November/December, Vol 2, No 6 by Green Hill Healthcare Communications, LLC

BREAST CANCER Weekly paclitaxel as effective, less toxic than docetaxel/capecitabine Based on a study by Aman U. Buzdar, MD

COST-EFFECTIVENESS RESEARCH New technology Based on research by David C. Miller, MD, MPH

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NOVEMBER/DECEMBER 2009 • VOL. 2, NO. 6

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Mu sec lti ond ple a My nnu elo al m Con an s ew ide sle rat tte ion www.jomcc.com rs si er n ies .

oncology careers

practice management

The Workforce Shortage and the Use of Non-physician Practitioners

Oncology at an Inflection Point

Photo courtesy of American Society of Clinical Oncology.

E Douglas W. Blayney, MD

ffective tobacco control strategies, improved hormonal and chemotherapy treatments, and targeted therapies have all contributed to impressively declining cancer death rates in the United States. “We have a good news story to tell,” stated the president of the American Society of Clinical Oncology (ASCO), Douglas W. Blayney, MD, medical director of the Comprehensive Cancer Center, University of Michigan Health System, Ann Arbor. He warned, how-

ever, that continued momentum toward reduced mortality in the United States is not guaranteed and is, in fact, threatened by contrary workforce trends. The solution, Blayney said at the third annual Onmark National Payor/Provider Forum, is the wider use of “physician extenders.”

Physicians less productive; population aging Younger oncologists are less productive Continued on page 13

health economics

gastrointestinal cancers

Cost, Noncompliance Bitter Pills to Swallow in the Age of Oral Chemotherapy

Colorectal Cancer Screening Cost-effective: Fecal DNA Promising

s more oral cancer therapies are introduced into practice, adherence to therapy is likely to play a larger role in outcomes, said Angela DeMichele, MD, associate professor of medicine and epidemiology at the University of Pennsylvania, Abramson Cancer Center, Philadelphia, Pennsylvania. Drug cost is one major barrier to adherence, she said, potentially leading to drug-taking behaviors that can

olorectal cancer (CRC) is the second most common solid tumor in the United States, accounting for nearly 150,000 new cases annually and 50,000 deaths. Robert Mayer, MD, Stephen B. Kay Family Professor of Medicine, Harvard Medical School, and Dana-Farber Cancer Institute, Boston, chaired the update on CRC screening at the annual meeting of the American Society of Clinical Oncology, emphasizing

Continued on page 16

Continued on page 17

An interview with Bruce A. Cutter, MD

ith declining reimbursement for oncology drugs, regulatory changes, and other pressures on oncology practice, oncologists in community cancer practices are having to find new ways to provide quality care for their patients and control costs. In this interview, Bruce A. Cutter, MD, discusses challenges facing oncology Bruce A. Cutter, MD practices and suggests innovative approaches that can help them adapt to change and potentially lead to better outcomes for their patients. Dr Cutter is past president and currently a chairperson of the quality and the pharmacy and therapeutics committees of Cancer Care Northwest, Seattle, Washington. Continued on page 8

MULTIDISCIPLINARY TUMOR BOARD CASE STUDY Treating a Second Breast Cancer John F. Turner, MD Victor L. Randolph, MD Sonia Y. Newton, MD Billy Jo Day, RN, BSN

Mayur A. Patel, MD Poonam Srivastava, MD Ashok Kumar, MD

Page 10

Opportunities Abound

T mark J. krasna, mD st. Joseph cancer institute EDITOR-IN-CHIEF

his edition of Journal of Multidisciplinary Cancer Care highlights the varied challenges to providing quality cancer care in the community practice setting. From cost control to workforce shortages to keeping up with the latest in clinical research, each challenge can also be an opportunity. As Dr Bruce Cutter explains, small practices have the opportunity to work with their payers to incentivize and reward quality and value. He explains that quality can be more than just the best clinical care. It can be viewed as a measure to provide and document value. By focusing on what clinical outcomes you are trying to achieve and what costs they entail, we can change the reimbursement model and thrive regardless of the current and future economy. We can also be spurred to action by the

current workforce shortage, a shortage that is expected to worsen as the number of patients increases in coming years. American Society of Clinical Oncology president Douglas Blayney puts forth a workforce plan that can be implemented to help your practice fill the shortage gap. By expanding the oncology clinical workforce through more use of nurse practitioners, physician assistants, and clinical pharmacists, a community practice will be able to see more patients. He also details how checklists can help your practice operate more effectively and how streamlined information transfer can help improve practice efficiency. Many community practices are already realizing the clinical and financial value of electronic health records and e-prescribing, but new technology is not limited to comput-

er systems. Oncologists can now offer new biologics, targeted therapies, cancer vaccines, diagnostic imaging, proton beam radiotherapy, and robotic surgery. Take, for example, the case presented by the group in Pennsylvania. In a rural setting, the multidisciplinary team uses technology to present each case. Using this inventive solution, the team prospectively discusses each patient without losing time to travel. Coming together not only provided this patient with individualized care that met both her physical and emotional needs, but also provided the team an opportunity to learn from the patient’s response to her treatment. By making each challenge an opportunity, we can realize the goal of high-quality, patientcentered care for all of our patients. Only in this way can we influence cancer care nationwide. n

News Notes News Updates of Relevance to Everyday Oncology Practice n Metastatic Lobular Breast Cancer Tumor DNA Sequenced Canadian researchers, in an attempt to precisely characterize all somatic coding mutations that occur during the development and progression of an individual cancer, have sequenced all 3 billion letters in the

DNA sequence of one estrogen receptor–positive metastatic lobular breast cancer tumor. With the recent advances in next-generation sequencing, the researchers were able to sequence the genome in just weeks. They found 32 somatic nonsynonymous coding mutations in the metastatic tumor. On comparison

EDITORIAL CORRESPONDENCE should be addressed to EDITORIAL DIRECTOR, Journal of Multidisciplinary Cancer Care®, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. E-mail: karen@greenhillhc.com. YEARLY SUBSCRIPTION RATES: United States and possessions: individuals, $105.00; institutions, $135.00; single issues $17.00. Orders will be billed at individual rate until proof of status is confirmed. Prices are subject to change without notice. Correspondence regarding permission to reprint all or part of any article published in this journal should be addressed to REPRINT PERMISSIONS DEPARTMENT, Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. The ideas and opinions expressed in Journal of Multidisciplinary Cancer Care® do not necessarily reflect those of the Editorial Board, the Editorial Director, or the Publisher. Publication of an advertisement or other product mentioned in Journal of Multidisciplinary Cancer Care® should not be construed as an endorsement of the product or the manufacturer’s claims. Readers are encouraged to contact the manufacturer with questions about the features or limitations of the products mentioned. Neither the Editorial Board nor the Publisher assumes any responsibility for any injury and/or damage to persons or property arising out of or related to any use of the material contained in this periodical. The reader is advised to check the appropriate medical literature and the product information currently provided by the manufacturer of each drug to be administered to verify the dosage, the method and duration of administration, or contraindications. It is the responsibility of the treating physician or other healthcare professional, relying on independent experience and knowledge of the patient, to determine drug dosages and the best treatment for the patient. Every effort has been made to check generic and trade names, and to verify dosages. The ultimate responsibility, however, lies with the prescribing physician. Please convey any errors to the Editorial Director. ISSN # 1949-0321. Journal of Multidisciplinary Cancer Care® is published by Green Hill Healthcare Communications, LLC, 241 Forsgate Drive, Suite 205C, Monroe Twp, NJ 08831. Telephone: 732.656.7935. Fax: 732.656.7938. Copyright ©2009 by Green Hill Healthcare Communications, LLC. All rights reserved. Journal of Multidisciplinary Cancer Care® is a registered trademark of Green Hill 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.

November/December 2009

with the patient’s primary tumor from 9 years prior, five of those mutations were prevalent, six were present at lower frequencies, 19 were not present, and two were undetermined. The five mutations were not previously known to researchers as being involved in cancer, thus identifying new avenues to pursue for the development of personalized medicines for patients (Nature. 2009;461:809-813).

n PV-10 Compassionate Use Program Extended to United States PV-10, an investigational agent being developed as a therapeutic for a broad spectrum of cancers, is now available to patients under the US Food and Drug Administration’s compassionate use guidelines. The agent will be available for indications that do not involve visceral organs and are not subject to enrollment in ongoing clinical trials. Cancers that meet these indications include certain breast cancers, basal cell carcinoma, squamous cell carcinoma, certain head and neck cancers, and melanoma. The agent is currently available through St. Luke’s Hospital & Health Network, Bethlehem, Pennsylvania, and will be extended to more sites in the upcoming months (Provectus Pharmaceuticals). n UnitedHealthcare Offers Free Access to NCCN Drugs & Biologics Compendium UnitedHealthcare now provides its in-network physicians and their staff free access to the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium. The Centers for Medicare & Medicaid recognizes the NCCN compendium as a mandated reference for oncology coverage policy. In January 2008, UnitedHealthcare began basing its benefit coverage for chemotherapy drugs used in outpatient settings on the compendium as well. The free access reflects the company’s ongoing commitment to ensuring physicians and patients have access to evidence-based care. The access will also help save time by eliminating time spent on phone calls for coverage confirmation (UnitedHealthcare). n

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EDITOR’S LETTER

A Letter from the Editor

No. 6

November/December 2009 Departments

Feature Articles CONTENTS

Cost-effectiveness Research

Managing Editor Dawn Lagrosa

News Notes

Multidisciplinary Tumor Board Case Study

Directors, Client Services John W. Hennessy john@greenhillhc.com

Viewpoint

Cristopher Pires cris@greenhillhc.com

How the US government rations health care

Health Economics

Head and Neck Cancer

Production Manager Marie RS Borrelli

Oncology Drug Codes

Breast Cancer Studies look at factors that influence CPM Weekly paclitaxel as effective, less toxic than docetaxel/capecitabine

Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrator Andrea Boylston

Leukemias

No link found between cancer and bisphosphonate use

Editor’s Letter

2010 Medicare physician fee schedule

Editorial Director Karen Rosenberg karen@greenhillhc.com

Should we stop the unconditional adoption of new technology in healthcare?

Treating a second breast cancer

PUBLISHING STAFF Publisher Philip Pawelko phil@greenhillhc.com

Recent FDA Approvals

In the Literature

GH Green Hill Healthcare Communications

, LLC ™

Your Innovative Partners in Medical Media

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Supportive Care

241 Forsgate Drive, Suite 205C Monroe Twp, NJ 08831

Systems approach can improve cancer pain management

eDitorial BoarD EDITOR-IN-CHIEF

Mark J. Krasna, MD St. Joseph Cancer Institute Thoracic Surgery

Practice Management Section Editor Steven L. D’Amato, RPh, BCOP Maine Center for Cancer Medicine Oncology Pharmacy John F. Aforismo, BSc, Pharm, RPh, FASCP RJ Health Systems International Oncology Pharmacy Elizabeth Bilotti, RN, MSN, APNc John Theuer Cancer Center Hackensack University Medical Center Oncology Nursing Nicole A. Bradshaw, MS, CIC Mountain States Tumor Institute Performance Improvement

Anna M. Butturini, MD Children’s Hospital Los Angeles Hematology-Oncology

Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Oncology Pharmacy

Scott E. Eggener, MD University of Chicago Genitourinary Cancer

Patricia Molinelli, RN, MSN, AOCNS Somerset Medical Center Oncology Nursing

Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Oncology Nursing

Judy A. Olson, RT(R), RDMS St. Luke’s Mountain States Tumor Institute Breast Care

Mehra Golshan, MD Dana-Farber Cancer Institute Breast Cancer

Nicholas Petrelli, MD Helen F. Graham Cancer Center Christiana Care Health System Surgical Oncology

Patrick A. Grusenmeyer, ScD Christiana Care Health System Practice Management

Greg Pilat, MBA Advocate Health Care Practice Management

Marilyn L. Haas, PhD, CNS, ANP-BC Mountain Radiation Oncology Oncology Nursing

Andrew Salner, MD Hartford Radiation Oncologists Association Radiation Oncology

Dawn Holcombe, MBA, FACMPE, ACHE DGH Consulting Practice Management

Ritu Salani, MD Ohio State University Medical Center Gynecologic Malignancies

Shaji K. Kumar, MD Mayo Clinic Hematologic Malignancies

Timothy G. Tyler, PharmD, FCSHP Comprehensive Cancer Center Desert Regional Medical Center Oncology Pharmacy

Terry Macarol, RT(R)(M)(QM) Advocate Health Care Breast Imaging

Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska Medical Center Oncology Pharmacy

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November/December 2009

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Viewpoint VIEWPOINT

How the US Government Rations Health Care The agency that would likely run the “public option” was slow to pay for implantable cardiac defibrillators.

resident Barack Obama deflects criticism that his healthcare plan will bring on government rationing of medical care by arguing that insurance companies ration care. Scott Gottlieb, MD Everyone knows private payers limit access to some health care. But government does it in far more byzantine and arbitrary ways. Consider the $450 billion Medicare program. It provides a model for— indeed its bureaucracy could well end up running—the “public option” health plan that Mr. Obama wants to offer all Americans under the age of 65. In recent years, Medicare’s staff has been aggressively restricting coverage for costly treatments. Looking for ways to control spending on medical products—and preserve the illusory “trust fund” that pays Medicare claims—is what shapes the culture of the organization and motivates the agency’s staff. This often means limiting access to the costliest technologies. To do this Medicare relies on its rationing and pricing systems. National coverage decisions (NCDs) are assessments issued by Medicare’s medical staff that define who is eligible for new but often expensive treatments. Medicare then assigns medical products and procedures with “codes” that determine which regulated category they fall into. Finally, price “schedules” are developed by Medicare’s staff each year to assign each unique code with its own updated payment rate. The process for getting a favorable code on a new product is a source of intense lobbying. It can make or break a technology. For a remote agency like Medicare, far removed from clinical practice, it’s easier to try and manage the use of a high-cost but specialty treatment than a much lower-cost but very widely used product. Yet cheaper, more commonly used products can still be mispriced and account for more total cost to the

agency. For example, low-tech orthotic devices and other “durable medical equipment” are a known source of wasteful spending. These medical products often evade Medicare’s attention in favor of less used but more expensive items such as a biological cancer drug. Take the agency’s tortured decisions concerning the use of implantable defibrillators that jump-start stopped hearts during cardiac arrest. Medicare sharply restricted their use in the 1990s. Mounting research proved that the $30,000 devices could be saving many more lives. So in 2003 Medicare adopted a novel theory to expand coverage to some, but not everyone, who needed one. The agency said only patients with

reviews and denied new or expanded coverage in fully 53% of cases. Medicare’s methods can also be arbitrary. Take the travails of the pharmaceutical company Sepracor and its drug Xopenex, an innovative respiratory medicine that competes with the chemically distinct and much cheaper generic albuterol. Both are inhaled aerosols used to treat asthma and chronic obstructive pulmonary disease. Xopenex has the same benefits as albuterol, but some believe fewer of its cardiac side effects. Medicare didn’t agree. The agency tried to make a “national coverage decision” on Xopenex but couldn’t come up with a clinical justification to limit the drug’s usage. So

Since 2008, according to my review of Medicare data, it conditioned access in 29% of its reviews and denied new or expanded coverage in fully 53% of cases. certain measures on their electrocardiograms (called “wide QRS”) seemed to benefit. It was an easily measurable but ultimately imprecise way to allocate the devices. After another major study firmly refuted the QRS theory, Medicare expanded coverage again in 2005, potentially saving 2,500 additional lives according to a press release issued with that decision. That experience wasn’t unique. From 1999 to 2007, Medicare denied access in a third of the treatments it evaluated through its coverage process, taking an average of eight months to complete its reviews. When coverage was granted, in 85% of cases the treatments were restricted, usually to patients with more advanced illnesses. Medicare is lately increasing its use of the national coverage process and is becoming more tightfisted. Since 2008, according to my review of Medicare data, it conditioned access in 29% of its

Medicare manipulated its payment process, saying it would pay Xopenex a price equivalent to the “least costly alternative” form of generic albuterol, 10 cents a treatment compared to about $2.50 for Xopenex. Then Medicare was sued by a patient, and a Federal court recently ruled the agency exceeded its authority. Medicare finally succeeded in reigning in the use of Xopenex with its coding system. By issuing Xopenex the same classification as generic albuterol, it was able to pay both products the same “blended” price—an average of the cost of each individual drug. That lowered the price on Xopenex, but ironically increased what Medicare paid for the generics. It’s not a stretch to say that Medicare spent hundreds of cumulative man-hours focusing on Xopenex while other priorities languished. The question is why? There weren’t safety concerns. Xopenex may have been used in lieu of a cheaper

alternative, but at peak Medicare sales of about $300 million it represented far less than one one-thousandth of the agency’s budget. Simply put, a few staffers inside Medicare were consumed with the drug and its higher price—revealing a process that is capricious and often disconnected from science. Worse still is how impenetrable these programs have become. Drug and device companies spend millions of dollars trying to influence Medicare decisions. The hundreds of consultants they hire to advise them typically command $20,000-a-month retainers. Formal patient and provider appeals to Medicare took an average of 21 months, according to a report issued in 2003 by the Government Accountability Office (using 2001 data), with delays in “administrative processing” due to “inefficiencies and incompatibility” of data systems eating up 70% of the time spent processing appeals. There’s nothing inherently wrong with a program like Medicare seeking value for taxpayers. But it shouldn’t make up the rules as it goes. When private plans ration care, patients can appeal directly to an insurer’s medical staff. Only a small fraction of Medicare’s denied claims—about 5%—are ever formally appealed because its process is so impenetrable. People can also switch insurers, and in many cases patients chose a policy because it matched their preferences in the first place. These options don’t exist in a government health program. n —Scott Gottlieb Dr. Gottlieb is a resident fellow at the American Enterprise Institute and a former senior official at the Centers for Medicare & Medicaid Services. He is partner to a firm that invests in healthcare companies, and he advises health plans. Reprinted with permission. © Scott Gottlieb. Originally printed in Opinion Journal. The Wall Street Journal. September 30, 2009.

