cost for the acquisition of the assay, using the assay results in a reduction of 1106 unnecessary biopsies in a health plan with 1 million members.

Implications This analysis demonstrates that a commercial health plan would realize cost-savings with the coverage of the epigenetic assay. The upfront cost of the assay will be recovered based on the savings associated with avoided biopsies and the associated complications. The inclusion of the epigenetic assay in the management of men who are screened for prostate cancer would result in a net cost-savings of –$530,801 in the first year after the assay became available in the United States in a health plan with 1 million members.

The epigenetic assay provides clear and actionable results that aid the urologist in treatment decision-making, improving patient care, and yielding significant healthcare savings. A key assumption is that a health plan inclusion of the epigenetic assay in

Table 3 Total Annual Costs and Budget Impact: Reference Scenario versus New Scenario Reference scenario (standard of care) Cost

New scenario (epigenetic assay)

Total annual cost, $

PMPM cost, $

Total annual cost, $

PMPM cost, $

Total cost of epigenetic assay

0

0

1,623,143

0.14

Total cost of repeated biopsies

2,864,142

0.33

710,198

0.06

0

0

2,152,276

0.18

2,864,142

0.24

2,333,341

0.19

3172

0.24

2584

0.19

Total cost of repeated biopsies avoided Total diagnostic cost to health plan Total diagnostic cost per patient Total budget impact to plan Total budget impact to plan PMPM

–530,801 –0.442

PMPM indicates per member per month.

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medical policy and coverage decisions will motivate a change in the behavior of urologists, resulting in a reduction of repeated biopsies. Policy tools that promote appropriate patient management according to evidence-based guidelines, such as value-based payment (eg, financial incentives for choosing evidence-based interventions) or coverage restrictions for repeated biopsies, may further enhance such outcomes. n References

1. Loeb S, Carter HB, Berndt SI, et al. Complications after prostate biopsy: data from SEER-Medicare. J Urol.

2011;186:1830-1834. Epub 2011 Sep 23.

2. Ekwueme DU, Stroud LA, Chen Y. Cost analysis of screening for, diagnosing, and staging prostate cancer based on a systematic review of published studies. Prev Chronic Dis. 2007;4:A100.

3. Van Neste L, Herman JG, Otto G, et al. The epige­ netic promise for prostate cancer diagnosis. Prostate.

2012;72:1248-1261.

4. Mosquera J-M, Mehra R, Regan MM, et al. Prevalence of TMPRSS2-ERG fusion prostate cancer among men undergoing prostate biopsy in the United States. Clin Cancer Res. 2009;15:4706-4711.

5. National Cancer Institute. Surveillance Epidem­ iology and End Results. 2012. http://seer.cancer. gov/csr/1975_2009_pops09/results_single/sect_01_ table.01.pdf. Accessed November 1, 2012.

6. US Preventive Services Task Force. Screening for Prostate Cancer. May 2012. www.uspreventiveser vicestaskforce.org/prostatecancerscreening/prostate finalrs.htm. Accessed September 20, 2012.

7. Crawford D, Grubb R, Pinsky P, Black A. Factors influencing initial treatment decisions in PLCO: comparison of screening and control arms. Abstract LBA4.

Proceedings of the AUA Annual Meeting; May 21, 2012; Atlanta, GA. 8. Stewart G, Van Neste L, Delvenne P, et al. Clinical utility of a multiplexed epigenetic gene assay to detect cancer in histopathologically negative prostate biopsies: results of the multicenter MATLOC study. J Urol.

2012. doi: 10.1016/j.juro.2012.08.219.

9. Kehinde EO, Al-Maghrebi M, Sheikh M, Anim JT. Combined ciprofloxacin and amikacin prophylaxis in the prevention of septicemia after transrectal ultrasound-guided biopsy of the prostate. J Urol. September 23, 2012. pii: S0022-5347(12)04945-2. doi: 10.1016/j. juro.2012.08.237.

10. Trock B, Brotzman MJ, Mangold LA, et al. Evaluation of GSTP1 and APC methylation as indicators for repeat biopsy in a high-risk cohort of men with negative initial prostate biopsies. BJU Int. 2012;110:56-62.

11. Rabets JC, Jones JS, Patel A, Zippe CD. Prostate cancer detection with office based saturation biopsy in a repeat biopsy population. J Urol. 2004;172:94-97.

