May/June 2009, Vol 2, No 3 by Green Hill Healthcare Communications, LLC

BUSINESS Are You Getting the Most from Your KRAS Testing? An interview with Christopher Ung, MSc, MBA

page 13 Visit us at www.jomcc.com

To R da eg w y is w fo te w r r .c Yo oe ur xm .c om

M Se ul co tip nd le a M nn A Review by Deena Damsky Dell, ye ua MSN, RN-C, AOCN lo l C m o a ns page 24 ne id w er sle at tt ion May/June 2009 • Volume 2 • Number 3 er s se in rie s. CLINICAL Recent Advances in the Treatment of Colorectal Cancer

der in t a e L The ursemen r Reimb pdates fo U Code mmunity Co logists Onco

In This Issue Clinical Colon and Rectal Cancers NCCN Guideline Updates Deborah Brauser

Treatment of Metastatic Colon Cancer: A Multidisciplinary Approach Roseleen Charania, MD; Shubham Pant, MD; Susie Morgal, RN, MS, AOCNS; Emily Borders, PharmD

Business New ACCC President Seeks to Shine a Light on Oncology Workforce Shortage An interview with Luana Lamkin, RN, MPH

Medications Used for the Treatment of Colorectal Cancer ICD-9-CM and J-codes, with FDA- and Compendia-approved uses and AWP-based and ASP + 6% pricing

Health Economics Updates from the Academy of Managed Care Pharmacy 21st Annual Meeting and Showcase: April 15-18, 2009

Illustration courtesy of the American Society of Clinical Oncology.

page 12

A CME/CE-Certified Regional Workshop 8:30 AM—9:00 AM Registration/Breakfast • 9:00 AM—11:00 AM Scientific Session Visit www.veritasime.com and enter CML9 to find the Regional Workshop nearest you. Look for an On-Demand Workshop with highlights from the Regional Workshops, available online in August 2009.

Chair

Nurse Contributor

Intended Audience

Jerald P. Radich, MD Associate Professor, Medicine and Oncology University of Washington Clinical Research Division Fred Hutchinson Cancer Research Center Seattle, Washington

Mary Beth Rios, RN Research Nurse Manager, Leukemia University of Texas M.D. Anderson Cancer Center Houston, Texas

Hematologists, hematologist/oncologists, medical oncologists, oncology nurses, nurse practitioners, and physician assistants who treat patients with chronic myeloid leukemia

Distinguished Faculty Daniel J. DeAngelo, MD, PhD Associate Professor, Medicine Harvard Medical School Clinical Director, Adult Leukemia Program Medical Oncology Dana-Farber Cancer Institute Boston, Massachusetts

B. Douglas Smith, MD Associate Professor, Oncology The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins Baltimore, Maryland

Statement of Need The progression of new therapies for patients with chronic myeloid leukemia (CML) from the bench to bedside has been rapid, in parallel with the swift advances in molecular biology. The impact of molecular biology on the diagnosis, monitoring, and treatment strategies for CML has also been substantial. Although community clinicians have access to a number of CME/CE activities regarding available treatments and the associated clinical data, a need remains for education regarding the correlation of molecular response with the well-understood hematologic and cytogenetic response. Community clinicians need to understand molecular response, its association with residual disease, how it is measured, and the interpretation and application of molecular tests. Although the technologies, facilities, and educators to address these issues are readily available at most academic medical centers, they are not within reach of most community oncologists and their staffs. Utilizing a true workshop format, these regional meetings will combine the presentation of actual clinical situations (illustrated by the faculty presenter) with an in-depth inquiry and interactive discussion related to critical decisions. Finally, community clinicians—physicians, nurses, nurse practitioners, and physician assistants— will have access to the hands-on education they need regarding the basis for and evidence supporting recent guidelines and recommendations concerning the monitoring of molecular response to available therapies.

Accreditation/Designation of Credit Statements Veritas Institute for Medical Education, Inc. is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. Veritas Institute for Medical Education, Inc. designates this educational activity for a maximum of 2.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

Nurse Practitioners Veritas Institute for Medical Education, Inc. approved as a provider for nurse practitioner continuing education by the American Academy of Nurse Practitioners: AANP Provider Number 040309. This program has been approved for 2.0 contact hours of continuing education (which includes 2.0 hours of pharmacology).

Nurses Veritas Institute for Medical Education, Inc. approved by the California Board of Registered Nursing, Provider #13986 for 2.0 Contact Hours. Please visit our Web site at: www.veritasime.com and enter code CML9 to find a location workshop near you.

Financial and Unlabeled Use Disclosures The relevant financial relationships of those persons in a position to control the content of this CME/CE activity will be disclosed prior to the start of the educational activity. Participants are advised that this CME/CE activity will contain references to unlabeled/ unapproved/investigational uses of drugs to treat ADHD.

Sponsorship and Support Sponsored by Veritas Institute for Medical Education, Inc. Supported by educational grants from Bristol-Myers Squibb and Novartis Oncology, with additional support from MolecularMD.

Learning Objectives

THERE IS NO FEE FOR THIS ACTIVITY.

• You will assess the methodologies used for monitoring response and evaluate the relationship between cytogenetic response, molecular response, and residual disease.

HOW TO REGISTER

• You will evaluate the prognostic significance of the timing, depth, and stability of molecular response and be better able to use molecular monitoring results in guiding management decisions. • You will be able to explain molecular response results in relation to the development of resistance-conferring mutations and disease progression, validating the role of frequent molecular testing in guiding management decisions. • In light of updated recommendations and guidelines, you will be able to implement frequent molecular monitoring into your practice.