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November/December 2009

ANNUAL MEETING KEYNOTES: TECHNOLOGY OF THE FUTURE MICHAEL BOUVET, MD, Professor of Surgery, UCSD ARNO J. MUNDT, MD, Professor and Chair of Radiation Oncology, UCSD TONY REID, MD, PhD, Associate Professor of Medicine, UCSD HELP! WHAT DO OUR CANCER PATIENTS WANT? MICHAEL PUKSZTA, AIA, Principal, Cannon Design

Annual Meeting * & Oncology 101

EVIDENCE-BASED MEDICINE IN ONCOLOGY GUIDELINES & ASCO’S QOPI DOUG BLAYNEY, MD, Medical Director, Univ. of Michigan Comprehensive Cancer Center; ASCO President NATIONAL CANCER INSTITUTE (NCI) INFORMATION TECHNOLOGY UPDATE KENNETH H. BUETOW, PhD, National Cancer Institute

ANNUAL MEETING SESSIONS INCLUDE: • Non-Physician Productivity Models/ Physician Productivity

• Oncology Clinical Leadership Assessments & Succession Planning

• Program Differentiation Through Clinical Excellence

• From Day One and Beyond: A New Cancer Survivorship Model

• Cancer Program Accreditation: Challenges and Opportunities

SPECIAL EVENT:

• Oncology Financial Reporting and Accountability… Winning with Facts

TOUR OF UCSD MOORES CANCER CENTER Included in registration fee!

• New SPIN on Strategic Planning

FEBRUARY 13–16, 2010 CONTINUING EDUCATION CREDITS: Oncology Nursing Society (ONS) American College of Healthcare Executives (ACHE)

• Affiliations and Partnerships • Patient and Family Centered Care

ONCOLOGY 101 ONE DAY PRE-CONFERENCE PROGRAM* ON SATURDAY,

FEBRUARY 13, 2010 * Separate registration is required

New oncology administrators, new ACE Members, and those seeking a refresher course are urged to attend Oncology 101. This one-day program precedes the ACE Annual Meeting and will prepare you for the topics and issues that you will face as an oncology program executive.

ONCOLOGY 101 SESSIONS INCLUDE:

WESTIN GASLAMP QUARTER IN THE HISTORIC HEART OF

SAN DIEGO

• The Role of the Administrator

• The Basics of Business Planning

• Cancer Care 101

• Billing & Coding… The Secret Words

• What is Comprehensive Cancer Care?

• Environment of Care

• Marketing & Branding

C A L I F O R N I A ACE EXPO: Industry leading products and services will be on display at special times during the meeting.

THE CAN’T MISS EVENT OF THE YEAR FOR ALL ONCOLOGY ADMINISTRATORS! 4 4 4 4 4

Four days of educational sessions with expert speakers Great networking opportunities Tour of UCSD Moores Cancer Center New technologies and services in the EXPO Hall Take away tools and strategies you can implement the moment you return

2009 Exhibitors (as of 10/1/09) Accuray Association of Community Cancer Centers (ACCC) FKP Architects GE Healthcare Heery HONI Journal of Multidisciplinary Cancer Care

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Cost-effectiveness Research COST-EFFECTIVENESS RESEARCH

Should We Stop the Unconditional Adoption of New Technology in Healthcare?

he near-universal adoption of new technology in oncology represents a “perfect storm” that brings together rare or life-threatening conditions, strong patient demand, exDavid C. Miller, MD, pensive products and MPH implementation, along with uncertain evidence of benefit, said David C. Miller, MD, MPH, assistant professor of urology and epidemiology and research scientist at the VA Center for Clinical Management Research, University of Michigan, Ann Arbor. Miller discussed the challenge of new technologies, including biologics and other drugs, devices, and diagnostic tools. New technology is an area of great “tension,” he noted, marked by a tug of war between forces—patients, physicians, and manufacturers—that favor rapid adoption and coverage of technology and other forces—including payers, evidence-based medicine advocates, and policymakers—who are calling for “prudent” adoption and coverage. There are individual motivations to adopt new technologies, including “reputational” and financial incentives, as well as the earnest desire to provide all available diagnostic and treatment options for

patients with serious conditions. The “perfect storm,” where all these things converge, has created a scenario in which technology is adopted in spite of limited advantages.

The cost of innovation All sections of oncology care are experiencing the temptation of new technology. In surgical oncology, robotics and cryosurgery have made inroads. In radiation oncology, it is proton beam radiotherapy. In medical oncology, novel biologics and targeted agents are entering clinical use for virtually all tumor types. The cost of these innovations is tremendous. The average monthly cost of treating cancer clustered around $1000 in the early 1990s; it is now close to $5000/month, and, for example, exceeding $10,000 when cetuximab is prescribed, or $23,000 with alemtuzumab. “We are using very expensive therapies that do not have a large therapeutic margin,” Miller observed. Cost-effectiveness and coverage The utility of these technologies is assessed and approved by various parties, including the US Food and Drug Administration, payers, private corporations, physician specialty societies, and health service researchers. Medicare, the country’s largest payer, makes coverage decisions based on

whether a technology is “reasonable and necessary,” without explicit consideration of costs. Some local coverage decisions apply to limited geographic areas, and rarely, to national coverage. There are four potential outcomes from these national coverage decisions: 1. No change in coverage 2. Noncoverage 3. Coverage without special conditions 4. Coverage with special conditions— patients with specific characteristics, providers or facilities meeting certain criteria, coverage only when additional data provided. “There is a recent movement within CMS [Centers for Medicare & Medicaid Services],” Miller said, “to move toward more prudent evaluation of new technology, in recognition that the ‘pie’ of money is not infinitely expanding.” Part of this greater scrutiny includes comparative effectiveness research (CER), which aims to compare technologies for their “bang for the buck,” he said. The Obama Administration has allotted $700 million to accelerate the development and dissemination of CER, specifically research that compares clinical outcomes, effectiveness, and appropriateness of products and services used to prevent, diagnose, and treat diseases. The determination of cost-effective-

ness often uses the incremental cost-effectiveness ratio of cost per quality-adjusted life-year (QALY), with an arbitrary threshold set at $50,000 for US patients. The United Kingdom’s National Institute for Health and Clinical Excellence (NICE) makes coverage decisions based on both comparative and costeffectiveness research and considers treatments cost-effective at $34,500 per QALY. In light of new targeted agents, this cap is being revisited. For the treatment of renal cell carcinoma, for example, the cost per QALY (Steinbrook R. N Engl J Med. 2008; 359:1977-1981) exceeds: • $122,000 for sunitinib • $162,000 for temsirolimus • $176,000 for sorafenib • $294,000 for bevacizumab. “The political uproar when NICE declined these agents demonstrates the challenge of considering cost-effectiveness in approving treatments,” Miller added. The current industry trend is to evaluate coverage for therapies or for technologies that are not cost-effective based on a patient response to treatment. Under this scenario, the manufacturer of a drug would reimburse the payer when the drug is not effective in a particular patient—a revolutionary idea. n —CH

practice management

Inflection Point Continued from cover What are of the challenges facing community oncology practices? There are both clinical challenges and business challenges, but I’d like to address the latter. From a business point of view, the challenges are decreasing revenues and increasing costs. Other issues include adoption and implementation of information technology, how to deal with the quality movement and the related aspect of consumerism, how to get appropriate data and information, and how to then utilize that data and information in a way that both enhances your clinical practice of medicine and enhances your business. Community cancer practices are facing not only increasing drug costs but also increasing costs of salaries and benefits, health insurance, technology, and energy. It doesn’t matter how good a job you do taking care of patients, if you don’t run an excellent business, 8

you’re going to be at risk. Underlying all of this are challenges that relate to leadership and governance because those are important aspects of a business, and many oncologists really are not trained in leadership skills. Both large and small practices need to have a leadership structure in place that allows them to deal with other business challenges, including revenue cuts and cost increases. Related to that is the whole issue of change management and change management skills.

How can community practices adapt to change? In business terms, oncology is at an inflection point, which means a discontinuity or time of major change that is permanent, not temporary. It involves major threats to the way of doing things in the past, but it also

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provides major opportunities to those who can successfully navigate the inflection point and deal with change. In oncology, the inflection point is driven by regulatory change and by the revenue and cost issues. Quality is very important and costs are very important. I call it the value equation, that is, quality plus outcomes divided by cost, and the question is how do we in medicine deliver better value? We are being called upon to enhance our quality and to do so in a way that controls or decreases cost. At the same time, we may be seeing 20 or 30 patients per day and trying to understand and deal with all of the clinical changes that face us.

In your practice, how do you deal with these pressures? We have tried to develop a relationship with payers that allows us to define

and document quality and value. We have been rewarded for that via a payfor-performance contract with the dominant local payer. We also have good pricing arrangements with other payers. It is important to point out, however, that we do not just say we provide value; we’re actually measuring it and attempting to document it. This approach is good for all parties—patients, payers, society—and it’s good for our business. On the revenue side, we’re not just a medical oncology group. We have medical oncologists, radiation oncologists, surgical oncologists, gynecologic oncologists, and breast surgeons, all working together to provide the very best care in a coordinated, integrated fashion. We demonstrate to commercial payers that we do not just offer standard care, we provide value and can be held accountable for that. On the cost side, you have to look at November/December 2009

your costs rigorously and see how you can do better. You have to consider ways to gain more purchasing power, such as increasing the size of your practice or becoming part of a network or purchasing group. One of the problems is that when you have to start changing operations and processes within the organization that also means changes in the ways physicians practice. The ability to undergo change and deal with this inflection point is very important.

Where do oncologists learn practice management and leadership skills and how do you make sure that change is implemented in an efficient way? You need to have a partnership between physicians, nurses, pharmacists, other clinical staff members, and practice administrators to be able to institute leadership and change. The physicians in the practice have to be willing to take the time to learn leadership and management skills, whether through courses or on-thejob training, and put them into practice. Often because physicians are busy seeing patients, the important work of leadership and change management is not a priority. Further, if physicians do take the time to do this kind of work, they may not be compensated for their time. But when we are at an inflection point, as we are now, altering how we do things is very important work that deserves every bit as much recognition and compensation as clinical work. There is real value and real return to the business for doing this work. How can small community practices survive? They are distinctly challenged. In the old business model, a medical oncologist’s income was based primarily on chemotherapy drug margins. That money not only paid his salary but also supported the rest of the cancer delivery system. Now those margins are going away. One potential solution for smaller practices is to join an oncology network. You have to be willing to give up some of your individualism and autonomy to get the benefits of the larger entity. Do you foresee some positive changes coming out of the changing practice environment? From a medical oncology point of view, there is going to be continued pressure on the key revenue and income stream so clinicians will need to think about what replaces that. One replacement that is very useful and attractive is the concept of delivering value for patients. That’s the same as the rest of the US economy. The principle of our system is that if you provide value for your customer, you get to keep a portion of that value as profit. This then drives your business; you get more business and you’re able to deliver greater value. The more value you provide for your customers, the more you prosper as a business. We all strive to provide quality patient care. The issues are: How do we define quality? How do we measure quality? and How do you get November/December 2009

rewarded for quality and value? The current payment system does not tend to reward quality and value. Medicare is the best example of this; people pretty much get paid the same no matter what value they deliver. I think we are moving toward a realization that the key factors to focus on are quality and value. To get there, there will need to be changes in the reimbursement model for physicians. We have to think about how we can do the very best for our patients at less cost or at least the same

costs. You have to ask “What outcomes are we trying to achieve and at what costs?” You have to focus on both sides of that equation. If you start asking different questions and measuring different things, you can do much better for your patients. You have to change the rules of the game if you expect things to change fundamentally. One of the problems we have now is that there is pressure to change the game, but nobody has come up with new rules yet. If you and your competitors are defin-

ing and measuring quality and outcomes, you can compete on quality and efficiency, and you can start changing the game. That has the potential to improve outcomes and at the same time control or decrease costs. The bottom line is that it’s a challenging time and there are a lot of pressures out there, but it is also a time of great opportunity. If we do this right, we can fundamentally change how we do things for the better. n —Karen Rosenberg

Presents The Second Annual 2009 Curriculum for

CONSIDERATIONS IN MULTIPLE MYELOMA A Newsletter Series for Cancer Care Professionals Center of Excellence Media, along with Editor-in-Chief Sagar Lonial, MD, of Emory University, are pleased to offer your multidisciplinary cancer team with this series of newsletters focusing on the challenges in treating patients with multiple myeloma.

SAGAR LONIAL, MD Associate Professor of Hematology and Oncology Emory University School of Medicine

# Earn Continuing Education Credits # 8 part newsletter series

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• To Transplant or Not to Transplant…That is the Question

• Perspectives on Relevant End Points of Clinical Trials

• Sequencing Strategies

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Target Audience This activity was developed for physicians, nurses, and pharmacists.

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PRACTICE MANAGEMENT

Inflection Point

CASE STUDY

Multidisciplinary Tumor Board Case Study Treating a Second Breast Cancer John F. Turner, MD; Mayur A. Patel, MD; Victor L. Randolph, MD; Poonam Srivastava, MD; Sonia Y. Newton, MD; Ashok Kumar, MD; Billy Jo Day, RN, BSN At the Thyra M. Humphreys Center for Breast Health, Evangelical Community Hospital, a community hospital in rural Pennsylvania, the members of the multidisciplinary team hold a virtual meeting each week to prospectively discuss all newly diagnosed breast cancer cases. Using commercially available software (Go To Meeting), participants in multiple locations are able to view the case presentation and make comments. The goal is to get opinions from each therapeutic specialty before any intervention, both for the benefit to the patient and to encourage discussion among members of the treatment team. The breast surgeon identifies patients and submits them to the tumor registrar, who prepares a case presentation for the team members. The virtual tumor board meeting begins with a brief health history, pertinent radiologic findings, biopsy technique, pathology, and any other relevant diagnostic workups. National Comprehensive Cancer Network (NCCN) guidelines are reviewed, and Adjuvant!Online is used to determine possible gains from therapy as well as potential recurrence risk and mortality risk. This article presents a recently discussed case of a 74-year-old woman with a history of breast cancer and a new primary cancer in the opposite breast.

CASE PRESENTATION Chief complaint: A 74-year-old white women noticed a palpable change in her left breast several months previously. She had no nipple discharge. She had significant pain in the area of the mass, for which she was using ibuprofen on a regular basis.

Medical history: Hypercholesterolemia.

History of illness: The patient had had a right breast lumpectomy with axillary lymph node dissection for stage II infiltrating lobular breast cancer in February 2002. She had refused chemotherapy at that time, but she did receive postoperative radiation and 5 years of anastrozole (completed 2007). Her stage II status was based on one positive node.

Social history: Denies smoking.

Dr Turner is a breast surgeon at Central Susquehanna Surgical Specialists and the medical director of the Thyra M. Humphreys Center for Breast Health at Evangelical Community Hospital, Lewisburg, Pennsylvania. Dr Patel is a medical oncologist and hematologist at Cancer Care of Central PA, Sellinsgrove, Pennsylvania, and at The Donehower Center, Lewisburg, Pennsylvania. Dr Randolph is a medical oncologist and hematologist at Cancer Care of Central PA, Sellinsgrove, Pennsylvania, and at The Donehower Center, Lewisburg, Pennsylvania. Dr Srivastava is a medical oncologist and hematologist at Cancer Care of Central PA, Sellinsgrove, Pennsylvania, and at The Donehower Center, Lewisburg, Pennsylvania. Dr Newton is a pathologist at Evangelical Community Hospital, Lewisburg, Pennsylvania. Dr Kumar is a medical oncologist and hematologist at Cancer Care of Central PA, Sellinsgrove, Pennsylvania, and at The Donehower Center, Lewisburg, Pennsylvania. Ms Day is a breast health specialist at the Thyra M. Humphreys Center for Breast Health at Evangelical Community Hospital, Lewisburg, Pennsylvania. 10

Surgical history: No other prior surgery. Family history: Postmenopausal breast cancer in her mother, sister, and maternal great aunt.