12. Laurila M, van der Kwast T, Bubendorf L, et al.

Detection rates of cancer, high grade PIN and atypical lesions suspicious for cancer in the European Randomized Study of Screening for Prostate Cancer.

Eur J Cancer. 2010;46:3068-3072.

13. Pinsky PF, Crawford ED, Kramer BS, et al. Repeat prostate biopsy in the prostate, lung, colorectal and ovarian cancer screening trial. BJU Int. 2007;4:775-779.

14. Resnick MJ, Lee DJ, Magerfleisch L, et al. Repeat prostate biopsy and the incremental risk of clinically insignificant prostate cancer. Urology. 2011;77:548-552.

15. National Cancer Institute Trends Progress Report2009/2010 Updated. www.cancer.gov/newscenter/ newsfromnci/2010/ProgressReport2010. Accessed No­vem­ber 1, 2012.

16. Merril J. Prostate cancer market snapshot: more than provenge. The Pink Sheet. November 22, 2010. Elsevier Business Intelligence Publications and Products. www. elsevierbi.com/Publications/The-Pink-Sheet/72/47/ Prostate-Cancer-Market-Snapshot-More-Then-Prove nge?result=2&total=2&searchquery=%253fq%253dP rostate%252520Cancer%252520Market%252520Snap shot%2526date%253don%25253a11%25252f22%2525 2f2010. Accessed January 29, 2013.

17. Thompson I, Thrasher JB, Aus G, et al. Guideline for the management of clinically localized prostate cancer: 2007 update. J. Urol. 2007;177:2106-2131.

18. Stricker S. The era of personalized medicine in oncology: novel biomarkers ushering in new approaches to cancer therapy. Am Health Drug Benefits.

2011;4(6):387-388.

Dr Aubry is Associate Clinical Professor of Medicine, Philip R. Lee Institute for Health Policy Studies, University of California, San Francisco, and Senior Medical Director, Quorum Consulting, San Francisco, CA; Dr Lieberthal is Assistant Professor, Jefferson School of Population Health, Thomas Jefferson University, Philadelphia, PA; Dr A. Willis is Associate Dean of Clinical Sciences and Professor of Urology, Aureus University School of Medicine, Oranjestad, Aruba; Dr Bagley is Senior Advisor, HillCo HEALTH, Washington, DC; Mr S.M. Willis is a thirdyear medical student, Aureus University School of Medicine, Oranjestad, Aruba; and Mr Layton is Director, Information Technology, Quorum Consulting, San Francisco, CA.

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Personalized Medicine

Tumor Subtype Fails to Explain Racial Disparity in Breast Cancer Survival

By Charles Bankhead

Washington, DC—Black women had worse survival across all breast cancer subtypes, indicating that the survival disparity compared with white women cannot be blamed entirely on more frequent diagnosis of less treatable subtypes, based on data from a breast cancer survivor study.

Consistent with previous data, black women more often had difficultto-treat triple-negative breast cancer and were less likely than white women to have the more treatable luminal A subtype. Mortality was twice as high in blacks as in whites, as documented in most studies.

However, a significant survival disparity in favor of whites persisted across all cancer subtypes, including a 2-fold greater likelihood of dying of luminal A, luminal B, or HER2-positive breast cancers.

“Even though African American women more often had hard-to-treat tumors, [they] appeared to have a poorer prognosis regardless of subtype,” said Candyce Kroenke, MPH, ScD, a scientist at the Kaiser Permanente Division of Research in Oakland, CA, at the 2013 American Association for Cancer Research meeting. “It seems from our data that the black-white breast cancer survival difference cannot be explained entirely by variable breast cancer subtype diagnosis.”

Studies have consistently shown

worse outcomes in black versus white patients with breast cancer, including approximately a 40% higher mortality risk. Although the precise reason (or reasons) for the disparity has yet to be identified, explanations include more advanced stage at diagnosis and differences in treatment, comorbidity burden, and disease aggressiveness.

“Even though African American women more often had hard-to-treat tumors, [they] appeared to have a poorer prognosis regardless of subtype. It seems from our data that the black-white breast cancer survival difference cannot be explained entirely by variable breast cancer subtype diagnosis.”