BY PHONE: Call (877) 225-2927. ONLINE: Visit www.veritasime.com, and enter code CML9.

Americans With Disabilities Act On-site event staff will be glad to assist you with any special needs. To make arrangements in advance, please contact Rachel Moss, Veritas Institute for Medical Education, Inc., (201) 727-1115, ext. 2346.

TABLE OF CONTENTS A Letter From the Editor 5 Scientific Advances and the Prospective Case Presentation Mark J. Krasna, MD

Clinical 10

Preventing Skin Toxicity from EGFR Inhibitors Caroline Helwick

Colon and Rectal Cancers NCCN Guideline Updates Deborah Brauser

ASCO Recommends KRAS Testing to Predict Colorectal Cancer Response to Anti-EGFR Therapy

Coriell Institute Makes the Genome Personally Useful

pg 7

Daniel M. Keller Illustration courtesy of the American Society of Clinical Oncology.

Coriell Institute Aims to Give Patients “Actionable Information” From Their Genomes Daniel M. Keller

Publisher Philip Pawelko phil@greenhillhc.com Editorial Director Karen Rosenberg karen@greenhillhc.com Managing Editor Dawn Lagrosa Directors, Client Services John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com Cristopher Pires cris@greenhillhc.com Production Manager Marie RS Borrelli Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrators Thiel Hennessy Lisa Russo

John Schieszer

Journal of Multidisciplinary Cancer Care is a forum that provides oncologists, nurses, pharmacists, and their respective cancer care team members insights into the diverse aspects of oncology management. As an authoritative resource on the clinical, business, and regulatory changes affecting the oncology care community, this journal offers expert analysis of the dynamic nature and practical implications of current treatment, legislative, and reimbursement issues in the field.

Treatment of Metastatic Colon Cancer: A Multidisciplinary Approach Roseleen Charania, MD; Shubham Pant, MD; Susie Morgal, RN, MS, AOCNS; Emily Borders, PharmD

Recent Advances in the Treatment of Colorectal Cancer Deena Damsky Dell, MSN, RN-C, AOCN

pg 8

Colorectal Cancer Drugs in Phase 3 and 4 Trials in the United States

Business 9

Multidisciplinary Program Facilitates Care for Upper GI Cancers Caroline Helwick

New ACCC President Seeks to Shine a Light on Oncology Workforce Shortage An interview with Luana Lamkin, RN, MPH

Are You Getting the Most from Your KRAS Testing? An interview with Christopher Ung, MSc, MBA

29 Mission Statement

Folic Acid Fortification May Be Associated with Heighten Colon Cancer Risk Orlando/Orange County Convention & Visitors Bureau, Inc.®.

Medications Used for the Treatment of Colorectal Cancer

Health Economics 8 Health Economic Updates from the Academy of Managed Care

pg 15

Pharmacy 21st Annual Meeting and Showcase: April 15-18, 2009

Reimbursement Support Information for Colorectal Cancer Drugs

Departments 6 News Notes 7 In the Literature

Journal of Multidisciplinary Cancer Care

CLL First-line Therapy Trial Currently Recruiting Investigators

The ORIGINSM Trial CC-5013-CLL-008: A Phase 3, Multicenter, Randomized, Open-label, Parallel-group Study of the Efficacy and Safety of Lenalidomide Versus Chlorambucil as First-line Therapy for Previously Untreated Elderly Patients With B-cell Chronic Lymphocytic Leukemia Objective • To compare the efficacy and safety of oral lenalidomide versus oral chlorambucil as first-line therapy in elderly subjects with B-cell CLL Study Design • Approximately 428 subjects will be enrolled and randomized to receive either oral lenalidomide or oral chlorambucil

Key Inclusion Criteria* • Documented diagnosis of B-cell CLL • No prior therapy for CLL • ≥65 years old • ECOG performance status 0-2

*Other inclusion criteria apply.

Key Exclusion Criteria* • Prior treatment for B-cell CLL • Certain laboratory abnormalities (details noted in protocol) • Active infections

*Other exclusion criteria apply.

Investigational use of lenalidomide. For more information, visit www.clinicaltrials.gov or contact Javier Ferrada, Celgene Study Manager, at jferrada@celgene.com or by calling + 1-908-673-9552.

EDITORIAL BOARD EDITOR-IN-CHIEF Mark J. Krasna, MD St. Joseph Cancer Institute Thoracic Surgery John F. Aforismo, BSc, Pharm, RPh, FASCP R•J Health Systems International Oncology Pharmacy Elizabeth Bilotti, RN, MSN, APNc John Theuer Cancer Center Hackensack University Medical Center Oncology Nursing Scott E. Eggener, MD University of Chicago Genitourinary Cancer Beth Faiman, RN, MSN, APRN, BC, AOCN Cleveland Clinic Taussig Cancer Institute Oncology Nursing Mehra Golshan, MD Dana-Farber Cancer Institute Breast Cancer Shaji K. Kumar, MD Mayo Clinic Hematologic Malignancies Terry Macarol, RT(R)(M)(QM) Advocate Health Care Breast Imaging Patrick Medina, PharmD, BCOP Oklahoma University College of Pharmacy Oncology Pharmacy Greg Pilat, MBA Advocate Health Care Practice Management Ritu Salani, MD Ohio State University Medical Center Gynecologic Malignancies