Medications: Atorvastatin, 40 mg daily. Allergies: None. Physical examination: Palpable, fairly large, somewhat vague mass in the central aspect of the left breast, deep

John Turner (JT): A 74-year-old white woman presented to the office stating that several months ago she noticed a palpable change in her left breast. She complained of significant pain in the John F. Turner, MD area of the mass, for which she was using ibuprofen on a regular basis. The patient had previously been treated for stage II infiltrating lobular breast cancer by a right-breast lumpectomy with axillary lymph node dissection. At that time, she had refused chemotherapy but received postoperative radiation and 5 years of anastrozole. Physical examination revealed a palpable, fairly large mass in the central aspect of the left breast, deep to the 12:00 edge of the areola. The size was somewhat difficult to assess because of the depth of the mass. No cervical, supraclavicular, infraclavicular, or axillary adenopathy were found. Mammography revealed clips in the axilla of her right breast. The breast did not exhibit much scaring from the lumpectomy. The left breast, however, exhibited a somewhat irregular, very

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to the 12:00 edge of the areola. Size was difficult to assess. There was no cervical, supraclavicular, infraclavicular, or axillary adenopathy. Imaging studies: Mammogram: Right breast: no suspicious findings; clips noted in the axilla from axillary dissection; not much scaring from lumpectomy. Left breast: very dense mass, somewhat irregular, in the deep aspect close to the pectoralis muscle, deep to the nipple; measured about 18 mm; Breast Imaging Reporting and Data System (BI-RADS), 4C. Ultrasound: Irregular, poorly de-

dense mass in the deep aspect, close to the pectoralis muscle, deep to the nipple in the central aspect. The mass measured 18 mm and was categorized as Breast Imaging Reporting and Data System (BI-RADS) 4C (moderate concern but not classic for malignancy). Ultrasound showed an irregular, inhomogeneous, hypoechoic mass with shaggy borders. The mass appeared to be pushing through tissue planes rather than displacing tissue planes and with greater height than width. These are all signs of possible malignancy, most resulting from the infiltrating nature of the cancer (irregular and shaggy borders, violation of tissue planes, vertical axial orientation [height > width]).1 The mass did not exhibit posterior shadowing on ultrasound, likely because it was directly on the pectoralis muscle. The mass, which was considered to be solid rather than cystic, measured 10 mm x 9 mm x 12 mm, and was situated at the 12:00 subareolar position. The radiologist assigned a BI-RADS category of 4B (intermediate suspicion of malignancy), but it could easily have been given a category of 4C (moderate concern, but not classic [as in category 5] for malignancy). An ultrasound-guided, vacuum-

fined, hypoechoic mass in left breast; 10 mm x 9 mm x 12 mm at the 12:00 subareolar position; not a simple cyst; BI-RADS 4B, possibly 4C. It seemed to be pushing through tissue planes rather than displacing tissue planes. Positron emission tomography: Marked activity in left breast corresponding to area of density. No evidence of abnormal uptake elsewhere; no evidence of metastatic process. Laboratory values: Liver functions: normal; complete blood count: normal; cancer antigen 27.29: 17 U/mL; no BRCA mutation detected.

assisted biopsy of the mass was performed. Postbiopsy imaging confirmed accurate sampling. After the biopsy, the mass was much less dense and the biopsy marker was in the correct position. Sonia Newton (SN): The initial biopsy showed an invasive ductal carcinoma, which was high grade (Nottingham grade 3/3). The patientâ&#x20AC;&#x2122;s estrogen-receptor (ER) status was positive. Sonia Y. Newton, MD Her progesteronereceptor (PR) status was low-positive (ie, 1% to 9%). Her human epidermal growth factor receptor type 2 by immunohistochemistry was equivocal with a score of 2+, so the biopsy sample was sent for fluorescence in situ hybridization (FISH) analysis. The FISH result was negative, not amplified. JT: After the biopsy report, the patient underwent magnetic resonance imaging (MRI) of her breasts, which showed the tumor in her left breast with no additional tumors in either breast. The tumor was situated on the pectoralis muscle. In addition, enhancement extended anterior from the tumor November/December 2009

Treatment options Mayur Patel (MP): The patient had a grade 3 tumor, possibly a fairly large tumor or at least one that might involve the pectoralis muscle and was quite deep. She refused chemotherapy in the past. Mayur A. Patel, MD I weighed against any neoadjuvant chemotherapy in this case. Data from the European consortium suggest that neoadjuvant hormonal therapy could be used in a case such as this.2-4 It could be argued, however, that this patient finished her adjuvant hormonal therapy 2 years ago and the tumor grew in a relatively short period of time. But if we wanted to use a neoadjuvant approach, which would not have been a bad idea in someone like her, hormonal therapy was a possibility. November/December 2009

If restaging studies 3 months into therapy had shown that enhancements were being picked up on MRI, that would have given more evidence that the patient’s disease was more locally advanced than previously thought. If she had pectoralis muscle involvement, she would eventually need a mastectomy. Another option was mastectomy upfront with hormonal therapy afterward, depending on what was found. If we had found larger-than-anticipated disease, we could have considered systemic chemotherapy. Ashok Kumar (AK): I was worried about the high-grade tumor and the possible involvement of the pectoralis muscle. If she was going to have surgery, I thought it would be better if we gave Ashok Kumar, MD chemotherapy initially to control the disease. Chemotherapy can have a quicker effect than hormonal therapy, and that is why it might have been a better option to start with. Victor Randolph (VR): I was very concerned that she was not likely to respond to hormonal therapy, even though her tumor was ERpositive. She was off hormonal therapy only 2 years when Victor L. Randolph, she developed a new MD tumor, which suggested that she was not truly hormonesensitive. This suggests that hormonal therapy is not going to be effective. JT: I then pointed out that the patient had indicated that she did not want a mastectomy and was willing to accept chemotherapy. I asked the medical oncologists if that made a difference in their recommendations. MP: What I had been saying was based on the prior premise that she did not want chemotherapy. Obviously, that probably would give her a better response upfront. She might still require a mastectomy in the future though. JT: Because she did not want to have a mastectomy, we had to consider whether we could use chemotherapy to clean up the tissue planes and get to the point where she was a candidate for lumpectomy. The normal criteria for labeling a tumor as locally advanced did not apply to this patient. She was not an N2 patient nor a T4 patient, but the reasoning was different in this case—to try to recruit her into lumpectomy. The NCCN recommends a taxane-based regimen in a case like this.5 If during surgery, the tumor was found to be close to the pectoralis, I could remove a portion of pectoralis muscle with it so as to not run the risk of leaving some tumor on the anterior pectoralis.

Treatment plan JT: After the initial meeting of the tumor board and discussion with the patient, she began chemotherapy, four cycles of docetaxel/cyclophosphamide (TC). She also underwent a left sentinel lymph node biopsy, which showed no metastatic process. Then, the tumor board

CASE STUDY

to the nipple, creating concern about whether the tumor was localized or was invading the pectoralis muscle and extending along the ductal system. Outside of the area of left breast corresponding to the density, there was no evidence of uptake or of metastatic process on positron emission tomography (PET)/computed tomography scan. The laboratory findings were not remarkable. The patient’s liver functions and complete blood count were normal. Her cancer antigen 27.29 level was 17.2 U/mL, which is normal. Because this was a second cancer in this patient and because of her family history, the patient was tested for BRCA status; no BRCA mutation was detected. Her tumor was 12 mm on ultrasound and slightly >1 cm on MRI in its primary component. She had no palpable lymph nodes and no evidence of distant metastases, so she was considered clinical T1c (tumor >1 cm but <2 cm in greatest dimension). At first, there was some question about whether she could be a T4 because of extension to the pectoralis muscle; however, the clinical stage T4, by definition, does not include extension to this muscle. Because she did not have lymph node or distant metastases, she was considered cN0 and cM0. Therefore, her clinical stage was designated T1c N0 M0 stage I cancer. Her tumor was grade 3. To help devise a treatment plan, we used Adjuvant!Online. This software provided estimates of the patient’s risk of negative outcome (cancer-related mortality or relapse) without systemic adjuvant therapy, estimates of the reduction of these risks afforded by therapy, and risks of side effects of the therapy. Based on her data, the software estimated that without additional therapy 75% of such patients would be alive in 10 years, 7.4% would die of their cancer in 10 years, and 17.6% would die of other cancers. With hormonal therapy, an additional 2.1% of lives would be saved. With chemotherapy, 1.8% of lives would be saved. With combination therapy, 3.3% of lives would be saved. We also utilized the NCCN guidelines in our discussions. The question before us was whether to perform primary surgery or to administer neoadjuvant therapy.

Figure 1. Ultrasound showing area of concern before chemotherapy.

Figure 2. Ultrasound showing area of concern after chemotherapy. Note that the tumor appears only slightly smaller.

Figure 3. MRI showing the area before chemotherapy. reconvened to discuss further treatment. Upon comparison, the ultrasound from before chemotherapy showed a tumor with about a 12-mm maximum diameter, and the recent ultrasound showed the tumor as a little bit smaller but not changed to a tremendous degree (Figures 1 and 2). Her postchemotherapy MRI showed less anterior extension than the prechemotherapy MRI, although the radiologist commented that the uptake and release curves on the postchemotherapy image were perhaps

disturbing (Figures 3 and 4). Clinically, the mass felt smaller. Findings on physical examination were much improved. The patient still strongly did not want a mastectomy, so the team elected to go ahead with a lumpectomy. During surgery, an assessment ultrasound and a specimen mammogram on the lumpectomies were obtained. On the ultrasound more than on the mammogram, the tumor appeared a little bit close to the edges, so the peripheral edges were reexcised. Some pectoralis

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CASE STUDY

World Health Organization Criteria for the Diagnosis of Medullary Carcinoma, medullary carcinomas of the breast would have to have >75% syncytial growth pattern, diffuse lymphocytes and plasmacytes, nuclear pleomorphism, and histologic circumscription (which this one did), and no glandular structures (which this one did not).6 However, this was how the tumor appeared after chemotherapy. At this point, it seemed as if the diagnosis may have to be changed, but before doing so, I reexamined the original slides to see if that tissue also met the criteria for medullary carcinoma. Although the original slides showed the bluish pattern on the left-hand side and Figure 4. MRI showing the area after chemotherapy. Note that the tumor the normal breast stroma on the righthand side, it was difficult to determine exhibits less anterior extension. where the tumor stopped and the normal stroma began (Figure 6). The tumor was high grade but did not have the lymphoplasmacytic infiltrate seen on the postchemotherapy biopsy. Because the original biopsy did not meet the criteria for medullary carcinoma, namely circumscription and lymphoplasmacytic inflammation, I attributed the new findings to the chemotherapy effect and maintained the original diagnosis of high-grade invasive ductal carcinoma. In addition, the lumpectomy specimen had some lobular neoplasia. Four of her six margins were <1 cm with one being only 2 mm, but, fortunately, all the “close” margins were reexcised at the initial surgery based on the intraoperative specimen ultrasound, and the reexcised margins were negative for residual tumor. I noticed too that tumor size was 18 mm instead of 12 mm as it appeared to be initially. Poonam Srivastava (PS): This Figure 5. Pathology slide from the lumpectomy (after chemotherapy). Note that brought up a questhe tumor and stroma are well demarcated. tion as to whether a PET image should be obtained again in a case like this (when there is a question of mastectomy versus lumpecPoonam Srivastava, tomy) to determine MD how much active cancer is left. We did a lumpectomy on this patient because that was her choice, but if we had told her that the chance of residual disease or local recurrence were higher, she might have chosen a mastectomy. JT: It was clear that her desire was for lumpectomy, and whenever I can, I default to the patient’s wishes. My reasoning is that if the lumpectomy does not work, you can do a mastectomy afterward. In this case, the lumpectomy worked out fine.

Figure 6. Pathology slide from the original biopsy (before chemotherapy). Note that the tumor and stroma tissue are not well demarcated. muscle on the deep side also was removed. SN: Upon examination, the lumpectomy slides showed that the tumor was well circumscribed. The tumor was high grade. It showed a syncytial pattern and numer12

ous lymphocytes and plasma cells scattered throughout the stroma (Figure 5). The differential diagnosis for this histologic pattern includes a high-grade invasive ductal carcinoma and a medullary carcinoma. According to

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Discussion MP: This case also brought up two questions. First, in patients who have received neoadjuvant treatment, is there any histologic or pathologic evidence of shrinkage of the tumor? Second, in this case, did chemotherapy trigger an immunologic response that allowed her tumor to be walled off? SN: In breast cases, I do not frequently see an increase in lymphocytes and plasmacytes, although in other tumors that is a known response. With

chemotherapy, fibrosis and necrosis are more common responses. VR: The original National Surgical Adjuvant Breast and Bowel Project trial looked at neoadjuvant therapy and found that a tumor could completely disappear.7 Those patients invariably did extraordinarily well in terms of survival. It seemed that this patient was somewhere along that spectrum and could be considered to have had a good partial pathologic response. SN: She clearly showed some response. There was a real change from the original biopsy to the lumpectomy specimen. JT: Given her partial response to neoadjuvant chemotherapy and her past history with anastrozole, I asked the medical oncologists what they would recommend next. PS: Before surgery, she received four cycles of TC because she was ER- and PR-positive. And if she had received a full regimen of three cycles of doxorubicin and cyclophosphamide and three of taxotere, she might have had a complete response. There was the option of giving her another couple of cycles, but this would delay her radiation. MP: She had a very good response to therapy in terms of how the disease was walled off. In addition, the whole area was resected with deep margins that were clearly negative. I recommended holding off on any additional adjuvant chemotherapy, especially because of her strong ER and PR status. Because she was strongly positive and she already had a nonsteroidal agent, a steroidal such as exemestane would be a good choice for this patient. JT: The current plan is to proceed with external-beam radiation therapy followed by exemestane for 5 years. She will be followed every 6 months with a complete blood count and a Chem-12 blood test every visit. For the first 2 years, she will have a mammogram every 6 months on the left and yearly on the right, with yearly bilateral mammograms thereafter. n

References 1. Madjar H. The Practice of Breast Ultrasound. New York, NY: Thieme Medical Publishers; 2000:153. 2. Smith I, Dowsett M; for the IMPACT Trialists. Comparison of anastrozole vs tamoxifen alone and in combination as neoadjuvant treatment of estrogen receptor-positive (ER+) operable breast cancer in postmenopausal women: the IMPACT trial. Breast Cancer Res Treat. 2003: Abstract 1. 3. Semiglazov VF, Semiglazov V, Ivanov V, et al. The relative efficacy of neoadjuvant endocrine therapy vs chemotherapy in postmenopausal women with ER positive breast cancer. J Clin Oncol. 2004;22(14S):Abstract 519. 4. Eiermann W, Paepke S, Appfelstaedt J, et al; for the Letrozole Neo-Adjuvant Breast Cancer Study Group. Preoperative treatment of postmenopausal breast cancer patients with letrozole: a randomized double-blind multicenter study. Ann Oncol. 2001;12:1527-1532. 5. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Breast Cancer. V.1.2009. www.nccn.org/professionals/ physician_gls/PDF/breast.pdf. Accessed September 18, 2009. 6. Ellis IO, Schnitt SJ, Sastre-Garau X, et al. Invasive breast carcinoma. In: Tavassoli FA, Devilee P, eds. Tumours of the Breast and Female Genital Organs. Lyon, France: IARC Press; 2003:13-59. 7. Fisher B, Bryant J, Womark N, et al. Effect of preoperative chemotherapy on the outcome of women with operable breast cancer. J Clin Oncol. 1998;16:2672-2685.

November/December 2009

ONCOLOGY CAREERS

Continued from cover than older ones, Blayney said. An ASCO-commissioned Rand Corporation “workforce study” (Erikson C, et al. J Oncol Pract. 2007;3:79-86) found that a male US oncologist aged 45 to 64 years in a private practice conducts an average of 103.1 visits per week. A male US oncologist not in that age range, however, conducts only 83.9 visits weekly. Weekly visit numbers are lower in academic settings (63.9 vs 44.5, respectively) and among female oncologists in either setting. The impending problem is apparent considering that during the next 15 years the capacity for conducting visits is projected to rise by only about 14%, but the demand for visits by about 48% because of the aging population. The lesser lifetime produc-

tivity of the younger oncologists along with better therapies increasing the number of cancer survivors can only confound the problem. The Rand Corporation report concluded that no single potential remedy will fully close that gap.