—Candyce Kroenke, MPH, ScD

However, survival disparities have been observed in controlled clinical trials wherein stage at diagnosis, uniformity of treatment, and follow-up

were comparable for all patients.

Previous studies had not examined the race-survival disparity after accounting for the distribution of breast cancer subtype, as determined by the PAM50 Breast Cancer Intrinsic Classifier gene array classifier, said Dr Kroenke.

The Life After Cancer Epidemiology (LACE) and Pathways studies of breast cancer survivors afforded an opportunity to examine the relationship between intrinsic tumor subtype

by PAM50 and subsequent survival.

A cohort study involved 1643 breast cancer survivors with archived tumor specimens available for analysis. The study population comprised 1213 white women, 132 black women, 144 Latina women, and 154 Asian/Pacific Islander women.

Clinical and demographic information was obtained for each LACE participant by means of a mailed questionnaire and electronic medical records. Investigators analyzed 1-mm punch samples from tumor specimens, determining PAM50 molecular subtype by quantitative polymerase chain reaction assay of tumor RNA. Luminal A subtype accounted for 76% of specimens from white women compared with 6% from blacks, 7% from Latinas, and 10% from Asian/ Pacific Islanders. Compared with white women, black women were 50% as likely to have luminal A or luminal

B intrinsic tumor subtypes, including almost a 40% lower likelihood of luminal A tumors, Dr Kroenke reported.

Black women were more than 4 times as likely to have basal-like tumors versus luminal A subtype tumors in comparison with their white counterparts.

During a median follow-up of 6.3 years, 499 LACE participants died, including 268 deaths from breast cancer.

The data showed that black women had a 57% risk of recurrence and a 71% increased risk of breast cancer mortality compared with whites. The Latina and Asian/Pacific Islander subgroups did not differ significantly from whites with respect to either outcome.

The hazard ratios for breast cancer death by tumor subtype were consistently higher for blacks compared with whites, but these ratios were not statistically significant: • Luminal A, 2.30 • Luminal B, 2.59 • Basal-like, 1.27 • HER2, 2.44.

However, a clear trend toward higher mortality risk was observed for all intrinsic tumor subtypes, noted Dr Kroenke.

“We need to examine other potential reasons for the black-white survival disparity. The distribution of different tumor subtypes does not explain the disparity,” she noted. n

Gene Expression May Simplify Search for Effective Therapy in Head and Neck Cancer Washington, DC—Therapeutic development in head and neck cancer could eventually hone in on a handful of gene-expression patterns and signaling pathways that can identify a few discrete subtypes of the disease, data from The Cancer Genome Atlas suggest.

Sequencing of the entire tumor genome of 279 patients revealed 18 frequently mutated genes, of which expression patterns in squamous-cell carcinoma of the head and neck have simplified the search for new, more effective therapies.

“The data allow us to recognize patterns and simplify things somewhat,” said D. Neil Hayes, MD, MPH, Associate Professor of Clinical Re­

44

search, Division of Hematology/ Oncology, Department of Otolary­n­ gology/Head and Neck Cancer Sur­ gery, North Carolina Cancer Hos­pital, Chapel Hill, NC, at a press briefing during the 2013 American As­sociation for Cancer Research annual meeting.

“Gene-expression data defined 4 subtypes of head and neck cancer, not hundreds, but 4, that might be leveraged in terms of pathways that might be altered and therapies that might be offered for patient benefit.”

The discovery of the 18 frequently mutated genes has redefined the mutation rates that are traditionally associated with head and neck cancer. For example, mutations in p53 occur in 72% of head and neck cancers, where-

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as historical estimates placed the rate at 46%.

The research also has provided in-

“Gene-expression data defined 4 subtypes of head and neck cancer, not hundreds, but 4, that might be leveraged in terms of pathways that might be altered and therapies that might be offered for patient benefit.”

—D. Neil Hayes, MD, MPH

sight into differences in tumors that originate from human papillomavirus (HPV) and those that are HPVnegative. In general, HPV-positive tumors have almost no actionable or druggable mutations. The one notable exception is PIK3CA, which harbors mutations in approximately 40% of head and neck cancers, including HPV-positive tumors.