A Letter From the Editor Scientific Advances and the Prospective Case Presentation This issue of the Journal of Multidisciplinary Cancer Care is my inaugural edition as editor-in-chief. Although my clinical experience is with lung and esophageal cancer, as a cancer institute medical director, it is clear to me that the approach to colorectal cancer has been revolutionized over the past few years. We are now diagnosing colon cancer sooner, discovering tumors at an earlier stage than ever before. We are seeing wider use of fecal occult blood and colonoscopy screening programs. We are reaching out to minority patients, bringing them in to the clinician sooner rather than later. Newer treatments are constantly being discovered in the management of colorectal cancer. Minimally invasive surgery is but one example of where technology has improved patient satisfaction and outcomes with treatment of early-stage colon cancer. Multimodality therapy has become the paradigm for patients with rectal or anal cancer, bringing radiation therapy into the armamentarium of cancer treatments early on. In addition, chemotherapy practice has evolved, thanks to the completion of several important clinical trials. These scientific advances highlight the key advantages of multidisciplinary care—prospectively discussing all new patients to develop a consensus and the possibility of having all involved clinical and support specialists examine the patient in a shorter period of time. This collaboration helps ensure that each patient is treated according to established national guidelines, such as those of the National Comprehensive Cancer Network, the American Society of Clinical Oncology (ASCO), and others. In addition, the newest standards for reporting, which have been adopted from the American College of Surgeons and ASCO’s Quality Oncology Practice Initiative, have provided us nationwide outcome measures to which we can compare ourselves. The mainstay of multidisciplinary cancer care is the prospective case presentation. This, in addition to the multidisciplinary clinic (be it physical or virtual) guided by a disease-site nurse navigator/coordinator, can help us achieve the ultimate goal of multidisciplinary care—an early impact on our patients’ outcomes and quality of life. The use of molecular markers and tissue banking are the beginning of personalized therapy for colorectal cancer, similar to the approach used to treat breast cancer. Colon cancer, like lung cancer, remains a lethal disease and even small improvements can have a huge impact. Integrating advances in diagnosis and treatment with outreach and survivorship programs ultimately will influence cancer care nationwide. Models of integrated cancer care, such as the National Cancer Institute Community Cancers Center Program, have brought all these pillars of excellence to the community as well as the academic cancer center setting. —Mark J. Krasna, MD St. Joseph Cancer Institute Editor-in-Chief Journal of Multidisciplinary Cancer Care

Timothy G. Tyler, PharmD, FCSHP Comprehensive Cancer Center Desert Regional Medical Center Oncology Pharmacy Gary C. Yee, PharmD, FCCP, BCOP University of Nebraska Medical Center Oncology Pharmacy

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 # applied for. 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 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.

Journal of Multidisciplinary Cancer Care

News Notes News Updates of Relevance to Everyday Oncology Practice Invests in u FDA Product Safety

The US Food and Drug Administration (FDA) has requested a budget of $3.2 billion to protect and promote the public health—a 19% increase over the current year’s budget. The 2010 request proposes two major initiatives: protecting America’s food supply and safer medical products. The safer medical products effort ($166.4 million) provides resources to improve the safety of human and animal drugs, medical devices, vaccines, blood, and other medical products by strengthening the safety and security of the supply chain for medical products. Included in this effort is the Follow-on Biologics and Drug Importation Initiative ($5 million), which proposes a new authority for the FDA to approve followon biologics and provides funding for the FDA to develop policies to allow Americans to buy drugs approved in other countries (www.fda.gov/bbs/top ics/NEWS/2009/NEW02013.html).

Expands u Medicare Coverage of PET Scans as Cancer Diagnostic Tools

The Centers for Medicare & Medicaid Services (CMS) issued a final national coverage determination (NCD) to expand coverage for initial testing with positron emission tomography (PET) for Medicare beneficiaries who are diagnosed with and treated for most solid tumor cancers. It also expands coverage of PET scans for subsequent follow-up testing in beneficiaries who have cervical or ovarian cancer, or who are being treated for myeloma. This NCD removes the clinical study requirement for PET scan use in patients with solid tumors. Since 2005, Medicare coverage of PET scans for diagnosing some forms of cancer and guiding treatment required that providers collect clinical information about how the scans have affected treatment decisions. It is important to note that the NCD still requires providers to report data when using PET scans to monitor the progress of treatment or remission of cancer in some cases. More information about the types of cancer covered by this new policy is available in CMS’ final decision memorandum (www.cms.hhs.gov/mcd/viewdecision memo.asp?id=218).

May/June 2009

Package u Stimulus Increases Cancer Research Funding

With the American Recovery and Reinvestment Act of 2009, the National Cancer Institute (NCI) will receive $1.3 billion during 2009 and 2010. This increase in available financing for research allows the NCI to support the best 25% of grant applications that pass peer review. This is almost double the amount of applications approved for funding last year. The stimulus money, however, will not go into the NCI’s general budget, leaving some applications to receive only 4 years of funding instead of the standard 5 years (www.cancer.gov/ncicancer bulletin/042109/page4).

Patients Not u Medicare Covered for Virtual Colonoscopies

Although the American Cancer Society, the American College of Radiology, and the Multi-Society Task Force on Colorectal Cancer have endorsed virtual colonoscopy as an acceptable screening method for colorectal cancer, the Centers for Medicare & Medicaid Services (CMS) has announced a decision to deny payment for this test to Medicare patients. According to CMS, virtual colonoscopies, which use noninvasive computed tomography scans to image the colon, require a patient in whom polyps are detected to undergo a conventional colonoscopy to have the polyps removed. Citing that studies supporting virtual colonoscopy were performed in patients with a mean age of 58 years, CMS decided that those results may not fully apply to the Medicare population. Because older patients are more likely to have polyps, the requirement for a follow-up conventional colonoscopy would make virtual colonoscopy less cost-effective in this population (www.cms.hhs.gov/mcd/ viewdraftdecisionmemo.asp?from2=vi ewdraftdecisionmemo.asp&id=220&).