Physician extenders One remedy, Blayney stated, is greater reliance on physician extenders, such as nurse practitioners and physician assistants, to arrange patients’ schedules, manage chemotherapy infusions, assess treatment side effects, and manage symptoms and complications through both face-to-face and telephone contacts. Physician extenders would also write chemotherapy orders and perform

Filling the Workforce Gap with Nurse Practitioners, Physician Assistants, and Clinical Pharmacists In the words of Douglas W. Blayney, MD

e don’t need people with 12 years of post–high school education to manage adjuvant hormonal therapy for breast cancer. My nurse practitioners do a much better job than I do discussing some of the sexual function side effects of hormonal therapy. They also monitor for other long-term sequelae of hormonal treatment and are very well-trained to manage chemotherapy side effects, including nausea and vomiting and pain control, or other symptom management problems that arise during the course of treatment. Many of the nurse practitioners we work with have experience as oncology nurses. We work very closely with the University of Michigan nursing school nurse practitioner program, and I have nurse practitioner students who rotate into my private practice. That’s good experience for them as students and for me. It allows me to have a look at people I might want to hire when they finish their training, and they get to see the private practice side of the world. The same is true for the physician assistant training programs. The programs are clinically oriented. Usually those in training have had some other healthcare-related job, such as dietician or respiratory therapist, and already know that they enjoy helping sick and vulnerable people. We have many physician assistants and nurse practitioners who are affiliate members of the American Society of Clinical Oncology, and we are

November/December 2009

thinking about developing training opportunities specifically for their needs as well as about finding ways to work with their respective professional associations. Also, I work closely with a clinical pharmacist both on the inpatient side and in the outpatient clinic. Clinical pharmacists can have a role in specialized niches that take advantage of their expertise. For example, we have a pharmacist on our team who manages the erythropoiesis-stimulating agents given to cancer patients, and who helps manage antibiotic treatment and prophylaxis in leukemia patients. These clinical pharmacists play an invaluable role in helping us manage these patients with complex, chronic therapy regimens. They don’t devote their time to filling prescriptions. They counsel patients about the side effects of medications and alert them to possible medication interactions. I find working together daily with these highly skilled people very rewarding, and the patients get the benefit. Together we work for the safety and care of our patients. Finally, we do need to work carefully with regulators and third-party payers. They need to see that they are getting value for their dollar so that they develop flexibility regarding payment for services. If we take good advantage of these non-physician providers, there has to be compensation for them. n —WA

procedures. “There will be changes in our care model. We have to do our work in more efficient ways,” Blayney said. Many oncologists, he commented further, will choose this course. The clear advantage is that expanding the oncology clinical workforce through more use of extenders will enable practitioners to see more patients and offer their services more effectively, Blayney added. Currently, only a minority of physician assistants working in internal medicine and 1% of nurse practitioners specialize in oncology, ASCO data reveal. About his own institution, where the use of extenders has been cultivated, Blayney said, “the group is an experienced and loyal group with about half of them having 3 to 10 years of oncology experience, and half having worked solely in their careers for the University of Michigan” (see sidebar). Changes in training and in reimbursement will facilitate better use of physician extenders. Constructive steps

10:86-101) and in The New York Times (2007 Dec 30) describing how a simple checklist for catheter insertion made extremely favorable clinical differences. The checklist, created by Peter Pronovost, MD, PhD, of John Hopkins University, Baltimore, Maryland, and modeled after lists developed for pilots in aviation, consists of five steps: (1) wash hands with soap; (2) clean patient’s skin with chlorhexidine antiseptic; (3) put sterile drapes over the entire patient; (4) wear sterile mask, hat, gown, and gloves; and (5) put a sterile dressing over the catheter site once the line is in. The effect was dramatic. The hospital’s catheter-induced bloodstream infection rate went from 4% to 0% in 15 months, saving 1500 lives and nearly $200 million. “The message,” Blayney said, “is do it right every time.” He further said that oncologists can borrow data- and quality-improvement tools from other industries to help themselves

The clear advantage is that expanding the oncology clinical workforce through more use of extenders will enable practitioners to see more patients and offer their services more effectively. include establishing best practices and expanding training and continuing education. ASCO and the University of Michigan have stated their interest in going forward along these lines. “Given enough flexibility by payers, I think we can off-load some of the work currently done by oncologists to our collaborators who are trained professionals,” Blayney said.

Digitize, standardize Another step toward meeting the workforce gap is in streamlining information transfer. Although physicians are likely to book travel online, the notion of switching to online patient records meets resistance, Blayney said, for several reasons. Reducing personal contact and interaction with patients diminishes the “social side” and deprives the physician of valuable cues. Hesitation over the inevitable learning curves associated with adjusting to and integrating new technologies, along with fear “of being turned into data entry clerks,” loom large. Blayney acknowledged the validity of such reservations, but said, nonetheless, “the patients and our young physician colleagues are ready for this. We need to do our work in standard ways.” The value of standardizing procedures has been well documented. Citing the substantial evidence verifying the value of checklists in medicine, Blayney made reference to articles by Atul Gawande, MD, MPH, of Brigham and Women’s Hospital, Boston, Massachusetts, in The New Yorker (2007 Dec

better do their jobs. A subsequent study of 100 Michigan hospitals using the checklist found that 30% of the time, surgical teams skipped one of the five steps. Despite this, the worst rate among the Michigan hospitals was better than that of the average US hospital. The key for importing the checklist strategy to other processes, for example, in ordering chemotherapy, is to make processes uniform, Blayney said. The outcome is reduced waste and less duplication of efforts. Further efforts in Michigan hospitals toward monitoring internal quality improvement and working toward greater efficiency have also paid off. The average time patients wait for infusions has been reduced from 41 minutes to 20 minutes. Other efforts have led to less use of chemotherapy in the last 2 weeks of life.

What assessment does Beneficial Hawthorne effects (improvements arising simply from having the patterns of an institution or practice observed) come into play through use of quality-assessment tools like the ASCO Quality Oncology Practice Initiative. The idea behind such tools is to allow groups to see where they stand in relation to norms, not to pit one group against another, Blayney underscored. He concluded, making reference to his opening comment, “to continue the good news story, we need to figure out how to do our work with less expensive and potentially less well-trained people.” n —Walter Alexander

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oncology careers

Use of Non-physician Practitioners

ABRAXANE delivers efficacy* to make more possible 速

速

nab defined: nab technology exploits the natural properties of albumin, facilitating the delivery of water-insoluble compounds to the tumor.

*In a pivotal randomized phase III trial in metastatic breast cancer patients,

ABRAXANE delivered nearly double the overall response rate vs solvent-based paclitaxel 1

Reconciled target lesion response rates (TLRR)* in the randomized phase III clinical trial in metastatic breast cancer patients1

21.5% vs 11.1%

15.5% vs 8.4%

For all study patients (P=.003).1 95% Cl, 16.2% to 26.7% for ABRAXANE 95% Cl, 6.9% to 15.1% for solvent-based paclitaxel

For study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy (P=NS).1 95% Cl, 9.3% to 21.8% for ABRAXANE 95% Cl, 3.9% to 12.9% for solvent-based paclitaxel

*Reconciled TLRR in the randomized, open-label, phase III trial was the rigorous protocol-specific primary end point based on independent radiologic assessment of tumor responses reconciled with investigator responses (which also included clinical information) for the first 6 cycles of therapy. (Tumor response was assessed using Response Evaluation Criteria in Solid Tumors [RECIST].)2 It is well established that reconciled TLRR are lower than investigator-reported response rates typically reported in the scientific literature.3

BOUND AND DETERMINED

ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated.

IMPORTANT SAFETY INFORMATION WARNING: ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Dose adjustment is recommended for patients with moderate to severe hepatic impairment. The need for further dose adjustments in subsequent courses should be based on individual tolerance. ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Men should be advised to not father a child while receiving treatment with ABRAXANE. It is recommended that nursing be discontinued when receiving ABRAXANE therapy. ABRAXANE contains albumin (human), a derivative of human blood. Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for 7 days or

more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended. Sensory neuropathy occurs frequently with ABRAXANE. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension. In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%; severe 3%), vomiting (any 18%; severe 4%), diarrhea (any 27%; severe <1%), and mucositis (any 7%; severe <1%). Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines. You are encouraged to report negative side effects of prescription drugs to the FDA. Visit www.fda.gov/medwatch or call 1-800-FDA-1088. Please see the Brief Summary of the ABRAXANE full prescribing information on the next page. References: 1. ABRAXANE [prescribing information]. Bridgewater, NJ: Abraxis BioScience, LLC; September 2009. 2. Gradishar WJ, Tjulandin S, Davidson N, et al. Phase III trial of nanoparticle albumin-bound paclitaxel compared with polyethylated castor oil-based paclitaxel in women with breast cancer. J Clin Oncol. 2005;23:7794-7803. 3. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst. 2000;92:205-216. All Abraxis BioScience, LLC. corporate names, names of services, and names of products referred to herein are trade names, service marks, and/or trademarks that are owned by or licensed to Abraxis BioScience, its divisions or its affiliates, unless otherwise noted. ©2009 Abraxis BioScience, LLC. All Rights Reserved. AB 1429 10/09 Printed in USA

Cost, Noncompliance Bitter Pills HEALTH ECONOMICS

Continued from cover compromise outcome (Table 1). Currently, about 10% of therapeutic agents used in oncology are oral therapies, and this percentage is expected to increase to as much as 30% over the next 5 years. Oral therapies include cytotoxic agents, targeted therapies, and supportive therapies. The monthly cost of these oral regimens ranges from $2200 to almost $8000, representing a chief reason for nonadherence. “We can have the best

Table 1. Impact of Cost on Adherence • Patients ration medication • Patients/families lose assets, financial security • Potential for poorer outcomes (including disease resistance) at higher cost

Table1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule (cont.) Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 10 2 Severe Symptomsf Myalgia / Arthralgia Any Symptoms 44 49 f Severe Symptoms 8 4 Asthenia Any Symptoms 47 39 8 3 Severe Symptomsf Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 4 1 Severe Symptomsf Diarrhea Any Symptoms 27 15 f Severe Symptoms <1 1 Mucositis Any Symptoms 7 6 <1 0 Severe Symptomsf Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1

Rx Only

Brief Summary of Full Prescribing Information. WARNING ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS. INDICATION: ABRAXANE® for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. CONTRAINDICATIONS: ABRAXANE should not be used in patients who have baseline neutrophil counts of < 1,500 cells/mm3. WARNINGS: Bone marrow suppression (primarily neutropenia) is dose dependent and a dose limiting toxicity. ABRAXANE should not be administered to patients with baseline neutrophil counts of < 1,500 cells/mm3. Frequent monitoring of blood counts should be instituted during ABRAXANE treatment. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm 3 and platelets recover to a level >100,000 cells/mm3. The use of ABRAXANE has not been studied in patients with renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. Pregnancy – Teratogenic Effects: Pregnancy Category D : ABRAXANE can cause fetal harm when administered to a pregnant woman. Administration of paclitaxel protein-bound particles to rats on gestation days 7 to 17 at doses of 6 mg/m 2 (approximately 2% of the daily maximum recommended human dose on a mg/m2 basis) caused embryo- and fetotoxicity, as indicated by intrauterine mortality, increased resorptions (up to 5-fold), reduced numbers of litters and live fetuses, reduction in fetal body weight and increase in fetal anomalies. Fetal anomalies included soft tissue and skeletal malformations, such as eye bulge, folded retina, microphthalmia, and dilation of brain ventricles. A lower incidence of soft tissue and skeletal malformations were also exhibited at 3 mg/m2 (approximately 1% of the daily maximum recommended human dose on a mg/m2 basis). There are no adequate and well-controlled studies in pregnant women using ABRAXANE®. If this drug is used during pregnancy, or if the patient becomes pregnant while receiving this drug, the patient should be apprised of the potential hazard to the fetus. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Use in Males Men should be advised to not father a child while receiving treatment with ABRAXANE (see PRECAUTIONS: Carcinogenesis, Mutagenesis, Impairment of Fertility for discussion of effects of ABRAXANE exposure on male fertility and embryonic viability). Albumin (Human) ABRAXANE contains albumin (human), a derivative of human blood. Based on effective donor screening and product manufacturing processes, it carries an extremely remote risk for transmission of viral diseases. A theoretical risk for transmission of Creutzfeldt-Jakob Disease (CJD) also is considered extremely remote. No cases of transmission of viral diseases or CJD have ever been identified for albumin. PRECAUTIONS: Drug Interactions No drug interaction studies have been conducted with ABRAXANE. The metabolism of paclitaxel is catalyzed by CYP2C8 and CYP3A4. In the absence of formal clinical drug interaction studies, caution should be exercised when administering ABRAXANE concomitantly with medicines known to inhibit (e.g. ketoconazole and other imidazole antifungals, erythromycin, fluoxetine, gemfibrozil, cimetidine, ritonavir, saquinavir, indinavir, and nelfinavir) or induce (e.g. rifampicin, carbamazepine, phenytoin, efavirenz, nevirapine) either CYP2C8 or CYP3A4 (see CLINICAL PHARMACOLOGY). Hematology ABRAXANE® therapy should not be administered to patients with baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of myelotoxicity, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for seven days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses of therapy is recommended (see DOSAGE and ADMINISTRATION). Nervous System Sensory neuropathy occurs frequently with ABRAXANE. The occurrence of grade 1 or 2 sensory neuropathy does not generally require dose modification. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE (see DOSAGE and ADMINISTRATION). Hepatic Impairment Because the exposure and toxicity of paclitaxel can be increased with hepatic impairment, administration of ABRAXANE in patients with hepatic impairment should be performed with caution. The starting dose should be reduced for patients with moderate and severe hepatic impairment. (See CLINICAL PHARMACOLOGY and DOSAGE AND ADMINISTRATION, Hepatic Impairment) Injection Site Reaction Injection site reactions occur infrequently with ABRAXANE and were mild in the randomized clinical trial. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Carcinogenesis, Mutagenesis, Impairment of Fertility The carcinogenic potential of ABRAXANE has not been studied. Paclitaxel has been shown to be clastogenic in vitro (chromosome aberrations in human lymphocytes) and in vivo (micronucleus test in mice). ABRAXANE was not mutagenic in the Ames test or the CHO/HGPRT gene mutation assay. Administration of paclitaxel protein-bound particles to male rats at 42 mg/m2 on a weekly basis (approximately 16% of the daily maximum recommended human exposure on a mg/m2 basis) for 11 weeks prior to mating with untreated female rats resulted in significantly reduced fertility accompanied by decreased pregnancy rates and increased loss of embryos in mated females. A low incidence of skeletal and soft tissue fetal anomalies was also observed at doses of 3 and 12 mg/m2/week in this study (approximately 1 to 5% of the daily maximum recommended human exposure on a mg/m2 basis). Testicular atrophy/degeneration has also been observed in single-dose toxicology studies in rodents administered paclitaxel protein-bound particles at 54 mg/m2 and dogs administered 175 mg/m2 (see WARNINGS). Pregnancy: Teratogenic Effects: Pregnancy Category D : (See WARNINGS section). Nursing Mothers It is not known whether paclitaxel is excreted in human milk. Following intravenous administration of carbon-14 labeled paclitaxel to rats on days 9 to 10 postpartum, concentrations of radioactivity in milk were higher than in plasma and declined in parallel with the plasma concentrations. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions in nursing infants, it is recommended that nursing be discontinued when receiving ABRAXANE® therapy. Pediatric Use The safety and effectiveness of ABRAXANE in pediatric patients have not been evaluated. Geriatric use Of the 229 patients in the randomized study who received ABRAXANE, 11% were at least 65 years of age and < 2% were 75 years or older. No toxicities occurred notably more frequently among elderly patients who received ABRAXANE. Ability to Drive and Use Machines Adverse events such as fatigue, lethargy, and malaise may affect the ability to drive and use machines. ADVERSE REACTIONS: The following table shows the frequency of important adverse events in the randomized comparative trial for the patients who received either single-agent ABRAXANE® or paclitaxel injection for the treatment of metastatic breast cancer. Table1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule Percent of Patients ABRAXANE® Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225) Bone Marrow Neutropenia < 2.0 x 109/L < 0.5 x 109/L Thrombocytopenia < 100 x 109/L < 50 x 109/L Anemia < 11 g/dL < 8 g/dL Infections Febrile Neutropenia Bleeding Hypersensitivity Reactione All Severef Cardiovascular Vital Sign Changesg Bradycardia Hypotension Severe Cardiovascular Eventsf Abnormal ECG All patients Patients with Normal Baseline

80 9

82 22

2 <1

3 <1

33 1 24 2 2

25 <1 20 1 2

4 0

12 2

<1 5 3

<1 5 4

60 35

52 30

a b c d e

f g

Based on worst grade. ABRAXANE dose in mg/m2/duration in minutes. paclitaxel injection dose in mg/m2/duration in hours. paclitaxel injection pts received premedication. Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. Severe events are defined as at least grade 3 toxicity. During study drug dosing.

Myelosuppression and sensory neuropathy were dose related. Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metastatic breast cancer treated with single-agent ABRAXANE ® in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm. Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm. Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE® in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy. Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents. In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE®. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Cranial nerve palsies and vocal cord paresis have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety. Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage. Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE® administration, and resolved within a few days. Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial. Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment.

drugs in the world, but they are not going to work if patients do not, or cannot, take them,” said DeMichele at the annual meeting of the American Society of Clinical Oncology. The magnitude of the effect of nonadherence is startling (Table 2). Up to two thirds of hospital admissions are due to poor medication adherence overall, with an estimated cost to the system of about $110 billion per year, she said. Oncology-specific data are lacking, and cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE® in the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise. Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Accidental Exposure No reports of accidental exposure to ABRAXANE® have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Hepatic Impairment No dose adjustment is necessary for patients with mild hepatic impairment. Patients with moderate and severe hepatic impairment treated with ABRAXANE may be at increased risk of toxicities known to paclitaxel. Patients should not receive ABRAXANE if AST > 10 x ULN or bilirubin > 5.0 x ULN. Recommendations for dosage adjustment for the first course of therapy are shown in Table 4. The dose of ABRAXANE can be increased up to 200 mg/m2 in patients with severe hepatic impairment in subsequent cycles based on individual tolerance. Patients should be monitored closely. (See CLINICAL PHARMACOLOGY: Hepatic Impairment and PRECAUTIONS: Hepatic Impairment) Table 4: Recommendations for Starting Dose in Patients with Hepatic Impairment SGOT (AST) Levels Mild

<10 x ULN

Moderate

<10 x ULN

Severe

<10 x ULN > 10 x ULN

Bilirubin Levels >ULN to ≤ 1.25 x ULN AND OR

260 mg/m2 200 mg/m2

2.01 to 5.0 x ULN

130 mg/m2 b

> 5.0 x ULN

not eligible

Dosage recommendations are for the first course of therapy. The need for further dose adjustments in subsequent courses should be based on individual tolerance. A dose increase to 200 mg/m2 in subsequent courses should be considered based on individual tolerance.

Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. Preparation and Administration Precautions ABRAXANE is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE® contacts mucous membranes, the membranes should be flushed thoroughly with water. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions (see PRECAUTIONS: Injection Site Reaction). No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE. Preparation for Intravenous Administration ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. 1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. 2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over a minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. 3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. 4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. 5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. 6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL) The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Inject the appropriate amount of reconstituted ABRAXANE® into an empty, sterile IV bag (plasticized polyvinyl chloride (PVC) containers, PVC or non-PVC type IV bag). The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Stability Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 25°C) and lighting conditions for up to 8 hours. HOW SUPPLIED: Product No. 103450 NDC No. 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton. Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006 REFERENCES: 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication No. 83-2621. For sale by the Superintendent of Documents, US Government NIH Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):15901592. 3. National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences. 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncological Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm, 1990; 47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES.) Am J Health-Syst Pharm, 1996; 53:1669-1686. 8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41. This Brief Summary is based on the ABRAXANE Full Prescribing Information Revised: September 2009

Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial. Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely. Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some

ABRAXANE a

1.26 to 2.0 x ULN

the area is clearly understudied. In a disease as potentially lethal as cancer, one might assume that nonadherence to a treatment regimen would be minimal, but “even in oncology, we have glimpses that patients are nonadhering a fair percentage of the time,” said DeMichele. “By having this lack of adherence, it can lead us to some mistakes or really not being able to optimize therapy for our patients, or to optimize the development of drugs for our diseases.” Nonadherence in clinical trials can lead to an underestimation of a drug’s efficacy. “Particularly in randomized trials where an oral agent is being compared with an intravenous agent, there can be a perceived inferiority of the oral drug when it is compared with an intravenous drug if the oral drug is one that people are poorly adherent to,” DeMichele noted. An important contributor to nonadherence in oncology is the uncertainty in coverage by insurance companies, which is highly variable.

An important contributor to nonadherence in oncology is the uncertainty in coverage by insurance companies, which is highly variable. Oral cancer therapies are not covered by a medical benefit but rather fall under a patient’s prescription drug benefit. “The patient responsibility is tremendous,” she said. “There are copays and deductibles. When set up by payers, they weren’t designed to take into account the extreme expense of these medications that patients would be using for oncology indications. Only Oregon so far has passed some legislation that would adjust patient copays and deductibles for oncology medications, and make those rules different than they are for patients taking medications for other indications.” Anecdotal evidence indicates that rationing of medications is occurring in oncology, said DeMichele. Rationing creates the potential for poorer outcomes at a higher cost. Furthermore, taking medications on a schedule different from the intended schedule (ie, less frequently, missing doses) may increase the likelihood of changing the biology of the disease. “Are cancers going to mutate or become more aggressive if they are only going to Continued on page 17

G REEN H ILL H EALTHCARE C OMMUNICATIONS

November/December 2009

Continued from cover the importance of screening in the average-risk population. In its “war on cancer,” the National Cancer Institute highlights its recommendation to increase the rates of CRC screening, as part of advances in cancer care in 2009. CRC almost always arises from adenomatous polyps, found in nearly 33% of persons aged ≥50 years and in almost 50% of those >65 years. Removal of polyps prevents cancer. The National Comprehensive Cancer Network and the American Cancer Society (ACS) screening guideline recommendations are outlined in the Table. The fecal occult blood test (FOBT) was the first screening method developed, but its high false-positive rate continues to be problematic. Colonoscopy is the best-established and most reliable screening method, but questions about screening frequency, operator variability, and diagnostic accuracy remain, Mayer said. Computed tomography (CT) or virtual colonography has gained interest, but the Centers for Medicare & Medicaid Services (CMS) has been reluctant to endorse its coverage for Medicare

patients. CT colonography is “seemingly equivalent” to endoscopy, but “it is not clear that the expertise is there” outside of specialty centers, Mayer said. Few if any head-to-head comparisons of the screening methods have been conducted; therefore, the optimal method has not been declared. Meanwhile, “surveillance colonoscopy represents the gold standard, but whether it can achieve wider and more cost-effective use remains to be determined,” noted Mayer.

CT colonography coverage Advances in software have yielded better image interpretation, said Michael Pignone, MD, MPH, University of North Carolina, Chapel Hill, “but CT colonography is still a bit of a moving target.” In addition to accuracy, the potential for slight radiation exposure, and the additional work-up cost and anxiety related to extracolonic findings are concerns. “CT colonography is very cost-effective compared with no screening, and it buys additional life-years at a reasonable cost” compared with FOBT. But it is less cost-effective compared with colonos-

Table. 2009 NCCN/ACS Screening Recommendations for Average-Risk Personsa Screening test

Frequency (begin age 50)

Colonoscopy Fecal occult blood test If positive: colonoscopy If negative: sigmoidoscopy Virtual colonography Double-contrast barium enema (soon to be eliminated) Fecal DNA test: roll still uncertain

Every 10 years Annually

Every 5 years Every 5 years N/A

ACS indicates American Cancer Society; NCCN, National Comprehensive Cancer Network. a No family history before age 50, no hereditary syndromes.

copy, Pignone said. “We need more primary data to answer whether CT colonography or optical colonoscopy is clearly superior.” Organizations differ on their conclusions, but the ACS says “there are sufficient data to include CT colonography as an acceptable option for screening.” CMS recently decided against coverage, citing insufficient evidence in

An exciting new possibility is a molecular approach that identifies mutations and genes associated with cancer in stool. the Medicare age-group. Pignone believes that CMS is mostly concerned about cost. CT colonography is covered by some insurers, and in some states coverage is mandated.

New molecular approaches A noninvasive approach to screening would greatly increase screening rates, but FOBT is not very effective. An exciting new possibility is a molecular approach that identifies mutations and genes associated with cancer in stool. The key mutations occur in 50% to virtually 100% of cancerous polyps and can be identified by polymerase chain reaction (PCR) analysis of DNA fragments. According to Luis Diaz, MD, of Johns Hopkins University, Baltimore, while the technology is advancing, “it’s still like finding a needle in a haystack, with the tumor DNA being the needle and the nontumor DNA being the haystack. There are about five mutant tumor DNA fragments in a pool of 10,000 total DNA fragments.” The next generation of markers will be “epigenetic markers,” such as the methylation marker vimentin, which can be enriched in tumor cells compared with normal tissue and have been

health economics Cost, Noncompliance Bitter Pills Continued from page 16 Table 2. The Importance of Nonadherence In practice • May lead to false conclusions about the effectiveness of therapy • May lead to a change to a less efficacious or more toxic regimen due to perceived lack of effectiveness In clinical trials • May lead to underestimation of drug efficacy • A perceived inferiority of drug when compared with intravenous formulation In policy • Increases healthcare costs • Wastes resources

be partially treated, in the same way we are seeing the emergence of resistance with antibiotics and in the HIV world?” she asked. In one study in which 5 years of tamoxifen treatment was equally effective as 10 years in preventing breast cancer recurrence, only 81% of patients adhered to the medication over 5 years, and the study authors concluded that such nonadherence may have underestimated the true effect of continuing the drug for the full 10 years by approximately one third. n —WK

November/December 2009

found in stool samples of 46% to 87% of persons with CRC. The sensitivity of a two-panel assay that searches for epigenetic markers and mutant DNA is 86%, with a specificity of 73%. “At this point, we have gone from a single DNA analysis, with a sensitivity of about 40%, to multiple gene analysis, with a sensitivity of 50%, to an analysis of methylation markers plus

multiple gene assay, with a sensitivity of up to 80%,” Diaz said. These are all analog approaches. Next to come is digital PCR, which should increase the sensitivity to nearly 90%, he added. Compared with analog assays, digital PCR can detect more mutant molecules, quantify more accurately, and genotype more easily, but it is both more labor intensive and more expensive.

Fecal DNA screening Despite its high sensitivity, the adoption of the fecal DNA test has been controversial. The ACS deems fecal DNA acceptable as a test that “primarily detects cancer,” and the US Preventive Services Task Force maintains the evidence is insufficient “for or against” it. Modeling studies show that screening with fecal DNA every 5 years is clinically effective and cost-effective compared with no screening, but not compared with FOBT and colonoscopy. “Significant technical improvements in sensitivity have been achieved in small studies, but large prospective trials are needed,” Diaz concluded. n —Caroline Helwick

2010 Medicare Physician Fee Schedule

he Centers for Medicare & Medicaid Services (CMS) announced the final policies and payment rates for services rendered during the 2010 calendar year by practitioners who are paid under the Medicare Physician Fee Schedule. In a success for radiation oncology, CMS will not implement its proposed 19% cut; instead radiation oncology payments will be reduced by only 5% over the next 4 years. CMS will also continue to use specialty supplemental survey data to determine practice expenses for medical oncology. n

G REEN H ILL H EALTHCARE C OMMUNICATIONS

GASTROINTESTINAL CANCERS

Colorectal Cancer Screening

ONCOLOGY DRUG CODES

Oncology Drug Codes Medications Used for the Treatment of Leukemias The following sections include: • Associated ICD-9-CM codes used for the classification of leukemias • Drugs that have been FDA-approved in the treatment of leukemias. Please note: if a check mark appears in the FDA column it will NOT appear in the Compendia section even if a drug is included in the NCCN (National Comprehensive Cancer Network) Drugs & Biologics Compendium • Drugs included in the NCCN Drugs & Biologics Compendium for off-label use in leukemias. NCCN is recognized by the Centers for Medicare & Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current Code Price (AWP-based pricing) • Most recent ASP plus 6% (Medicare allowable) • Possible CPT Administration Codes for each medication

Associated ICD-9-CM Codes Used for Leukemias 204

Lymphoid leukemia 204.00 Acute—without mention of having achieved remission 204.01 Acute—in remission 204.02 Acute—in relapse

205

204.10 Chronic—without mention of having achieved remission 204.11 Chronic—in remission 204.12 Chronic—in relapse Myeloid leukemia 205.00 Acute—without mention of having achieved remission 205.01 Acute—in remission 205.02 Acute—in relapse

206

205.10 Chronic—without mention of having achieved remission 205.11 Chronic—in remission 205.12 Chronic—in relapse Monocytic leukemia 206.00 Acute—without mention of having achieved remission 206.01 Acute—in remission 206.02 Acute—in relapse 206.10 Chronic—without mention of having achieved remission 206.11 Chronic—in remission 206.12 Chronic—in relapse

Generic (brand) name

HCPCS code: code description

alemtuzumab (Campath) arsenic trioxide (Trisenox) asparaginase (Elspar) azacitidine (Vidaza) bendamustine (Treanda) betamethasone (Celestone Soluspan)

J9010: injection, alemtuzumab, 10 mg J9017: injection, arsenic trioxide, 1 mg J9020: injection, asparaginase, 10,000 units J9025: injection, azacitidine, 1 mg J9033: injection, bendamustine HCl, 1 mg J0702: injection, betamethasone acetate, 3 mg and betamethasone sodium phosphate, 3 mg J8510: busulfan, oral, 2 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0172: chlorambucil, oral, 2 mg

busulfan (Myleran) chlorambucil (Leukeran) chlorambucil (Leukeran)

FDAapproved for leukemias

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NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

✓

$660.90

$570.22

96413, 96415

✓

$43.58

$37.44

96413, 96415

✓

$70.42

$58.01

96401, 96413

✓

$5.74

$4.87

✓

$21.60

$18.53

✓

$6.85

$6.56

✓

$4.46

$3.22

N/A

✓

NDC level pricing $3.86

NDC level pricing S0172: not payable by Medicare

N/A

✓

96401, 96409, 96413 96413 11900, 11901, 20600, 20605, 20610, 96372

N/A

November/December 2009

NHL Mantle Cell Trial Now Recruiting Investigators and Enrolling Study Participants Celgene CC-5013-MCL-001

A Phase 2 Study for Patients With Relapsed/Refractory Mantle Cell Non-Hodgkin’s Lymphoma Primary Investigator André Goy, MD Primary Objective To determine the tumor response and duration of response of lenalidomide monotherapy in subjects with mantle cell lymphoma (MCL) who have relapsed or progressed after treatment with bortezomib or are refractory to bortezomib Key Eligibility Criteria* • Individuals with MCL previously treated with all of the following (alone or in combination): – Bortezomib† – An anthracycline or mitoxantrone – Rituximab – Cyclophosphamide • Individuals must have documented relapse after bortezomib treatment or be refractory to bortezomib • Excluding individuals who are candidates for high-dose chemotherapy/allogeneic stem cell transplant *Additional criteria apply. †Note: When the agent bortezomib is mentioned this also includes ANY BORTEZOMIB-CONTAINING REGIMEN.

Study Design

Pretreatment Phase (4 Weeks)

N=133

• MCL diagnosis conﬁrmed by local pathological review

Treatment Phasea (until disease progression)

• Lenalidomide starting dose 25 mg po once dailyb

Lenalidomide will be dosed po once daily on days 1-21 of each 28-day cycle. Subjects with creatinine clearance ≥30 mL/min but <60 mL/min will receive a lower starting dose of lenalidomide 10 mg po once daily. Dose may be escalated to 15 mg po once daily if no dose-limiting toxicities occur during the ﬁrst 2 cycles.

Investigational use of lenalidomide. For more information contact Deborah Ingenito, Celgene Study Manager dingenito@celgene.com (908) 673-9581 www.clinicaltrials.gov (NCT00737529)

ONCOLOGY DRUG CODES

Generic (brand) name

HCPCS code: code description

FDAapproved for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

J9065: injection, cladribine, per 1 mg J9027: injection, clofarabine, 1 mg J8530: cyclophosphamide, oral, 25 mg J9090: cyclophosphamide, 500 mg J9091: cyclophosphamide, 1.0 gram J9092: cyclophosphamide, 2.0 grams J9100: injection, cytarabine, 100 mg J9110: injection, cytarabine, 500 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified daunorubicin J9150: injection, (Cerubidine) daunorubicin, 10 mg dexamethasone J1100: injection, (Decadron) dexamethasone sodium phosphate, 1 mg dexamethasone J8540: dexamethasone, (Decadron) oral, 0.25 mg doxorubicin HCl J9000: injection, doxorubicin (Adriamycin) hydrochloride, 10 mg fludarabine J9185: injection, (Fludara) fludarabine phosphate, 50 mg gemtuzumab J9300: injection, gemtuzumab ozogamicin (Mylotarg) ozogamicin, 5 mg hydrocortisone J1720: injection, (Solu-Cortef) hydrocortisone sodium succinate, up to 100 mg hydroxyurea J8999a: prescription drug, (Hydrea) oral, chemotherapeutic, not otherwise specified hydroxyurea S0176: hydroxyurea, (Hydrea) oral, 500 mg

✓

$58.20

$25.64

96413, 96415

✓

$135.00

$116.40

96413, 96415

✓

$2.09

$0.81

✓

$30.34

$21.51

96409, 96413, 96415

✓

$54.62

$43.03

96409, 96413, 96415

✓

$98.30

$86.06

96409, 96413, 96415

✓

$3.60

$1.72

✓

$10.20

$3.92

✓

NDC level pricing $25.20

NDC level pricing $15.24

✓

$0.15

$0.08

✓

$0.09

$0.38

11900, 11901,20600, 20605, 20610, 96372, 96374 N/A

✓

$13.20

$3.69

96409

✓

$330.32

$154.27

96413

✓

$3,104.82

$2,622.30

96413, 96415

✓

$2.46

$2.92

96365, 96366, 96372, 96374

✓

NDC level pricing $1.28

idarubicin (Idamycin) imatinib (Gleevec)

J9211: injection, idarubicin hydrochloride, 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified S0088: imatinib, 100 mg

✓

$381.56

NDC level pricing S0176: not payable by Medicare $98.56

✓

NDC level pricing $42.12

J9214: injection, interferon, alfa-2b, recombinant, 1 million units J9230: injection, mechlorethamine hydrochloride (nitrogen mustard), 10 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified

✓

$21.90

✓

cladribine (Leustatin) clofarabine (Clolar) cyclophosphamide oral (Cytoxan) Cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) cyclophosphamide injection (Cytoxan) cytarabine (Cytosar-U) cytarabine (Cytosar-U) dasatinib (Sprycel)

imatinib (Gleevec) interferon alfa-2b (Intron-A) mechlorethamine (Mustargen) mercaptopurine (Purinethol)

NCCN Drugs & Biologics Compendium off-label use for leukemias

G REEN H ILL H EALTHCARE C OMMUNICATIONS

N/A

96409, 96413, 96415, 96450 96409, 96413, 96415, 96450 N/A

96409, 96413

N/A

96409

NDC level pricing S0088: not payable by Medicare $15.84

N/A

96372, 96401

$178.71

$147.34

96409

NDC level pricing

N/A

November/December 2009

NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

Generic (brand) name

HCPCS code: code description

mercaptopurine (Purinethol)