Mutations in p53 are almost universal in HPV-negative tumors, most of which also have mutational combinations. The most frequent combinations involve HRAS paired with either CASP8 or FAT1. Combinations of these 3 genes were found almost universally in HPV-negative tumors, whereas all Continued on page 45

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Personalized Medicine

Higher HER2 Expression Leads to Better Outcomes with T-DM1 in Patients with Metastatic Breast Cancer

By Phoebe Starr

“The data of our biomarker analysis will help personalize therapy for individuals with HER2-positive breast cancer and make informed treatment decisions.”

Photo © AACR/Phil McCarten 2013

Washington, DC—Among women with HER2-positive metastatic breast cancer, patients with the highest expression of HER2 had the best outcomes in treatment with ado-trastuzumab emtansine (T-DM1; Kadcyla), according to a biomarker analysis of the phase 3 EMILIA trial which was presented at the 2013 American As­ sociation for Cancer Research annual meeting. Furthermore, the analysis showed that T-DM1 achieved superior outcomes in all patients who were enrolled in the trial versus patients who received capecitabine (Xeloda) plus lapatinib (Tykerb).

The presence of PI3 kinase mutations (PI3KCA) had no effect on treatment with T-DM1, but these mutations compromised the effectiveness of capecitabine plus lapatinib and are known to interfere with the effectiveness of trastuzumab.

“HER2-positive breast cancer is the same in all patients. The data of our biomarker analysis will help personalize therapy for individuals with HER2positive breast cancer and make informed treatment decisions,” stated José Baselga, MD, PhD, Physician-inChief at Memorial Sloan-Kettering Cancer Center, New York.

T-DM1 is the first antibody-drug conjugate to be approved by the US Food and Drug Administration. The drug links the antibody trastuzumab to a highly potent toxic chemotherapy called emtansine. Trastuzumab attach-

—José Baselga, MD, PhD

es to the HER2 protein expressed in HER2-positive breast cancers and triggers the release of emtansine into the tumors, thereby killing tumor cells.

Emtansine could not otherwise be administered to patients, because it is so toxic, Dr Baselga noted.

EMILIA was designed to compare the effectiveness of T-DM1 versus lapatinib plus capecitabine in patients with metastatic HER2-positive breast cancer who previously received trastuzumab plus taxane chemotherapy.

T-DM1 significantly improved progression-free survival (PFS) and overall survival (OS) compared with capecitabine plus lapatinib.

Tumor samples were collected prospectively to study biomarkers. PFS and OS were correlated with biomarkers such as epidermal growth factor receptor, HER2 mRNA, and PI3KCA. Median HER2 mRNA concentration ratios and PI3KCA mutation frequencies were similar across all treatment arms at baseline.

T-DM1 achieved superior PFS and

Gene Expression May...

3 genes were absent in HPV-positive tumors. HPV-positive tumors also have few receptor tyrosine kinase mutations.

“These [18] genes must be the most important genes in head and neck cancer, because they are the most frequent,” said Dr Hayes. “These are the driving genes behind the cancer, and we really need to understand them.”

A better understanding of the genes of head and neck cancer may prove applicable to other cancers. Squamouscell lung cancer and cervical cancer have somatic copy number alterations similar to those found in head and neck cancer.

“This suggests there is the possibil­ ity to begin looking at cancer across

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Continued from page 44

tumor types as molecular patterns that can be leveraged and understood for both biologic and therapeutic sampling,” said Dr Hayes.

Profiling of messenger RNA expression has revealed 4 distinct gene-expression patterns, each associated with its own somatic copy number alterations and mutations: classical, basal, mesenchymal, and atypical.

Not every tumor has actionable mutations, leading researchers to go beyond individual genes and mutations and into signaling pathways.

“We can put these head and neck cancer mutations into pathways and determine which pathways might be most productive for targeting downstream events,” said Dr Hayes.—CB n

OS in all biomarker subgroups. How­ ever, high expressors of HER2 mRNA levels derived even more benefit from T-DM1 than those with lower levels of expression. In the high expressors, median PFS was 34.1 months with T-DM1 versus 24.8 months with capecitabine plus lapatinib.

The presence of PI3KCA mutations

had no effect on PFS or on OS in patients treated with T-DM1, but in the capecitabine plus lapatinib arm, the presence of PI3KCA mutations led to worse outcomes than with the PI3KCA wild type. “T-DM1 is PI3KCA mutation-neutral,” Dr Baselga said.