Shows Rise in u Survey Prescription Abandonment, Generic Drug Use

New data show an increasing rate of “prescription abandonment” by consumers and greater use of generic drugs. The Wolters Kluwer Health annual analysis of the US pharmaceutical market shows that prescrip-

tion abandonment (defined as failure of a patient to pick up a prescription submitted to a pharmacy) grew from an average of 5.15% in 2006 to 6.8% in 2008, a 34% increase. Abandonment increased as the copay rose, especially for new prescriptions. The data also show that 60% of all prescriptions filled in 2008 were for generic drugs (www.wolterskluwer health.com).

Therapies u Targeted Used More Often Among Informed Patients

Patients with colorectal cancer who search for health information on the Internet and in the news media are more likely to be aware of and receive targeted therapy. A retrospective analysis by researchers from the National Cancer Institute (NCI) Center of Excellence in Cancer Communication Research at the University of Pennsylvania Annenberg School showed a correlation between patient awareness of bevacizumab and cetuximab and use of these drugs. Patients did not, however, always understand which treatments were appropriate or inappropriate for their condition. The researchers emphasize the importance of exploring patient influence on physician prescribing patterns and understanding the impact of information seeking on cancer outcomes (Cancer. 2009;115: 1424-1434).

Guidelines u Screening Not Always Followed

Older adults with a life expectancy of <5 years and significant comorbidities who visit their doctor four or more times a year are as likely to be screened for colorectal cancer as healthier patients with fewer doctor visits, according to a study of Veterans Affairs (VA) medical center patients. VA, American Cancer Society, and the American Geriatrics Society guidelines recommend colorectal cancer screening for older adults only if they have a life expectancy of > _5 years and do not have significant comorbidities. In a study of 27,068 VA patients 70 years or older, Louise C. Walter, MD, and associates found that 41% of patients with severe comorbidity and life expectancy <5 years were screened. The authors concluded that more attention to

comorbidities is needed to better target colorectal cancer screening to older patients with substantial life expectancies and to avoid it in those with limited life expectancies (Ann Intern Med. 2009; 150:465-473).

Medicare u Updated Hospice Referral Process

Beginning in 2010, hospice physicians who certify or recertify a beneficiary as terminally ill will need to write a short narrative on the certification form that briefly describes the clinical evidence supporting a life expectancy of < _6 months, according to a proposed rule to update the Medicare Hospice Wage Index for fiscal year 2010 issued by the Centers for Medicare & Medicaid Services. This proposed regulation would bring the Medicare hospice wage index more in line with the index currently used for home health agencies, while maintaining the fiscal integrity of Medicare and allowing continued access to hospice services for its beneficiaries. This requirement will be in addition to a planned 1.1% cut in hospice care reimbursement rates, by eliminating the temporary adjustment (with a 2-year phase-out) used in calculating the wage index, partially offset by the estimated increase in the hospital market-basket indicator of costs (www.cms.hhs.gov/apps/media /press/factsheet.asp?Counter=3441).

Explains u Brochure Radiation Therapy

Treatments for Colon, Rectal, Anal Cancers

A new patient education brochure explains radiation therapy treatments for those with cancers of the colon, rectum, and anus. The American Society for Radiation Oncology (ASTRO) has created a two-page color booklet to help patients and their families understand how radiation therapy works, its lifesaving benefits, and what to expect during treatment. “Radiation Therapy for Cancers of the Colon, Rectum and Anus” is one of 16 brochures in English, Spanish, Japanese, and Arabic that ASTRO offers. The brochures can be downloaded free of charge (www.rtan swers.org/brochures/index.htm) or ordered ($7.50 for 50 copies) from ASTRO (www.astro.org). n

n the iterature I L Concise Reviews of Studies Relevant to Colorectal Cancer Molecular u Possible Explanation for Racial Disparity

Background: The codon 72 polymorphism of the p53 gene in colorectal adenocarcinoma has been shown to have prognostic value. Therefore, researchers sought to address whether it could be associated with race/ethnicity. Design: Colorectal adenocarcinomas from 137 African Americans and 236 non-Hispanic whites were assessed for p53 mutations and genotyped for the codon 72 polymorphism. The phenotypes were correlated with p53 mutational status, clinicopathologic features, and patient survival using the chi-square test and Kaplan-Meier and Cox regression models. Summary: Researchers found a possible genetic cause of the racial disparity between African Americans and non-Hispanic white Americans with colorectal adenocarcinoma. Although the incidence of mutation was similar, the homozygous Pro72 allele frequency was higher in African Americans and the Arg72 allele frequency was higher in whites. In African Americans but not whites, the Pro/Pro phenotype significantly correlated with a higher incidence of nodal metastasis. Also, African Americans, but not whites, with the Pro/Pro phenotype had significantly higher mortality and risk of death due to colorectal adenocarcinoma than those with the phenotype Arg/Arg or Arg/Pro. Takeaway: The higher frequency of Pro/Pro phenotype in African Americans with colorectal adenocarcinoma places that population at higher likelihood of advanced tumor stage and short survival. Katkoori VR, et al. Clin Cancer Res. 2009;15:2406-2416.

plus FOLFIRI u Cetuximab Reduces Risk of Progression of Metastatic Colorectal Cancer