S0108: mercaptopurine, oral, 50 mg

✓

$4.09

methotrexate

J8610: methotrexate, oral, 2.5 mg J9250: methotrexate sodium, 5 mg J9260: methotrexate sodium, 50 mg J1030: injection, methylprednisolone acetate, 40 mg J1040: injection, methylprednisolone acetate, 80 mg J2920: injection, methylprednisolone sodium succinate, up to 40 mg J2930: injection, methylprednisolone sodium succinate, up to 125 mg J7509: methylprednisolone, oral, per 4 mg J9293: injection, mitoxantrone hydrochloride, per 5 mg J8999a: prescription drug, oral, chemotherapeutic, not otherwise specified J9266: injection, pegaspargase, per single dose vial J3490a: unclassified drugs

✓

$3.56

S0108: not payable by Medicare $0.12

✓

$0.27

$0.21

✓

$2.68

$2.12

✓

$5.84

$3.79

✓

$11.46

$7.27

✓

$2.36

$2.56

✓

$4.15

$3.45

✓

$0.54

$0.06

✓

$116.50

$66.77

✓

NDC level pricing $3,280.00

NDC level pricing $2,747.51

methotrexate sodium methotrexate sodium methylprednisolone (Depo-Medrol) methylprednisolone (Depo-Medrol) methylprednisolone (Solu-Medrol) methylprednisolone (Solu-Medrol) methylprednisolone (Medrol) mitoxantrone (Novantrone) nilotinib (Tasigna) pegaspargase (Oncaspar) peginterferon alfa-2a (Pegasys) peginterferon alfa-2a (Pegasys)

✓

S0145: injection, pegylated interferon alfa-2a, 180 mcg per mL J3490a: unclassified drugs

✓

S0146: injection, pegylated interferon alfa-2b, 10 mcg per 0.5 mL pentostatin J9268: injection, (Nipent) pentostatin, per 10 mg prednisolone (Millipred, J7510: prednisolone, Orapred, Veripred) oral, per 5 mg prednisone J7506: prednisone, oral, per 5 mg rituximab J9310: injection, (Rituxan) rituximab, 100 mg teniposide Q2017: injection, (Vumon) teniposide, 50 mg thioguanine J8999a: prescription drug, (Tabloid) oral, chemotherapeutic, not otherwise specified tretinoin J8999a: prescription drug, (Vesanoid) oral, chemotherapeutic, not otherwise specified

✓

peginterferon alfa-2b (Peg-Intron)

✓

peginterferon alfa-2b (Peg-Intron)

November/December 2009

NDC level pricing $589.12

NDC level pricing $106.42

NDC level pricing S0145: not payable by Medicare NDC level pricing S0146: not payable by Medicare $1,426.47

CPT administration codes N/A

N/A 96372, 96374, 96401, 96409, 96450 96372, 96374, 96401, 96409, 96450 11900, 11901, 20600, 20605, 20610, 96372 11900, 11901, 20600, 20605, 20610, 96372 96365, 96366, 96372, 96374 96365, 96366, 96372, 96374 N/A 96409, 96413 N/A

96401, 96413, 96415 96372

96372

✓

$2,182.80

✓

$0.56

$0.02

N/A

✓

$0.05

N/A

$664.32

$563.33

96413, 96415

✓

$376.55

$325.57

96413, 96415

✓

NDC level pricing NDC level pricing

✓

ONCOLOGY DRUG CODES

FDAapproved for leukemias

96409, 96413

N/A

G REEN H ILL H EALTHCARE C OMMUNICATIONS

ONCOLOGY DRUG CODES

Generic (brand) name

HCPCS code: code description

vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS) vinCRIStine (Vincasar PFS)

J9370: vincristine sulfate, 1 mg J9375: vincristine sulfate, 2 mg J9380: vincristine sulfate, 5 mg

FDAapproved for leukemias

NCCN Drugs & Biologics Compendium off-label use for leukemias

Current code price (AWP-based pricing), effective 11/1/09

Medicare allowable (ASP + 6%), effective 10/1/09-12/31/09

CPT administration codes

✓

$8.12

$5.72

96409

✓

$16.24

$11.44

96409

✓

$40.60

$28.59

96409

a When billing a nonclassified medication using a CMS 1500 claim form you must include both the HCPCS code (ie, J8999 for Tasigna) in Column 24D and the drug name, strength, and National Drug Code (NDC) in Box 19 in order to ensure appropriate reimbursement. References • HCPCS Level II Expert 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 4; RJ Health Systems International LLC; 4th Quarter 2009 • FDA-approved indication (from products’ prescribing information) • NCCN Drugs & Biologics Compendium; 2009; www.ReimbursementCodes.com powered by RJ Health Systems International, LLC, Wethersfield, Connecticut • CMS-Medicare allowable 4th Quarter 2009 (effective dates 10/1/09-12/31/09).

Prices listed herein are effective as of November 1, 2009. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare & Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network.

This information was supplied by:

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Recent FDA Approvals Folotyn for Relapsed or Refractory Peripheral T-cell Lymphoma The first single-agent therapy for relapsed or refractory peripheral T-cell lymphoma, pralatrexate injection (Folotyn, Allos Therapeutics), has been approved by the US Food and Drug Administration (FDA). The approval for this indication was based on overall response rate. At current, improvement in progression-free survival and overall survival has not been demonstrated. Additional clinical studies are ongoing to verify and describe the agent’s clinical benefits.

Cervarix Cervical Cancer Vaccine The FDA has approved a new human papillomavirus (HPV) bivalent (types 16 and 18) vaccine, recombinant (Cervarix, GlaxoSmithKline) for the prevention of cervical precancers and cervical cancer associated with oncogenic HPV types 16 and 18 for use in girls and young 22

women aged 10 to 15 years. The approval was based on a study that showed the vaccine to be 93% efficacious in the prevention of cervical precancers associated with HPV 16 and 18 in women without evidence of current infection or prior exposure to these types of HPV at time of vaccination.

Votrient for Advanced Renal Cell Carcinoma The FDA has approved the oral agent pazopanib (Votrient, GlaxoSmithKline) for treatment of advanced renal cell carcinoma. The agent, which interferes with angiogenesis, was approved based on a 435-patient study that examined progression-free survival (PFS). PFS averaged 9.2 months for patients who received the drug compared with 4.2 months for those who did not.

Elitek for Management of Plasma Uric Acid Levels The FDA has approved rasburicase

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(Elitek, sanofi-aventis US) for use in the initial management of plasma uric acid (PUA) levels in adults with leukemia, lymphoma, and solid tumor malignancies who are receiving anticancer therapy expected to result in tumor lysis syndrome and subsequent elevations of PUA. Approval was based on a phase 3 trial that demonstrated that rasburicase significantly reduced PUA levels compared with oral allopurinol (the current standard therapy).

Arzerra for Chronic Lymphocytic Leukemia The FDA has granted accelerated approval of ofatumumab (Arzerra, GlaxoSmithKline/Genmab) for use in patients with chronic lymphocytic leukemia (CLL) that is refractory to fludarabine and alemtuzumab. Approval was based on a study in which 42% of patients with treatment-refractory CLL responded to treatment with ofatumumab, a monoclonal antibody drug

targeting the CD20 protein on B cells. These patients had a median duration of response of 6.5 months. Common adverse events included neutropenia, pneumonia, pyrexia, cough, diarrhea, anemia, fatigue, dyspnea, rash, nausea, bronchitis, and upper respiratory tract infections.

Istodax for Cutaneous T-cell Lymphoma The FDA has approved romidepsin (Istodax, Gloucester Pharmaceuticals) for the treatment of cutaneous T-cell lymphoma in patients who have received at least one prior systemic therapy. Approval of the histone deacetylase inhibitor was based on efficacy data from two studies totaling 167 patients. The overall response rates, defined as the proportion of patients with confirmed complete response or partial response, were 34% and 35%. The complete response rate was 6% in both studies. n November/December 2009

No Link Found between Cancer and Bisphosphonate Use DENVER—There appears to be no relationship between the use of bisphosphonates and the development of cancer, according to researchers at Columbia University College of Physicians and Surgeons. A letter to the editor in the January 1, 2009, issue of the New England Journal of Medicine cited reports of esophageal cancer following treatment with alendronate as well as alendronate combined with other oral bisphosphonates. Since then, controversy has surrounded this issue. “There is no relationship between the use of bisphosphonates and esophageal cancer,” said John Bilezikian, MD, professor of medicine at Columbia University College of Physicians and Surgeons, New York. Bilezikian and his colleagues examined clinical and postmarketing data regarding risedronate. This agent has been studied in placebo-controlled phase 3 trials for up to 3 years and in more than 19,000 patients. Risedronate has also been studied in active-controlled studies with 4000 additional patients. Patients in the placebo-controlled studies were randomized to receive risedronate 2.5 mg daily (N = 4998), risedronate 5 mg daily (N = 5395), or placebo daily (N = 5363). The incidence of esophageal cancer in these risedronate studies was 0.04%, 0.02%, and 0.04%, respectively. Overall, the researchers found that the incidence rate for esophageal cancer was 19 per 100,000 patient-years of observation in placebo patients, 22 per 100,000 in the 2.5-mg daily patients, and 9 per 100,000 in the 5-mg daily patients. In the active-control studies, no cases of esophageal cancer were reported in prevention, flexible-dosing, male osteoporosis, or open-label extension studies. In postapproval surveillance from May 1998 to January 9, 2009, with more than 18 million patient-years of exposure, reported esophageal cancer coincident with risedronate use was very rare or less than 0.1 per 100,000 patientyears of exposure. “Many clinicians and their patients are confused about this issue,” said Bilezikian in an interview with the Journal of Multidisciplinary Cancer Care. “After the New England Journal report, patients started calling their physicians and saying ‘I am not going to take that medicine,’ but it wasn’t true and they were misled. We are now trying to make the point by using data to argue that the report was not well founded.” He said healthcare providers should reassure their patients that there is no link between bisphosphonate use and esophageal cancer. According to the National Cancer Institute Surveillance, Epidemiology and End Results database, the incidence of esophageal cancer in American men and women 65 years of age is 23.3 per 100,000 per year. In November/December 2009

Caucasian women 65 years of age, the incidence is 11.2 per 100,000 per year. Bilezikian said the incidence of esophageal cancer events observed among risedronate or placebo-treated patients was consistent with the background rates in the population.

David Prelutsky, MD, associate clinical professor of medicine at Washington University School of Medicine, St. Louis, Missouri, said that “this study is clinically relevant, as it reassures primary care physicians, who prescribe the bulk of bisphosphonates, that they are doing no harm.

No physician wants to prevent one problem and then possibly cause another with a treatment. These data are reassuring,” said Prelutsky in an interview with the Journal of Multidisciplinary Cancer Care. n —John Schieszer

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Breast Cancer BREAST CANCER

Studies Look at Factors that Influence CPM

ore women appear to be electing to undergo contralateral prophylactic mastectomy (CPM). These women tend to be younger, have a family history of breast cancer, and a woman as their surgeon, according to a review of women undergoing breast cancer surgery in Minnesota. The findings were released at the annual meeting of the American Society of Clinical Oncology. In other data released at the meeting, the results of genetic testing were found to influence the decision to undergo CPM, especially for white and Hispanic women. Using a retrospective chart review of all women who underwent breast cancer surgery in a single healthcare system (six hospitals) in Minneapolis-St. Paul in 2006 and 2007, Amanda K. Arrington, MD, and colleagues assessed the rates of CPM and identified the factors associated with it. Of the 571 patients eligible for the analysis, 276 (48.3%) underwent lumpectomy, 130 (22.8%) underwent unilateral mastectomy, and 165 (28.9%) underwent mastectomy and a CPM. Among the patients who had a mastectomy, 55.9% underwent CPM. The rate of CPM in this study was

markedly higher than the reported 4.5% to 13.5% rates in the recent Surveillance, Epidemiology and End Results study, noted Arrington, department of surgery, University of Minnesota, Minneapolis.

going CPM, 7.9% had BRCA testing. The study included three female surgeons, all of whom were younger than 50 years, and 20 male surgeons. Rates of CPM were twice as high (46.2% vs 23.1%) when the surgeon was a woman.

Independent predictors of CPM were younger age, larger tumors, positive family history, lobular histology, multicentric disease, and having a female surgeon. Independent predictors of CPM were younger age, larger tumors, positive family history, lobular histology, multicentric disease, and having a female surgeon. Almost half (46.2%) of patients younger than 40 years underwent CPM, compared with 13.2% of those older than 70 years. Fifty percent of the patients with tumors larger than 5 cm but only 23.9% with tumors smaller than 2 cm underwent CPM. Thirteen patients (2.3%) underwent BRCA testing and five were found to have BRCA mutations. All BRCA-tested patients chose CPM, regardless of the results. Of the 165 patients under-

There was a trend toward increased CPM rates with younger surgeon age. Patients may be more comfortable discussing their options with female surgeons, who are more likely to recommend CPM than their male counterparts, according to the researchers. In a separate analysis, differences in the rates of CPM by race were analyzed by a team of investigators at The University of Texas M. D. Anderson Cancer Center in Houston, led by Kaylene Ready, MS, a cancer genetic counselor. They conducted a retrospective chart review of 881 women with a personal

history of breast cancer who underwent genetic testing for the BRCA1 and BRCA2 genes. Among those with a positive result, 45% of whites, 33% of African Americans, and 50% of Hispanics underwent CPM; these differences were not statistically significant. Whites and Hispanics with positive results were significantly more likely than their counterparts with negative results to undergo CPM (whites, 45% vs 16%; P <.001; Hispanics, 50% vs 11%; P = .004). Thirty-three percent of African Americans with positive results and 14% with negative results underwent CPM, a nonsignificant trend (P = .10). In contrast to previous literature, a younger age at diagnosis was not associated with an increased rate of CPM among women with a BRCA1 or BRCA2 mutation, but younger age at diagnosis was associated with an increased rate of CPM among women who tested negative for the mutations. “This may be because a young age of diagnosis is a risk factor for hereditary cancer, even in the absence of an identifiable BRCA1 or BRCA2 mutation,” the authors speculated. n —Wayne Kuznar

Weekly Paclitaxel as Effective, Less Toxic than Docetaxel/Capecitabine

eekly paclitaxel is just as effective as docetaxel in combination with capecitabine on the outcomes of progression-free survival and disease-free survival (DFS) in women Aman U. Buzdar, MD with early-stage breast cancer, but paclitaxel is better tolerated, especially with respect to myelotoxicity, said Aman U. Buzdar, MD, professor of medicine, The University of Texas M. D. Anderson Cancer Center, Houston, at the annual meeting of the American Society of Clinical Oncology. The two therapies were compared as preoperative and adjuvant therapy in a study in which patients with operable T1 to T3 breast cancer and no evidence of metastatic disease were randomized to either paclitaxel (80 mg/m2) weekly for 12 weeks or to docetaxel 75 mg/m2 on day 1, and capecitabine 1500 mg/m2 daily for 14 days of each 3-week cycle, for a planned four cycles. After completing 12 weeks of ran24

domized therapy, all patients received chemotherapy with 5-fluorouracil (500 mg/m2), epirubicin (100 mg/m2), and cyclophosphamide (500 mg/m2). The primary end point was DFS, and the secondary end point in patients receiving preoperative therapy was pathologic complete response (pCR). “The study was initially designed to

A total of 601 patients were randomized to weekly paclitaxel (n = 304) or to docetaxel/capecitabine (n = 297). In the preoperative setting, 111 patients were treated with docetaxel/ capecitabine and 110 with weekly paclitaxel; after a median follow-up of 40 months, the pCR rates were 18.9% and 16.4%, respectively. “Breast preservation

“The study…was stopped after slightly more than [600] patients had been enrolled, because the predictive probability of concluding this study in favor of docetaxel and capecitabine…was extremely low.” accrue 930 patients but was stopped after slightly more than [600] patients had been enrolled, because the predictive probability of concluding this study in favor of docetaxel and capecitabine on DFS and pCR was extremely low,” noted Buzdar.