At present, the working hypothesis is that tumors with high HER2 overexpression are hypersensitive to antiHER2 therapies and may not need additional chemotherapy. “But this is speculation at this point,” he explained.

T-DM1 is currently being studied earlier in the course of disease as adjuvant therapy and as first-line therapy for metastatic disease.

Novel antibody-drug conjugates are in development for other types of cancer, Dr Baselga noted. n

Liquid Biopsy Improves Detection of Secondary GIST Mutations Causing Drug Resistance

By Charles Bankhead Washington, DC—Analysis of circulating DNA provides information about secondary mutations that cause drug resistance in patients with previously treated gastrointestinal stromal tumors (GISTs), reported George D. Demetri, MD, Director of the Center for Sarcoma and Bone Oncology, Dana-Farber Cancer Institute, Boston, at the 2013 American Association for Cancer Research meeting.

Mutations associated with resistance to tyrosine kinase inhibitors (TKIs) were detected in 47% of plasma samples compared with 12% in tissue specimens. The “liquid biopsies” demonstrated high concordance with mutations identified by DNA analysis of tumor specimens.

Most of the KIT resistance mutations occurred in the difficult-to-treat activation loop domain, which has implications for future drug development.

“KIT mutations associated with TKI resistance were more readily detected in the plasma than by looking at archival tumor samples.”

More than 90% of GISTs arise from a single-gene mutation that triggers uncontrollable signaling by KIT or PDGFRA. Therapies that target the activated signaling kinase have dra-

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matically improved median survival in patients with GISTs from a few months to more than 5 years.

The use of targeted therapies for GIST shows that secondary mutations can render standard therapies ineffective. The ability to detect and target drug-resistance mutations is essential to the development of effective targeted therapy.

As tumor cells die, their DNA leaks into the bloodstream, possibly providing opportunities to identify most or all of the tumor mutations in a given patient. Liquid biopsies could offer a means to overcoming the limitations of conventional tissue-based biopsies, according to Dr Demetri.

In a recent study by Dr Demetri and colleagues (Demetri GD, et al.

Lancet. 2013;381:295-302), comparison of 2 biopsy techniques showed 89% to 100% concordance for primary KIT exon 9 mutations, 79% for primary KIT exon 11 mutations, and 84% overall concordance for the 2 mutations combined.

Mutational analysis also showed that regorafenib resulted in superior disease control versus placebo, irrespective of mutation type, Dr Demetri reported. n

www.ValueBasedCancerCare.com

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Hematologic Malignancies

No Loss of Efficacy with Anthracycline-Free Induction for Acute Lymphoblastic Leukemia

C

hildren with acute lymphoblastic leukemia (ALL) had no drop-off in efficacy with an anthracycline-free regimen that also reduced the long-term risk of cardiotoxicity, reported Andre Baruchel, MD, PhD, Chief of Pediatric Hematology, Robert Debré University Hospital, Paris, France.

Induction therapy without daunorubicin (Cerubidine) led to a 5-year event-free survival (EFS) rate of almost 97%, slightly better than the rate observed in children who received conventional induction that included the anthracycline agent.

“The patients had excellent survival with or without daunorubicin,” Dr Baruchel said. “We now have strong evidence that reducing the amount of chemotherapy initially administered

to these children does not negatively affect their immediate outcome.”

“Perhaps more important, we now know that eliminating harmful chemotherapy from their treatment can help minimize their risk of experiencing heart damage later in life. Anthra­ cyclines have an unclear benefit on efficacy but a clear risk of additive toxicity.”

A recent Cochrane Review of therapy for ALL included only 3 publications involving anthracycline-containing regimens, which were all published more than 20 years ago.

The results provide high-quality clinical trial results to support a practice that has become commonplace in the United States, said William G. Woods, MD, who heads the Aflac Cancer and Blood Disorders Center at

All Rights Reserved by American Society of Hematology

“We now know that eliminating harmful chemotherapy from [children’s] treatment can help minimize their risk of experiencing heart damage later in life.”

—Andre Baruchel, MD, PhD

All Rights Reserved by American Society of Hematology

By Charles Bankhead

“The hope is that we will be able to eliminate anthracyclines by substitution of other drugs, especially novel drugs.”