Background: Researchers investigated the efficacy of cetuximab plus FOLFIRI (irinotecan, fluorouracil, and leucovorin) as first-line treatment for metastatic colorectal cancer. The researchers also sought to find associations between the mutation status of the Kirsten rat sarcoma (KRAS) gene and clinical response to cetuximab. Design: Patients with epidermal

growth factor receptor–positive colorectal cancer with unresectable metastases were randomized to receive FOLFIRI either alone or in combination with cetuximab. Summary: This study adds to the growing number of reports showing the significant association between KRAS mutation status and tumor response. The researchers found that cetuximab benefit was limited to patients with wild-type KRAS tumors. However, they found no significant difference in overall survival. Grade 3/4 adverse events, which were more frequent with the combination therapy, included skin reactions, infusionrelated reactions, and diarrhea. Takeaway: Cetuximab plus FOLFIRI increased progression-free survival by 1.2 months in patients with metastatic colorectal cancer wild-type KRAS tumors. Van Custem E, et al. N Engl J Med. 2009;360:1408-1417.

Stem Cell Marker u Colon Discovered

Background: The mechanisms by which stem cells contribute to tumor initiation and progression is not yet known. Design: Through immunostaining, aldehyde dehydrogenase 1 (ALDH1) was investigated as a possible marker for identifying colonic stem cells. The cells were then tracked during cancer progression. Summary: During progression from normal epithelium to mutant epithelium to adenoma, ALDH1-positive cells increase in number and become distributed farther up the crypt bottom (where stem cells reside). Takeaway: Progressive colonic stem cell overpopulation occurs during colon tumorigenesis and drives colorectal cancer development. The researchers say that their discovery of an enzyme common to normal and malignant colon stem cells may help scientists better understand what drives tumor growth and develop treatments for advanced colon cancer. Huang EH, et al. Cancer Res. Epub March 31, 2009.

Therapy May u Hormone Help Prevent Colorectal Cancer

Background: The underlying mech-

anisms by which exogenous estrogens inhibit colorectal carcinogenesis are not clearly defined. Design: Researchers prospectively analyzed data from the Iowa Women’s Health Study, which recruited 41,836 Iowa women, aged 55 to 69 years in 1986. Oral contraceptive use and postmenopausal hormone use were assessed by self-report at baseline. Archived colorectal cancer tissue for 553 of the cases were retrieved. Multivariate Cox regression models were used to estimate adjusted relative risks and 95% confidence intervals. Summary: Women who reported use of estrogen therapy had a 28% lower incidence rate for colorectal cancer than women who did not. The team did not discover the mechanism for how estrogen compounds work in cancer prevention. Investigators did not detect any association between self-reported hormone use and V-raf murine sarcoma viral oncogene homolog B1 (BRAF) gene mutations. Takeaway: Postmenopausal hormone use has been found to be associated with a significantly lower colorectal cancer risk. Oral contraceptive use was not found to be associated with incidence of colorectal cancer. Limsui D, et al. AACR; 2009. Abstract 4871.

Approach to u New Preventing Colorectal Cancer

Background: Studies have shown that cyclooxygenase (COX)-2–derived prostaglandin (PG) E2 promotes colorectal cancer progression. However, gastrointestinal side effects of nonsteroidal anti-inflammatory drugs (NSAIDs) and cardiovascular risks of selective COX-2 inhibitors limit their use in chemoprevention. Summary: Researchers found that pharmacologic inhibition or gene silencing of the 11ß-hydroxysteroid dehydrogenase type II (11ßHSD2) enzyme prevented colorectal cancer progression in mice predisposed to the disease. By using glycyrrhizic acid, the researchers inhibited the production of PGE2 and prevented the development of adenomas and tumor growth and metastasis. Takeaway: Glycyrrhizic acid (a chemical component of licorice) may help prevent colorectal cancer with-

out the adverse gastrointestinal and cardiovascular effects of other preventive therapies. Zhang MZ, et al. J Clin Invest. 2009;119:876-885.

Bleeding or a u Rectal Change in Bowel Habits Warrant Evaluation

Background: Most symptomatic colorectal cancers present with only a low-risk symptom. There is a need to find a method of identifying those at highest risk of cancer from the large number presenting with such symptoms. Design: This case-control study used preexisting records of patients aged 30 years or older with a diagnosis of colorectal cancer. The researchers identified the features of the patients’ colorectal cancer recorded in the 2 years before diagnosis. Features independently associated with cancer were identified using multivariable conditional logistic regression. Each patient’s risk of cancer was then quantified. Summary: Six symptoms and two abnormal investigations (anemia and microcytosis) were independently associated with colorectal cancer. The symptoms with the most predictive values were (highest to lowest): rectal bleeding, change in bowel habit, diarrhea, abdominal pain, weight loss, and constipation. Positive predictive values were lower in women and younger patients. Only 27% of patients had reported either of the two higher risk symptoms. Takeaway: Because few patients present with high-risk symptoms before colorectal cancer diagnosis, patients with rectal bleeding or a change of bowel habits should be evaluated. Hamilton W, et al. BMC Med. April 17, 2009. Epub ahead of print.