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rates were identical between the two groups,” Buzdar pointed out, and clinical remission rates were also similar. Of the patients, 190 patients who received docetaxel/capecitabine and 192 patients who received weekly paclitaxel had local therapy before study

entry and were evaluable. DFS was again nearly identical between the two treatment arms. Docetaxel/capecitabine was associated with a higher incidence of hand-foot syndrome and myelosuppression, Buzdar pointed out. Nearly half (46.8%) of the patients in the docetaxel/capecitabine group had grade 2 myalgias, and 10.9% had grade 3 myalgias, compared with 36.7% (grade 2) and 6.1% (grade 3) in the weekly paclitaxel group. Grade 2 hand-foot syndrome occurred in 24.6%, and grade 3 hand-foot syndrome occurred in 18.4% of patients receiving docetaxel/capecitabine compared with 1.7% (grade 2) and 0.3% (grade 3) of patients receiving weekly paclitaxel. Neurotoxicity was slightly more common in the group assigned to weekly paclitaxel. The study was closed in June 2008 due to futility. If the trial had continued as planned, the predictive probability of concluding in favor of the docetaxel/ capecitabine arm for DFS and pCR were .005 and .001, respectively, Buzdar said. n —WK November/December 2009

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Supportive Care SUPPORTIVE CARE

Systems Approach Can Improve Cancer Pain Management SAN DIEGO—A systems approach to pain and symptom management can boost the overall well-being of patients with cancer, according to Barbara A. Murphy, MD, a medical oncologist who Barbara A. Murphy, works with a multiMD disciplinary healthcare team to improve patients’ quality of life (QOL) and ensure coordinated care. Speaking at the Scripps Cancer Center’s 29th annual conference on clinical hematology and oncology, she said it is “a moral imperative” to alleviate suffering in cancer patients. Murphy is director of the Pain and Symptom Management Program, Cancer Supportive Care Program; director of the Head and Neck Research Program; associate professor of medicine (hematology/oncology) and VICC member, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee. She told the audience it would require planning on their part to launch an assertive, proactive communication program and to manage dose requirements of opioids.

Improving QOL The holistic program used in her practice is committed to improving the patients’ QOL by addressing not only their physical cancer issues, but their emotional and spiritual issues as well. “I’m not just talking about drugs,” she said. “Pain is a problem, and we have had the tools to deal with that part of the problem.” The purpose of Murphy’s oncology supportive care program, she said, is to: • Improve patients’ overall wellbeing and thus the QOL • Enhance symptom control and functional outcome • Modify health behaviors. The global construct, Murphy said, includes patients’ perceptions of wellbeing, as influenced by their experiences, points of view, expectations, and beliefs. She reminded clinicians that healthrelated issues are only one factor when considering QOL. Commonly assessed QOL domains include well-being on several fronts: physical, functional, social, emotional, spiritual, and financial. Patients underreport psychological distress Murphy said numerous studies use self-report questionnaires to conclude that cancer patients do not have a lower QOL than healthy people. Murphy quoted the work of Breetvelt2 who wrote about the so-called response shift: “Under the influence of a highly signif26

icant life event, such as getting a lifethreatening disease…there will be a concurrent change in the internalized standard on which the patient bases their perceptions.” In other words, patients in these studies were underreporting their psychological distress; on their own, they had made the decision to move the bar. Breetvelt warned that the true nature of cancer and the resulting decrease in QOL could be “obscured totally.” He said these “I’m OK” studies were in contrast with other research that documented the de rigueur experience of treating physicians, nurses, and other caretakers. He advised physicians not to put a lot of stock in questionnaires.

Education of patients, physicians, and their staffs: what works? Murphy said patient education can help overcome barriers to improved QOL. “But patient education by itself will not improve their outcome,” she said. Barrier reduction can have more of an effect on the outcome if it focuses on such end points as knowledge, attitudes, practice patterns, and pain control, but, in studies, it has not been sufficient by itself. “We hoped education would improve patient outcome, but you can change knowledge and attitude and

patient reporting of pain levels, an assessment titration communication, and the physician’s cooperation. Patients, she suggested, could keep a pain diary and a brief pain index. She noted her current investigation of a nurse-managed narcotic-titration drugorder sheet,4 as a way to improve pain control. This phase 3 study is sponsored by the National Cancer Institute.

Critical steps for adequate pain outcome Murphy listed the critical steps that should be considered for adequate pain outcome: 1. Patient report of pain (and medical staff recognition of problem) 2. Assessment of pain by the provider 3. Pain treatment plan 4. Review of plan with patient 5. Document assessment and plan 6. Patient follows treatment plan. To elucidate the critical steps in a specific plan, Murphy discussed a study by Cleeland and colleagues, who examined a computerized telephone monitoring and alert system (with an interactive voice-response system) that alerted clinic staff via e-mail when cancer patient pain levels exceeded a specified threshold.5 Telephone calls primarily reinforced the patient’s use of prescribed medication, provided information for the management of symptoms, or

A model for adequate pain control would include patient reporting of pain levels, an assessment titration communication, and the physician’s cooperation. that has not made a significant difference in the outcome,” said Murphy. A study by Wells and associates found that a pain education program could improve knowledge and beliefs of the patient and their primary caregiver, but that continued access to pain-related information did not affect long-term pain outcomes.3

Moving beyond education “We need to move beyond education—but where next?” asked Murphy. “More interventions are needed that can be easily adopted by clinicians in various settings.” She suggested a “pain hotline” where patients could communicate their pain to their providers. “This had been used in a postoperative setting where it was found to be effective, but when studied in the oncology setting, it was not.” Murphy suggested that a model for adequate pain control would include

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addressed the need for and arranged a change of medication. The researchers found that this method reduced symptom severity and lowered symptomrelated interference for the monitored group compared with the control group. “The e-mail alert would go to a nurse, and she could react; we found this phone call intervention worked really well,” said Murphy.

VHA study An earlier report by Cleeland and associates described a joint collaborative (Veterans Health Administration [VHA] and Institute for Healthcare Improvement) which used a rapid-cycle improvement model to improve pain management within the VHA Health System. Each patient–healthcare provider dyad worked within a system to affect a better outcome.6 The study’s goals were to improve delivery of pain management to VHA

patients and to compare team process and patient report data on key goals from selected study units; 70 teams from 22 Veteran’s Integrated Service Networks participated. Findings were that the number of patients experiencing moderate or severe pain on study units dropped from 24% to 17% while pain assessment increased from 75% to 85%; pain-care plans for patients with mild pain increased from 58% to 78%; and the number of patients provided pain education increased from 35% to 62%. “This study highlights the critical issue of patients needing a plan of care,” said Murphy.

IT could address complex problem Murphy said that combining electronic medical records with systems approach gives data at a glance. The two basic components of a systems approach—elements and processes—can be applied in the medical records setting. She explained it this way: In a car, the dashboard gives the driver a glimpse of all the information needed to make decisions while operating the vehicle. Dashboards in IT are essentially the same. “You can look at the display and say, ‘What am I doing well, or not well?’ It allows you to search databases and identify outcome issues at the patient level; the clinic level, and the provider level,” said Murphy, who pointed out that, based on the patient’s report of pain, the provider could match the level of pain to the regimen prescribed. She said that a lot of data could be organized with this system so that providers could offer adequate pain control for the many stakeholders. She added, “Pain control is complex, but using information systems and technology may hold the key to this complex problem.” n —Kristina Rebelo

References

1. Murphy BA, Gilbert J, Cmelak A, Ridner SH. Symptom control issues and supportive care of patients with head and neck cancers. Clin Adv Hematol Oncol. 2007;5:807-822. 2. Breetvelt IS, Van Dam FS. Underreporting by cancer patients: the case of response-shift. Soc Sci Med. 1991;32:981-987. 3. Wells N, Hepworth JT, Murphy BA, et al. Improving cancer pain management through patient and family education. J Pain Symptom Manage. 2003;25:344-356. 4. Kane MN, Hamlin ER 2nd, Hawkins WE. Measuring preparedness to address patient preferences at the end of life. Am J Hosp Palliat Care. 2004;21:267-274. 5. Cleeland CS, Vaporcian A, Shi Q, et al. A computerized telephone monitoring and alert system to reduce postoperative symptoms: a randomized trial. J Clin Oncol. 2008;26(15S): Abstract 9536. 6. Cleeland CS, Reyes-Gibby CC, Schall M, et al. Rapid improvement in pain management: the Veterans Health Administration and the institute for healthcare improvement collaborative. Clin J Pain. 2003;19:298-305.

November/December 2009

Concise Reviews of Studies Relevant to Cancer Care n Cost-effectiveness of HPV Vaccination in Women Aged Older Than 30 Years Background: The US Food and Drug Administration is considering approval of the human papillomavirus (HPV) vaccine for women older than 30 years. The cost-effectiveness of this strategy versus the current standards of cytology every 1 to 3 years with HPV DNA testing for triage of equivocal cytology results or HPV DNA testing in combination with cytology every 2 to 3 years is being scrutinized. Design: Using a first-order Monte Carlo simulation model of the natural history of HPV and cervical disease, as well as primary and secondary prevention interventions, the researchers synthesized data from clinical studies and controlled trials to reflect the performance of screening tests and the HPV vaccine. They evaluated the cost-effectiveness of vaccinating women of a particular age who had been participating in a specific screening strategy and would continue that strategy after vaccination. Outcome was measured in incremental cost-effectiveness ratios (2006 $US per quality-adjusted life-year [QALY]). Summary: Among women screened annually or biennially using cytology with HPV triage, the cost of adding vaccination ranged from $116,950 to $272,350 per QALY gained. Among women who switched to combined cytology and HPV DNA testing after age 30, the cost of adding vaccination ranged from $193,690 to $381,590 per QALY gained. In the context of current US screening patterns, the cost of adding vaccination exceeded $125,000 per QALY regardless of vaccination age or screening strategy. Takeaway: HPV vaccination of women older than 30 years who participate in a screening program does not provide good health value for the resources invested. Kim JJ, et al. Ann Intern Med. 2009; 151:538-545. n Effectiveness of Palliative Care Interventions for Patients with Advanced Cancer Background: Because there are only a few randomized controlled trials on the effectiveness of palliative care interventions, the effect of nursing-led intervention on quality of life, symptom intensity, mood, and resource use in patients with advanced cancer was studied. Design: In a randomized controlled clinical trial conducted from November 2003 through May 2008 in a rural National Cancer Institute–designated comprehensive cancer center, and affiliated outreach clinics advanced practice nurses performed multicomponent, psychoeducational interventions with 322 patients with advanced cancer. Inventions consisted of four weekly educational sessions and monthly follow-up sessions until death or study completion (n = 161). The control group received usual care (n = 161). November/December 2009

Patients had gastrointestinal tract (41%), lung (36%), genitourinary tract (12%), and breast (10%) cancers. Outcomes were measured at baseline, 1 month, and every 3 months thereafter. Summary: The estimated treatment effects (intervention minus usual care) for all participants were a mean (standard error [SE]) of 4.6 (2) for quality of life (P = .02), -27.8 (15) for symptom intensity (P = .06), and -1.8 (0.81) for

depressed mood (P = .02). The estimated treatment effects in participants who died during the study were a mean (SE) of 8.6 (3.6) for quality of life (P = .02), -24.2 (20.5) for symptom intensity (P = .24), and -2.7 (1.2) for depressed mood (P = .03). Intensity of service (number of days in hospital or intensive care unit, number of emergency department visits, anticancer treatment) did not differ between the groups.

GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION BRIEF SUMMARY (OVARIAN). For complete safety please consult the package insert for complete prescribing information. INDICATION AND USAGE: THERAPEUTIC INDICATION—Ovarian Cancer—Gemzar in combination with carboplatin is indicated for the treatment of patients with advanced ovarian cancer that has relapsed at least 6 months after completion of platinum-based therapy. CLINICAL STUDIES: Ovarian Cancer—Gemzar was studied in a randomized Phase 3 study of 356 patients with advanced ovarian cancer that had relapsed at least 6 months after first-line platinum-based therapy. Patients were randomized to receive either Gemzar 1000 mg/m2 on Days 1 and 8 of a 21-day cycle and carboplatin AUC 4 administered after Gemzar on Day 1 of each cycle or single-agent carboplatin AUC 5 administered on Day 1 of each 21-day cycle as the control arm. The primary endpoint of this study was progression free survival (PFS). The addition of Gemzar to carboplatin resulted in statistically significant improvement in PFS and overall response rate. Approximately 75% of patients in each arm received poststudy chemotherapy. Only 13 of 120 patients with documented poststudy chemotherapy regimen in the carboplatin arm received Gemzar after progression. There was not a significant difference in overall survival between arms. CONTRAINDICATION: Gemzar is contraindicated in those patients with a known hypersensitivity to the drug (see Allergic under ADVERSE REACTIONS). WARNINGS: Caution—Prolongation of the infusion time beyond 60 minutes and more frequent than weekly dosing have been shown to increase toxicity (see CLINICAL STUDIES in the full Prescribing Information). Hematology—Gemzar can suppress bone marrow function as manifested by leukopenia, thrombocytopenia, and anemia (see ADVERSE REACTIONS), and myelosuppression is usually the dose-limiting toxicity. Patients should be monitored for myelosuppression during therapy. See DOSAGE AND ADMINISTRATION in the full Prescribing Information for recommended dose adjustments. Pulmonary—Pulmonary toxicity has been reported with the use of Gemzar. In cases of severe lung toxicity, Gemzar therapy should be discontinued immediately and appropriate supportive care measures instituted (see Pulmonary under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Renal—Hemolytic Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS (see Renal under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Hepatic—Serious hepatotoxicity, including liver failure and death, has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs (see Hepatic under Single-Agent Use and under Post-marketing experience in ADVERSE REACTIONS in the full Prescribing Information). Pregnancy—Pregnancy Category D. Gemzar can cause fetal harm when administered to a pregnant woman. Gemcitabine is embryotoxic causing fetal malformations (cleft palate, incomplete ossification) at doses of 1.5 mg/kg/day in mice (about 1/200 the recommended human dose on a mg/m2 basis). Gemcitabine is fetotoxic causing fetal malformations (fused pulmonary artery, absence of gall bladder) at doses of 0.1 mg/kg/day in rabbits (about 1/600 the recommended human dose on a mg/m2 basis). Embryotoxicity was characterized by decreased fetal viability, reduced live litter sizes, and developmental delays. There are no studies of Gemzar in pregnant women. If Gemzar is used during pregnancy, or if the patient becomes pregnant while taking Gemzar, the patient should be apprised of the potential hazard to the fetus. PRECAUTIONS: General—Patients receiving therapy with Gemzar should be monitored closely by a physician experienced in the use of cancer chemotherapeutic agents. Most adverse events are reversible and do not need to result in discontinuation, although doses may need to be withheld or reduced. There was a greater tendency in women, especially older women, not to proceed to the next cycle. Laboratory Tests—Patients receiving Gemzar should be monitored prior to each dose with a complete blood count (CBC), including differential and platelet count. Suspension or modification of therapy should be considered when marrow suppression is detected (see DOSAGE AND ADMINISTRATION in the full Prescribing Information). Laboratory evaluation of renal and hepatic function should be performed prior to initiation of therapy and periodically thereafter (see WARNINGS). Carcinogenesis, Mutagenesis, Impairment of Fertility—Long-term animal studies to evaluate the carcinogenic potential of Gemzar have not been conducted. Gemcitabine induced forward mutations in vitro in a mouse lymphoma (L5178Y) assay and was clastogenic in an in vivo mouse micronucleus assay. Gemcitabine was negative when tested using the Ames, in vivo sister chromatid exchange, and in vitro chromosomal aberration assays, and did not cause unscheduled DNA synthesis in vitro. Gemcitabine IP doses of 0.5 mg/kg/day (about 1/700 the human dose on a mg/m2 basis) in male mice had an effect on fertility with moderate to severe hypospermatogenesis, decreased fertility, and decreased implantations. In female mice, fertility was not affected but maternal toxicities were observed at 1.5 mg/kg/day IV (about 1/200 the human dose on a mg/m2 basis) and fetotoxicity or embryolethality was observed at 0.25 mg/kg/day IV (about 1/1300 the human dose on a mg/m2 basis). Pregnancy—Category D. See WARNINGS. Nursing Mothers—It is not known whether Gemzar or its metabolites are excreted in human milk. Because many drugs are excreted in human milk and because of the potential for serious adverse reactions from Gemzar in nursing infants, the mother should be warned and 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 and the potential risk to the infant. Elderly Patients—Gemzar clearance is affected by age (see CLINICAL PHARMACOLOGY in the full Prescribing Information). There is no evidence, however, that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in patients over 65, and in general, adverse reaction rates in the single-agent safety database of 979 patients were similar in patients above and below 65. Grade 3/4 thrombocytopenia was more common in the elderly. Gender—Gemzar clearance is affected by gender (see CLINICAL PHARMACOLOGY in the full Prescribing Information). In the single-agent safety database (N=979 patients), however, there is no evidence that unusual dose adjustments (i.e., other than those already recommended in DOSAGE AND ADMINISTRATION section in the full Prescribing Information) are necessary in women. In general, in single-agent studies of Gemzar, adverse reaction rates were similar in men and women, but women, especially older women, were more likely not to proceed to a subsequent cycle and to experience Grade 3/4 neutropenia and thrombocytopenia. Pediatric Patients—The effectiveness of Gemzar in pediatric patients has not been demonstrated. Gemzar was evaluated in a Phase 1 trial in pediatric patients with refractory leukemia and determined that the maximum tolerated dose was 10 mg/m2/min for 360 minutes three times weekly followed by a one-week rest period. Gemzar was also evaluated in a Phase 2 trial in patients with relapsed acute lymphoblastic leukemia (22 patients) and acute myelogenous leukemia (10 patients) using 10 mg/m2/min for 360 minutes three times weekly followed by a one week rest period. Toxicities observed included bone marrow suppression, febrile neutropenia, elevation of serum transaminases, nausea, and rash/desquamation, which were similar to those reported in adults. No meaningful clinical activity was observed in this Phase 2 trial. Patients with Renal or Hepatic Impairment—Gemzar should be used with caution in patients with preexisting renal impairment or hepatic insufficiency as there is insufficient information from clinical studies to allow clear dose recommendation for these patient populations. Administration of Gemzar in patients with concurrent liver metastases or a preexisting medical history of hepatitis, alcoholism, or liver cirrhosis may lead to exacerbation of the underlying hepatic insufficiency. GEMZAR姞 (GEMCITABINE HCl) FOR INJECTION