—William G. Woods, MD Children’s Healthcare in Atlanta, GA. Studies conducted in the United States in the 1980s and 1990s demonstrated the nonessential contributions of lowdose anthracyclines in induction therapy for ALL. Low-dose anthracyclines continue to be used in consolidation and maintenance therapy.

“The hope is that we will be able to eliminate anthracyclines by substitution of other drugs, especially novel

drugs,” noted Dr Woods.

Dr Baruchel presented the results from a randomized clinical trial of 1128 patients with newly diagnosed ALL. Each patient received a standard induction regimen that included vincristine (Oncovin), dexamethasone (Decadron), and asparaginase (Elspar).

The patients were randomized to daunorubicin or to no additional induction therapy. The primary end point was EFS. On completion of induction therapy, the rates of minimal residual disease (MRD) ≥1% were 1.8% among patients who received the anthracycline and 1.9% with those who were treated with the anthracycline-free regimen. De­ fining MRD as ≥0.1% resulted in rates of 6.5% for the daunorubicin group and of 9.3% for the patients who received the anthracycline-free regimen.

After a median follow-up of 69 months, the overall survival rate was 97% in the entire study population.

The 5-year EFS rate was 95.4% with daunorubicin induction and 96.8% with the anthracycline-free regimen.

Dr Baruchel emphasized that omission of daunorubicin pertained only to patients with standard-risk ALL that demonstrates a good early response to the other 3 drugs in the induction regimen. n

CHOP Disappearing as Standard of Care for Indolent NHL

A

long-standing treatment standard for indolent nonHodgkin lymphoma (NHL) has fallen victim to the chopping block, so to speak, at least in Germany.

The use of the cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine (Oncovin), and prednisone (Deltasone; CHOP) regimen with or without rituximab (Rituxan; R-CHOP) has declined rapidly with the emergence of bendamustine (Treanda), which is used either alone or with ri­tuximab.

An analysis of a German patient registry showed that 16% of patients with NHL received CHOP, as opposed to more than 70% who received bendamustine-based therapy.

“The use of CHOP continues to decline in Germany, and it will soon be dead,” said Wolfgang Knauf, MD, PhD, a hematologist with Onkologische Gemeinschaftspraxis in Frankfurt.

46

“CHOP or R-CHOP can no longer be considered standard of care.”

Rituximab remains popular as firstline systemic therapy for patients with indolent NHL, either as monotherapy

“The use of CHOP continues to decline in Germany, and it will soon be dead. CHOP or R-CHOP can no longer be considered standard of care.”

—Wolfgang Knauf, MD, PhD

or in various combinations, often with bendamustine, Dr Knauf said.

The findings and Dr Knauf’s observations came from the examination of data from a clinical registry of patients

Value-Based Cancer Care

I

MAY 2013

with B-cell lymphoid malignancies.

Investigators at 106 participating centers in Germany have contributed data for 2579 patients. The registry has a target enrollment of 1000 patients with indolent NHL, 1000 with aggressive lymphomas, 1000 with chronic mye­ logenous leukemia, and 500 patients with multiple myeloma.

Registries provide data that are useful for evaluating trends in the management of diseases, including the success of new therapies in clinical practice, said Dr Knauf. He reported findings for 645 patients with indolent NHL who were treated with systemic therapy as first-line treatment.

The results showed that 7% of patients had stage I disease at diagnosis, 15% had stage II, 24% had stage III, and 54% had stage IV disease.

Rituximab was a component of firstline therapy for 606 (94%) patients and bendamustine for 455 (71%) patients.

The 2 drugs were used in tandem as first-line treatment for 428 (66%) of these patients. R-CHOP was first-line systemic therapy for 105 (16%) patients.

The use of the bendamustine–rituximab combination as first-line therapy increased from 62% of cases in 2009 to 68% in 2011. In contrast, the use of R-CHOP decreased from 19% in 2009, continuing a decline that began before the registry, said Dr Knauf.

The registry data included 121 patients who received second-line systemic therapy. The bendamustine–ri­ tuximab combination was used in 60% of these cases, bendamustine monotherapy in 7%, and R-CHOP in 7%.