Messages About u Mixed Meat and Fish

Background: A recent World Cancer Research Fund/American Institute for Cancer Research report found limited but suggestive evidence that animal fat intake increases the risk of colorectal cancer. Two studies investigating this association found

Continued on page 10

Journal of Multidisciplinary Cancer Care

HEALTH ECONOMIC UPDATES FROM

The Academy of Managed Care Pharmacy 21st Annual Meeting and Showcase APRIL 15-18, 2009, ORLANDO, FLORIDA

of Care Associated u Cost with Second- and ThirdLine Therapies for NSCLC

In the second- and third-line settings, drug and total costs were similar between docetaxel and erlotinib monotherapy for non–small-cell lung cancer (NSCLC). These costs were significantly higher for pemetrexed monotherapy than erlotinib monotherapy. In a retrospective claims analysis, researchers calculated medication and total healthcare costs for patients with NSCLC receiving docetaxel, pemetrexed, or erlotinib as second- or thirdline therapy. Costs were compared on a per-member per-month (PMPM) basis. In this fully insured population, total healthcare costs for patients receiving second-line therapy were erlotinib, $8166 PMPM; pemetrexed, $13,636 PMPM; and docetaxel, $9743 PMPM. For patients receiving third-line therapy, the total costs were erlotinib, $9549 PMPM; pemetrexed, $13,895 PMPM; and docetaxel, $9841 PMPM. Ye X, Darkow T, Hille J. This study was supported by Genentech Inc.

Utilization and Cost u Drug Considerations of Eryth-

ropoiesis-stimulating Agents in Cancer Patients Receiving Chemotherapy Patients treated with epoetin alfa (EPO) had a 29% lower treatment cost than those who received darbopoetin alfa (DARB). Researchers analyzed the treatment patterns, dose ratio, and treatment costs of these two erythropoiesis-stimulating agents (ESAs) reported on medical claims data from

the PharMetrics Patient-Centric database from January 2006 to January 2008. Mean cumulative ESA dose was used to calculate drug cost and dose ratio. The mean cumulative ESA dose administered was 329,129 units EPO and 1289 µg DARB, which resulted in a dose ratio of 255:1 (units EPO:µg DARB). Drug cost per treatment episode was significantly lower in the EPO group (EPO, $4321; DARB, $6089). These real-world practice data collaborate findings of published clinical trials and observational studies. Laliberté F, McKenzie RS, Vekeman F, Bookhart BK, Lefeb P. This research was supported by Centocor Ortho Biotech Services LLC.

and Mortality u Cost Associated with

Hospitalizations for Neutropeniarelated Complications in Patients with Cancer A retrospective analysis suggests that neutropenia may contribute to the cost of cancer treatment and is a considerable cost-driver when associated with fever or infection. Using a large US healthcare database, researchers stratified patients into one of three groups: patients with neutropenia (N = 3785), neutropenia and fever or opportunistic infection (N = 1776), or neutropenia and opportunistic infection (N = 1156). Mean total cost of care was found to be $18,037, $22,805, and $27,574, respectively. Actual mortality rates were 8.2%, 13.6%, and 19.4%, respectively. The researchers concluded that neutropenia has a signifi-

Recent FDA Approvals Bevacizumab for brain cancer (glioblastoma) The US Food and Drug Administration (FDA) has approved bevacizumab (Avastin, Genentech) for patients with glioblastoma with pro-

May/June 2009

Consequences u Unintended of Payer Oral Oncologic

Orlando/Orange County Convention & Visitors Bureau, Inc.®.

gressive disease following prior therapy. The new indication was granted under the accelerated approval program. Approval was based on data from an open-label, multicenter, noncomparative phase 2 study that in-

cant economic impact and is associated with significant risk for mortality, which is further elevated in the presence of fever or infection. Schilling MB, Parks C, Deeter R. This study was funded by Amgen Inc.

of Systemic Therapies u Costs in Metastatic Melanoma: Evidence from the SEERMedicare Linked Database

Because systemic treatment for elderly patients with metastatic melanoma is costly to the Medicare system, new therapies should be aimed at limiting progression to stage IV disease. Using real-world data from the Surveillance, Epidemiology and End Results (SEER)-Medicare linked database, researchers analyzed costs per member per month (PMPM) (in 2007 $US) of active treatment, palliative care, and terminal care of patients aged 65 years or older with at least one stage IV melanoma diagnosis who had received at least one systemic treatment. They found that more than 90% of patients died following treatment initiation, with a median survival time of 6 months. For patients initiating firstline chemotherapy, mean active treatment costs were $9649 PMPM, palliative costs were $631 PMPM, and subsequent terminal care costs were $6429. For those initiating second-line therapy, costs were found to be similar, with the exception of palliative care ($2300-$2900 PMPM). Davis K, Kan H, Kotapati S, Mitra D. This research was funded by BristolMyers Squibb Co.

cluded 167 patients with glioblastoma that had progressed following initial treatment with temozolomide and radiation. According to an FDA analysis of the study, tumor responses were observed in 26% (95% confidence interval [CI]: 17.0%, 36.1%) of the 85 patients treated with beva-

Management

Patient cost-sharing and physician reimbursement differences based on route of administration illustrate the impact nontherapeutic factors can have on therapy selection. In the past decade, a growing number of oral agents have been introduced for cancer therapy. However, because these agents fall under patients’ pharmacy benefits, they are subject to tight formulary management, rigorous prior authorization procedures, and greater

For comparable clinical profiles, payers favored oral therapies and oncologists favored infused drugs. cost-sharing than their infused counterparts. Researchers conducted a two-arm concurrent web-based quantitative survey with managed care executives and oncologists. They found that for comparable clinical profiles, payers favored oral therapies and oncologists favored infused drugs. Both payers and oncologists recognized that current management policies unintentionally incentivize the use of infused therapies over oral alternatives. The researchers concluded that for oral therapies to gain market share, overcoming access/cost disadvantages is crucial. McConnell K, Wu J, Dautel N, for the Zitter Group. n

cizumab alone, and the median duration of response in these patients was 4.2 months (95% CI: 3.0 months, 5.7 months). In a separate study, safety in patients with glioblastoma that had progressed following prior therapy was consistent with bevacizumab experience in other tumor types. n