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Takeaway: The integration of a nurse-led palliative care intervention concurrent with anticancer treatment demonstrated a higher quality of life and lower depressed mood among patients with advanced cancer. The interventions did not, however, improve symptom intensity scores or lower resource use. Bakitas M, et al. JAMA. 2009; 302:741-749. n

Drug Interactions—No specific drug interaction studies have been conducted. For information on the pharmacokinetics of Gemzar and cisplatin in combination, see Drug Interactions under CLINICAL PHARMACOLOGY. Radiation Therapy—A pattern of tissue injury typically associated with radiation toxicity has been reported in association with concurrent and non-concurrent use of Gemzar. Non-concurrent (given >7 days apart)—Analysis of the data does not indicate enhanced toxicity when Gemzar is administered more than 7 days before or after radiation, other than radiation recall. Data suggest that Gemzar can be started after the acute effects of radiation have resolved or at least one week after radiation. Concurrent (given together or ≤7 days apart)—Preclinical and clinical studies have shown that Gemzar has radiosensitizing activity. Toxicity associated with this multimodality therapy is dependent on many different factors, including dose of Gemzar, frequency of Gemzar administration, dose of radiation, radiotherapy planning technique, the target tissue, and target volume. In a single trial, where Gemzar at a dose of 1000 mg/m2 was administered concurrently for up to 6 consecutive weeks with therapeutic thoracic radiation to patients with non-small cell lung cancer, significant toxicity in the form of severe, and potentially life-threatening mucositis, especially esophagitis and pneumonitis was observed, particularly in patients receiving large volumes of radiotherapy [median treatment volumes 4795 cm3]. Subsequent studies have been reported and suggest that Gemzar administered at lower doses with concurrent radiotherapy has predictable and less severe toxicity. However, the optimum regimen for safe administration of Gemzar with therapeutic doses of radiation has not yet been determined in all tumor types. ADVERSE REACTIONS: Combination Use in Ovarian Cancer—In the Gemzar plus carboplatin versus carboplatin study, dose reductions occurred with 10.4% of Gemzar injections and 1.8% of carboplatin injections on the combination arm, versus 3.8% on the carboplatin alone arm. On the combination arm, 13.7% of Gemzar doses were omitted and 0.2% of carboplatin doses were omitted, compared to 0% of carboplatin doses on the carboplatin alone arm. There were no differences in discontinuations due to adverse events between arms (10.9% versus 9.8%, respectively). Table 1 presents the adverse events (all grades) occurring in ≥10% of patients in the ovarian cancer study. Table 1: Adverse Events From Comparative Trial of Gemzar Plus Carboplatin Versus Single-Agent Carboplatin in Ovarian Cancera CTC Grades (% incidence) Gemzar plus Carboplatin (N=175) Carboplatin (N=174) All Grades Grade 3 Grade 4 All Grades Grade 3 Grade 4 Laboratory b Hematologic Neutropenia 90 42 29 58 11 1 Anemia 86 22 6 75 9 2 Leukopenia 86 48 5 70 6 <1 Thrombocytopenia 78 30 5 57 10 1 38 15 RBC Transfusions c c 9 3 Platelet Transfusions Non-laboratory b Nausea 69 6 0 61 3 0 Alopecia 49 0 0 17 0 0 Vomiting 46 6 0 36 2 <1 Constipation 42 6 1 37 3 0 Fatigue 40 3 <1 32 5 0 Neuropathy-sensory 29 1 0 27 2 0 Diarrhea 25 3 0 14 <1 0 Stomatitis/pharyngitis 22 <1 0 13 0 0 Anorexia 16 1 0 13 0 0 a Grade based on Common Toxicity Criteria (CTC) Version 2.0 (all grades ≥10%). b Regardless of causality. c Percent of patients receiving transfusions. Transfusions are not CTC-graded events. Blood transfusions included both packed red blood cells and whole blood. In addition to blood product transfusions as listed in Table 1, myelosuppression was also managed with hematopoetic agents. These agents were administered more frequently with combination therapy than with monotherapy (granulocyte growth factors: 23.6% and 10.1%, respectively; erythropoetic agents: 7.3% and 3.9%, respectively). The following are the clinically relevant adverse events, regardless of causality, that occurred in >1% and <10% (all grades) of patients on either arm. In parentheses are the incidences of Grade 3 and 4 adverse events (Gemzar plus carboplatin versus carboplatin): AST or ALT elevation (0 versus 1.2%), dyspnea (3.4% versus 2.9%), febrile neutropenia (1.1% versus 0), hemorrhagic event (2.3% versus 1.1%), hypersensitivity reaction (2.3% versus 2.9%), motor neuropathy (1.1% versus 0.6%), and rash/desquamation (0.6% versus 0). No differences in the incidence of laboratory and non-laboratory events were observed in patients 65 years or older, as compared to patients younger than 65. Post-marketing experience—The following adverse events have been identified during post-approval use of Gemzar. These events have occurred after Gemzar single-agent use and Gemzar in combination with other cytotoxic agents. Decisions to include these events are based on the seriousness of the event, frequency of reporting, or potential causal connection to Gemzar. Cardiovascular—Congestive heart failure and myocardial infarction have been reported very rarely with the use of Gemzar. Arrhythmias, predominantly supraventricular in nature, have been reported very rarely. Vascular Disorders—Clinical signs of peripheral vasculitis and gangrene have been reported very rarely. Skin—Cellulitis and non-serious injection site reactions in the absence of extravasation have been rarely reported. Severe skin reactions, including desquamation and bullous skin eruptions, have been reported very rarely. Hepatic—Increased liver function tests including elevations in aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transferase (GGT), alkaline phosphatase, and bilirubin levels have been reported rarely. Serious hepatotoxicity including liver failure and death has been reported very rarely in patients receiving Gemzar alone or in combination with other potentially hepatotoxic drugs. Pulmonary—Parenchymal toxicity, including interstitial pneumonitis, pulmonary fibrosis, pulmonary edema, and adult respiratory distress syndrome (ARDS), has been reported rarely following one or more doses of Gemzar administered to patients with various malignancies. Some patients experienced the onset of pulmonary symptoms up to 2 weeks after the last Gemzar dose. Respiratory failure and death occurred very rarely in some patients despite discontinuation of therapy. Renal—Hemolytic-Uremic Syndrome (HUS) and/or renal failure have been reported following one or more doses of Gemzar. Renal failure leading to death or requiring dialysis, despite discontinuation of therapy, has been rarely reported. The majority of the cases of renal failure leading to death were due to HUS. Injury, Poisoning, and Procedural Complications — Radiation recall reactions have been reported (see Radiation Therapy under PRECAUTIONS). Dosage and administration: Gemzar is for intravenous use only. Please consult full prescribing information for complete dosage and administration guidelines.

Literature revised May 7, 2007 PV 4067 AMP

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IN THE LITERATURE

In the Literature

GEMZAR/carboplatin is one option for 2nd-line treatment of your patients with platinum-sensitive* advanced ovarian cancer. Myelosuppression is usually the dose-limiting toxicity with GEMZAR therapy.

G MZ GE ZAR AR iin n cco om mb bin nat atio ion wi with t car th arbo bo b opl p attin n is in ndi d ca c te ed fo for or th t e tr t eaatm t en e t of o pattie ient nsw nt wiith th adv d an a ced ce ed o ovvar aria ian n caanc n er e tha h t has haas rre elaapsed psed ps d aatt le easst 6 mo m ntth hss aft fter er er comp co m le mp eti t on o of p pllat atin inum in u -b um -bas baasse ed d the eraapyy. My M ye ellossu up p ppr p essssiion pr on is us usua ua allly th he do ose se-l -lim -l im mittin ng to oxi x ciitty y wit ith h GEMZ GEMZ GE M AR A th he era rapy py py. y.

Overall response rate (%)†

Median progression-free survival (months) GEMZAR plus Carboplatin

95% Cl (8.0-9.7) (N=178)

Carboplatin 95% Cl (5.2-7.1) (N=178)

(p=0.0038)

GEMZAR plus Carboplatin (N=178)

8.6

Carboplatin (N=178)

5.8 6

(p=0.0016)

10%

47.2%

30.9% 20%

30%

40%

50%

* Pl Plat a in at num m-s -sen en nsiti siitive tivee ti †

pat a ie ient nts ar nt aree de defi fine ine ned d as pat a ie i ntts wh w o deve deveelo de lop di lop dise sease se asse pr prog oggre ress s ioon ≥6 m ss moont n hs h aft f er er rec ecei eivi ei viingg firrst st-l -lin -l inee p in pllat a in inum um-b um -bas asseed d che h mo m th ther erap er ap apy. py. Inve In veest stig iggat ator or-rrev or evie vie iewe wd we d..

The Th eo ovverralll su surv r iv rv ival a dif al iffe f rre fe enc n e be b tw wee een G GE EM EMZ MZ ZAR A /c /car a bo ar opl p attin ((18 18 8.0 mon nths) th hs) vs ca carb bop oplaattiin (1 opla ( 7. 7 3 mo mont nths nt nths hs)) wa was no ot si s gn g if i iccan nt (p=0 0.8 897 977) 7. 7) Se S ele ecctt IImp mp m por ortta an ntt Saffet ety y In nfo orm matio attio on GEMZ GE M AR MZ R ssho houl ho u d no ul not be b adm dmin inis in isste tere re red ed tto o pat a iie en ntts wi with th h kno nown wn nh hyp yper yp per e se s ns n itiv ittiv ivit itty tto o thi hs drrug. ug g. Infu In nfu usiion n times im mes es of GE GEMZ MZ ZAR A lon onge ge er th than an n 60 mi m nu nute t s an te nd mo more e fre requ qu q ue en n ntt th han week we e lyy dos ek osin ing in g ha ave e bee een n sh s ow wn to o in nccre reas asse to oxi xici c tyy. P ci Pu ulm lmon on nar aryy to oxxiiciityy has a be ee en en re epo port rted rt e . In casses ed e of se eve ere e lun u g to t xi xici c ty ci ty,, GE EMZ M AR AR the h ra apyy ssho houl ho uld ul d be b dis i co cont cont n in nu ue ed im mme medi d attel eya an nd ap ppr p op opri riiatte ssu upp por orti t ve ti e ccar arre m me eas asur u ess iins ur nssti n t tu ute ed. d Hem e ol o yytticc U em Ur micc Syndr yn ndrrom ome e (H HUS US)) an a d d//or o re en nal ffai aiilu l rre e havve be een n rrep epo epor ep orrte ted d ffo olllow o in ng on one e or mo ore ed dos o es os es of GEMZ GEMZ GE MZAR AR A R. Re R na n l fa f ililur ure ur e le ead din i g to o dea dea eath th h or re equ quir uir i in ng di d al a ys y is is,, de desp spit ie it d sccon di nti t nu nuat a iio at on of o tthe he h era apyy, ha h s be been e rarrel en e y re epo p rt rted e . Th ed he ma m jo jori r ty of th ri the e ca ase es of o r nal re na al fa f illur u e le lead ad ding in ng to o dea eath t wer ere e du due e to t HUS US.. Se eri r ou o s he h pa atto oto oxi x ci city ityy, in incllud udin din ing g lilive v r fa ve faililiurre a an nd de eat ah h,, has bee e n re r po p rt rted d vver eryy ra er are elyy in p pa ati te en nts ts rrec e eiivi ec ving ng g GEM MZA AR allon one or o in co c mb mbin in na attio on wi with tth h oth ther ther e potten nti t al a lyy h hep e at ep atot otoxxicc drru ug gss. GE EMZ M AR R is Prreg P e n na anc ncyy C Ca ate t go g ryy D. GE G MZ ZAR A can n cau usse e fet e al a ha arrm rm wh when n admin dmin dm nisste ere red d to to a pr p eg gna nant nt wom oman a . Use an Usse ca c ut u io ion n in pat pat atie ie ient entts wi with h pre re-e - xist -e xiissttin ing g re en na al impa im mpa air irme m n me ntt or hep e atticc iins n uffffiici ns c en ncyy. Ad A mi mini nisttra ni attiion n of GE EMZ MZAR AR A R may a exa acerb ce erb bat ate e un u d de erl r yi ying ng g he epa pati ticc in nsu uff f ic icie ienc ie n y. y T The h opt he p im i um u reg egim men n for saf afe e ad dmi m ni nist s ra st ati to on n of of GE EMZ MZAR A AR wiith the w the era r pe p ut utic iicc doses osess of ra os radi diat attio on ha as no nott ye et be been e det en ee errmine miin ne ed in n all tum u or ttyp yp pes e . G MZ GE ZAR R hass rrad adio ad io ose ens nsit itiz it izzin ng a accti t vi v ty ty a and nd d ra ad dia iati tion ti on n re eccal all re reac acti ac t on ti ns ha ave v bee een n repo re po p ort rted ed d. It iiss not no ot kn know ow o wn wh whet e he et h r GE GEMZ MZA AR R or itts meta me eta abo b liite es ar are e exxcrret e ed e in GEMZ G E AR AR® iss a rregistered gist s ere st ered e d tra t dema m rk ma k of E Eli Li L lly lyy and an n C Comp ompany om any. nyy GC58321 GC58 GC5 3 321 0509 PRIN 0509 NTED IN USA S © 200 09, Lilly USA USA, L LLC C. ALL RIGHT HT TS RE R SE SERV ER ED. ERV ED

human hu ma an mi m lk lk.. Th T e ef effe fect fe cttiivven e esss off G GEM EMZA EM ZA AR in in ped dia atrric ic pat a ie ent ntss h ha as n no ot be been e en de d emo on nsstrat trrat a ed ed.. Th T e to toxi xici xi citi ci t es ti e of GE G MZ MZAR A obsser erve v d in ve n ped e ia iatr ttrric pattie entts we were re e sim millar a to tho osse e rep epor orte or t d in te i adu d ltts. GEM MZA ZAR cl c eara ea ara ranc ncce is i aff ffec e te ec ed by b age g as we elll as gend ge end nder err. Pa ati t en nts reccei e viing g tthe he era r py py wit ith GE GEM MZ ZAR AR sho houl oul uld d be be mo on nit i or o ed clo lose osse elyy b byy a ph hys ysic icia ia an exp ex pe erriien ence ce ed in the eu use sse e of ca c nc ncer e cche er he emo moth her erap ap peu e ttiic ag agen ents en nts ts.. Ab bb brrev e ia ate ed Ad Adve Adve vers rsse Ev ven e ts t (% in ncciide enc nce e)) The most Th mo ostt sev e er e e ad adve vve ers rse e evve en nts t (Gr G ad des 3//4 4) wi w th h GEM MZA AR pl p us u car a bo op pllat atin in n ver ersu suss su cca arbop rb bopla opla op atin tin a ti allon one, e rres e, esspe ecttiv ivel e y, ffor el or the he tre eattm me ent n of pa pati tiien e ts wit ith ha ad dvva anc n ed d ovari va ari r an a c nc ca ncer er werre ne er euttro op pe eniia (7 71 vs v 12) 2));; th hro romb mb m boc o yt ytop open op e ia ia (35 3 vs 11 1); leu uko ope p ni n a (5 53 vss 7); a em an e ia a ((28 28 vs 11 28 1);; nau use ea (6 vs 3 3)); vo vomi m ti mi t ng g ((6 6 vs v 3 3); );; and nd const onst on stip ip ipat pat a io i n (7 7 vs 3) 3).. Th The e mo most stt comm co mm m mon na adv d er dv erse se e eve v nt ntss (a (alll Gra ade es) we erre ne neut u ro ut ope peni n a (9 90 vs v 5 58) 8);; leuk 8) leuk le u op open pen enia ia ((86 8 vs 7 86 70 0); ) an nem mia a (86 6 vs 75 7 ); thr h om mbo ocy cyto yto tope peniia (7 peni pe 78 vs v 57)); R RB BC trran nsf sfus u io us on (3 38 vs vs 15) 5 ; al a op o eccia a (4 49 vs vs 1 17) 7)); ne neur urrop opat atth a hyy/s /sen e sory en soryy (2 so 29 9 vs 27 7));; nau ause se ea (6 (69 9 vs 61) 1);; fa fati t gue ti gu ue (4 40 vs v 32)); vo omi m ting tiing (4 46 vs v 36)); di d ar a rhea rh hea a ((25 25 5 vs 14 4); ); and n con onst s ip st i a attio on (4 42 vss 37) 7).. Fo F or ad a di diti tion ti on nal a saf a etty in info ffo ormat rmat rm atio ion, n, pleas le ea asse se see e Br B iie ef Su S mm mmar a y of ar of Pre esc s ri r biing g IIn nfo form rm ma attion io on on o adj d ac a e en nt p pa age ge.. Fo or mo ore r iinf nffor n orma m ti ma to on n abo b utt can ance cerr tr ce trea ea e atm me en nt wi witth h GEM E ZA AR, vis isit itt GE G MZ ZAR AR.c .cco om m.