Dr Knauf acknowledged that small subgroups of patients might still benefit from R-CHOP, but the bendamustine–rituximab combination has established itself as standard therapy for most patients with indolent NHL.—CB n

Vol. 4

I

No. 4

SECOND

ANNUAL CONFERENCE

GLOBAL BIOMARKERS Clinical Approaches CONSORTIUM to Targeted Technologies â&#x201E;˘

October 4-6, 2013 â&#x20AC;˘ Seaport Boston Hotel â&#x20AC;˘ Boston, Massachusetts CONFERENCE CO-CHAIRS Professor Rob Coleman, MBBS, MD, FRCP Yorkshire Cancer Research Professor of Medical Oncology Director, Sheffield Cancer Research Centre Associate Director, National Institute for Health Research Cancer Research Network Department of Oncology, Weston Park Hospital Sheffield, United Kingdom

AGENDA* FRIDAY, OCTOBER 4 3:00 pm - 7:00 pm

Registration

5:30 pm - 7:30 pm

Welcome Reception and Exhibits

SATURDAY, OCTOBER 5 7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 8:30 am

Welcome to the Second Annual Conference of the Global Biomarkers Consortiumâ&#x20AC;&#x201D;Setting the Stage for the Meeting Professor Rob Coleman, MBBS, MD, FRCP

8:15 am - 11:45 am

General Session I â&#x20AC;˘ Personalized Medicine in Oncology: Evolution of Cancer Therapy from Nonspecific Cytotoxic Drugs to Targeted Therapies â&#x20AC;˘ Taking Stock of Molecular Oncology Biomarkers â&#x20AC;˘ Genomics â&#x20AC;˘ Bioinformatics â&#x20AC;˘ Validating Biomarkers for Clinical Use in Solid Tumors - Professor Rob Coleman, MBBS, MD, FRCP â&#x20AC;˘ Validating Biomarkers for Clinical Use in Hematologic Malignancies Jorge E. Cortes, MD â&#x20AC;˘ The Challenges of Biomarker-Based Clinical Trials â&#x20AC;˘ Keynote Lecture: Understanding Cancer at the Molecular Level

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 4:30 pm

This activity is jointly sponsored by Medical Learning Institute Inc, Center of Excellence Media, LLC, and Core Principle Solutions, LLC.

General Session II â&#x20AC;˘ Introduction to Case Studies - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part I â&#x20AC;˘ Lung Cancer â&#x20AC;˘ Breast Cancer â&#x20AC;˘ Multiple Myeloma â&#x20AC;˘ Prostate Cancer â&#x20AC;˘ Leukemia â&#x20AC;˘ Lymphoma â&#x20AC;˘ Panel Discussion: Management Controversies and Accepted Guidelines for the Personalized Management of Solid Tumors and Hematologic Malignancies â&#x20AC;˘ Keynote Lecture: The Medical-Legal Issues Surrounding the Use of Biomarkers in Oncology

4:30 pm - 6:30 pm

Meet the Experts/Networking/Exhibits

COMMERCIAL SUPPORT ACKNOWLEDGMENT

SUNDAY, OCTOBER 6

Jorge E. Cortes, MD Chair, CML and AML Sections D.B. Lane Cancer Research Distinguished Professor for Leukemia Research Department of Leukemia, Division of Cancer Medicine The University of Texas MD Anderson Cancer Center Houston, TX

CONFERENCE OVERVIEW

The only global meeting dedicated to advancing the understanding of value and clinical impact of biomarker research in oncology. Guided by the expertise of leaders in this field, participants will receive a thorough understanding of the current and future landscape of the relevance of tumor biomarkers and how to effectively personalize cancer care in the clinical setting.

TARGET AUDIENCE

This meeting will be directed toward medical oncologists and hematologists, pathologists, geneticists, advanced practice oncology nurses, research nurses, clinical oncology pharmacists, and genetic counselors involved in the management of patients with solid tumors or hematologic malignancies, and interested in the use of molecular tumor biomarkers to help optimize patient care.

LEARNING OBJECTIVES

Upon completion of this activity, the participant will be able to: â&#x20AC;˘ Assess emerging data and recent advances in the discovery of molecular biomarkers and their impact on the treatment of patients with solid tumors or hematologic malignancies â&#x20AC;˘ Discuss the role of molecular biomarkers in designing personalized therapy for patients with solid tumors or hematologic malignancies â&#x20AC;˘ Outline the practical aspects of integrating molecular biomarkers into everyday clinical practice in the treatment of patients with cancer

DESIGNATION OF CREDIT STATEMENTS SPONSORS

Grant requests are currently being reviewed by numerous supporters. Support will be acknowledged prior to the start of the educational activities.