Multidisciplinary Program Facilitates Care for Upper GI Cancers

AN FRANCISCO—The management of patients with newly diagnosed upper gastrointestinal (GI) cancers typically involves a number of specialists, which can make for fragmented and inefficient care. The Vermont Cancer Center in Burlington has met the challenge by creating a multidisciplinary program with a nurse navigator at the helm. The program was described at the 2009 Gastrointestinal Cancers Symposium by nurse navigator Nicole Messier, RN, along with Laurence E. McCahill, MD, associate professor of surgery at the University of Vermont, Burlington. The Upper GI Cancer Multidisciplinary Program at the Vermont Cancer Center has three key components: (1) a multidisciplinary clinic comprised of gastroenterologists, pathologists, radiologists, and medical, radiation, and surgical oncologists; (2) a treatment planning conference (which takes the place of traditional “tumor boards”) that meets three times a month, immediately prior to the clinic, and is attended by the above physicians; and (3) a dedicated subspecialty cancer nurse navigator. The structured approach to the management of patients with pancreatic, esophageal, gastric, liver, and biliary tract cancers has allowed for more timely evaluation and treatment in a highly coordinated fashion. The Institute of Medicine has reported that the delivery of cancer care in this country is often quite poor. In some parts of Europe, by contrast, a more focused multidisciplinary approach that revolves around a coordinating nurse has been shown to facilitate assessment and evidence-based treatment, McCahill noted.

“In the public health system in the United Kingdom, patients must be seen within 2 weeks of their diagnosis. At Vermont Cancer Center, we are trying to move toward that model,” he said. Messier said that before initiating the program, “It was not uncommon to see patients who were diagnosed 6 weeks earlier just coming in to discuss surgery. It took weeks to complete imaging studies and all appropriate consultations because so many different people were involved. “We saw that the nurse navigator program was working well for the breast cancer program, and Dr McCahill asked, ‘Why can’t we do that for our GI cancer patients?’” The two not only got the program up and running, but took it a step further by providing outcomes data to demonstrate its worth. “We are measuring everything we do,” he added, which he anticipates will be part of an emerging mandate to meet benchmarks of quality cancer care.

At the Center of Care As the dedicated nurse navigator, Messier is responsible for coordinating all aspects of the patient’s medical care and for serving as a patient educator and advocate. She starts by obtaining the patient’s history and medical records, which she uses for the initial determination of the disease stage, and scheduling diagnostic tests. “We follow NCCN [National Comprehensive Cancer Network] guidelines to make sure we are working up the patient appropriately, and not ordering inappropriate tests or overutilizing radiology services,” she added. She then books appointments— attempting to have patients complete several visits in 1 day—and organizes

the treatment planning conference, all before the patient is seen by the first and most appropriate physician (which she determines). “Initial testing and consults are accomplished within 2 weeks of my first contact with the patient, and treatment is initiated within 30 days. We are trying to tighten this up even more,” Messier said. She also serves as a liaison with the patient throughout the diagnostic and treatment course, transitions the patient from postoperative to outpatient care, and coordinates postoperative

The new program has improved communication and collaboration between the physicians involved in the care. visits. “The patients have me to look out for the loose ends, and to keep things moving smoothly. They have their oncologists and their surgeons and their primary nurses to deal with the nitty-gritty, but I am always in the background, looking at the whole picture,” she said.

Physicians’ Jobs Made Easier Richard Zubarik, MD, chief of endoscopy, said the new program has not only streamlined patient care, moving it beyond an ad hoc situation, but also has improved communication and collaboration between the physicians involved in the care. “I am on the front end of putting the patients into the system. After I receive referrals from the primary physician, I hand the patient over to the nurse navigator to arrange every-

Table. Comparison of Outcomes by Treatment Period Outcome

Group 1 (N = 78)

Group 2 (N = 55)

P value

7.9 21.1 25.2

11.3 24.3 32.3

.07 .39 .05

96%

—

64% 2.6

20% 5.8

<.001

Diagnostic efficiency Staging evaluation (days) Days to last pretreatment visit Days until first cancer treatment Multidisciplinary evaluation Treatment planning conference Coordination of care See all physicians in single day Number of pretreatment hospital/ clinic visits

thing else. Because of her, at the planning conference we have all the data we need when we discuss the case,” he said. He also thanks Messier for updating the referring physician—formerly his responsibility. Messier has observed that her efforts and the collaboration that occurs during the planning conference make patient care simpler for all providers. “Before, physicians were always paging each other about the patients. It was very inefficient,” she said. Jordan Berlin, MD, clinical director of GI Oncology at Vanderbilt-Ingram Cancer Center, Nashville, commented that having a nurse navigator to coordinate multidisciplinary care is especially valuable in GI oncology. “Many patients come for a second opinion and have already had tests done. Getting the correct data on them is important, which nurse navigators can do. They also can ensure that patients see the right subspecialist first, which in GI oncology is not always the case. Patients are often scheduled to see the medical oncologist when what they really need is the surgeon.”