PHYSICIAN CREDIT DESIGNATION

7:00 am - 8:00 am

Symposium/Product Theater

8:15 am - 11:45 am

General Session III â&#x20AC;˘ Review of Saturdayâ&#x20AC;&#x2122;s Presentations and Preview of Today - Jorge E. Cortes, MD â&#x20AC;˘ Case Studies: Optimal, Value-Based Use of Molecular Biomarkers in Oncology: The Expertâ&#x20AC;&#x2122;s Perspective on How I Treat My Patients, Part II â&#x20AC;˘ Melanoma â&#x20AC;˘ Colorectal Cancer and Other GI Malignancies â&#x20AC;˘ MDS â&#x20AC;˘ Myeloproliferative Neoplasms â&#x20AC;˘ Keynote Lecture: Promises and Challenges of Personalized Medicine in Improving Cancer Care â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Solid Tumors (attendee-contributed cases) â&#x20AC;˘ Tumor Board: Challenging Cases in the Use of Biomarkers in Managing Hematologic Malignancies (attendee-contributed cases)

12:00 pm - 1:00 pm

Symposium/Product Theater/Exhibits

1:15 pm - 3:00 pm

General Session IV â&#x20AC;˘ Keynote Lecture: Making Personalized Medicine a Reality: The Realization of Genomic Medicine â&#x20AC;˘ The Future of Personalized Medicine: Measuring Clinical Outcomes â&#x20AC;˘ Cost-Effective Technologies That Can Drive Therapeutic Decision Making â&#x20AC;˘ Regulatory Perspectives on PMO â&#x20AC;˘ PMO: The Payerâ&#x20AC;&#x2122;s Perspective â&#x20AC;˘ Panel Discussion: Can We Afford PMO? A Value-Based Analysis â&#x20AC;˘ Practical Considerations in Incorporating PMO into Everyday Cinical Management The official publication of â&#x20AC;˘ Reimbursement Challenges

â&#x20AC;˘ Closing Remarks

3:00 pm

Departures

The Medical Learning Institute Inc designates this live activity for a maximum of 12.5 AMA PRA Category 1 Creditsâ&#x201E;˘. Physicians should claim only the credit commensurate with the extent of their participation in the activity. This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education through the joint sponsorship of the Medical Learning Institute Inc and the Center of Excellence Media, LLC. The Medical Learning Institute Inc is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

REGISTERED NURSE DESIGNATION

Medical Learning Institute Inc Provider approved by the California Board of Registered Nursing, Provider Number 15106, for 12.5 contact hours.

REGISTERED PHARMACY DESIGNATION

The Medical Learning Institute Inc is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. Completion of this knowledge-based activity provides for 12.5 contact hours (1.25 CEUs) of continuing pharmacy education credit.

The Universal Activity Number for this activity is (To be determined).

CONFERENCE REGISTRATION

EARLY BIRD REGISTRATION NOW OPEN! $175.00 until June 30, 2013

www.globalbiomarkersconsortium.com

In partnership with *Agenda is subject to change.

GBCKsize20813

PMPMERSONALIZED EDICINE IN ONCOLOGY O

Implementing the Promise of Prognostic Precision into Personalized Cancer Care TM

TM

Get connected to the perspectives of 100 stakeholders who manage 143 million covered lives Connecting you with relevant information is part of our commitment to you.

That’s why Lilly commissioned the publication of a report based on the Managed Care Oncology Index.* This study surveyed managed care executives, practicing oncologists, and oncology practice managers who shared their views on interesting oncology topics such as: • Coverage and reimbursement of oncolytics • Oncology management strategies • Clinical pathways The publication, Trend Report on Oncology Management, is just one example of how Lilly Oncology can connect you with important information to assist your organization in managing members with cancer. To get your copy of the trend report, simply call 1-800-247-7832 and a Lilly Account Manager–Oncology Payer Services will contact you to arrange delivery of your copy and answer any questions you might have about other available services.

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