The Numbers Prove It McCahill and Messier evaluated the impact of this new approach on the efficiency of healthcare by comparing patients referred during the first 6 months of the new program (Group 1), with those treated under the traditional system (Group 2). Patients seen within the multidisciplinary program had significantly shorter time between their first visit and initiation of treatment and required significantly fewer hospital visits prior to treatment (Table). Commenting on the increase in patient numbers, McCahill said, “I think patients sense that we have coordinated care. They like that they are not coming in for an average of six visits before treatment, but more like three visits. That is a really big change.” “A lot of our patients travel more than 2 1/2 hours to come here,” added Messier, “so this is very important.” Running the program requires tremendous organization on her part, she acknowledged. “I have developed strategies to keep my patients organized, and it is not only for current patients but those who have finished treatment and still call me.” n —Caroline Helwick Contributing writer

Journal of Multidisciplinary Cancer Care

Preventing Skin Toxicity from EGFR Inhibitors S

AN FRANCISCO—Skin toxicity associated with the use of epidermal growth factor receptor (EGFR) inhibitors for colorectal cancer can be prevented with an upfront “preemptive” treatment regimen, according to investigators who presented their findings at the 2009 Gastrointestinal Cancers Symposium. Skin toxicity—mainly, a severe acneiform rash—is the main side effect of the EGFR inhibitors cetuximab and panitumumab. These agents have become key components in the treatment of metastatic colorectal cancer and are being evaluated in other tumors. The prophylactic approach is new, as management of skin toxicity is usually driven by symptoms that emerge during chemotherapy. In many cases, treatment must be delayed or even discontinued while the rash is treated. “I have had patients completely refuse to be treated with these drugs because they don’t want to look like

another patient they know,” said Edith Mitchell, MD, of Thomas Jefferson University, Philadelphia, who presented the findings. The lead author was Mario E. Lacouture, MD, director of the Cancer Skin Care Program at Northwestern University, Chicago. The preemptive regimen consisted of moisturizers, paraaminobenzoic acid (PABA)–free sunscreen rated sun protective factor (SPF) > _15, topical steroid cream (hydrocortisone 1%), and doxycycline 100 mg twice daily. Use of this preemptive regimen reduced by half the occurrence of skin toxicity in the study presented at the meeting. The study randomized 95 patients to preemptive therapy starting 24 hours before the first scheduled dose of panitumumab (with leucovorin, fluorouracil, irinotecan [FOLFIRI]) and continued for 6 weeks, or to “reactive” therapy administered after toxicity occurred. The primary end point was the incidence of grade 2 or

higher skin toxicity. At 6 weeks, patients randomized to preemptive skin therapy had a 29% incidence of protocol-specified grade 2 or higher skin toxicity, compared with 62% among patients in the reactive treatment arm, Mitchell reported. Specifically, grade 2 skin toxicity occurred in 23% and 40%, respectively, and grade 3 toxicity occurred in 6% and 21%, respectively. Manifestations of this toxicity are shown in the Table. Median time to first occurrence of grade > _2 skin toxicity was 2.1 weeks in the reactive treatment arm, but has not been reached in the preemptive arm. Preemptive therapy also helped patients stay on treatment, with 155 total panitumumab doses given compared with 141 doses in the reactive group. Dose delays occurred in 1% and 6% of the arms, respectively. Clinical response and other outcome measures were not negatively impacted by the treatments.

Table. Commonly Observed Skin Toxicities Preemptive skin treatment (N = 48) Any grade Grade 3 Grade 4 Toxicity N (%) N (%) N (%) Acneiform rash 37 (77) 2 (4) 0 (0) Pruritus 30 (63) 1 (2) 0 (0) Pustular rash Paronychia

12 (27) 8 (17)

In the Literature Continued from page 7 different, but not contradictory results. Design: Alexander and colleagues performed a meta-analyses of high compared with low animal fat intakes and categorical dose-response evaluations. Subgroup analyses, consisting of evaluations by study design, sex, and tumor site, were performed. Rohrmann and colleagues, using a prospective cohort study, assessed diet, anthropometric measures, lifestyle, and medication use in participants of the European Prospective Investigation into Cancer and Nutrition-Heidelberg cohort study. Dietary heterocyclic aromatic amine (HCA) intake was estimated by using information from food-frequency questionnaires on

May/June 2009

2 (4) 0 (0)

0 (0) 1 (2)

Reactive skin treatment (N = 47) Any grade Grade 3 Grade 4 N (%) N (%) N (%) 40 (85) 10 (21) 0 (0) 32 (68) 19 (40) 17 (36)

meat consumption, applied cooking methods, and preferred degree of browning. Multivariate Cox proportional hazards regression examined the association between colorectal adenoma risk and intake of HCAs. Summary: Alexander and colleagues did not find that the available epidemiologic evidence support an independent association between animal fat intake or animal protein intake and colorectal cancer. Rohrmann and colleagues did, however, find positive association between HCA intake and colorectal adenoma risk. Takeaway: Chemicals produced by cooking meat and fish at high temperatures pose some risk of colorectal cancer development; however, no overall adverse association between consumption of meat and fish and colorectal cancer was found. Alexander DD, et al. Am J Clin Nutr. 2009;89:1402-1409 (This study was sup-

6 (11) 8 (17) 3 (6)

0 (0) 0 (0) 0 (0)

ported by the National Cattleman’s Beef Association and the National Pork Board). Rohrmann S, et al. Am J Clin Nutr. 2009;89:1418-1424 (This study was supported by the Kurt-Eberhard-BodeFoundation, the European Commission, and German Cancer Aid).

Family u ErbB Immunohistochemical

Expression in Colorectal Cancer Patients with Higher Risk of Recurrence After Radical Surgery

Background: The expression of the ErbB receptor family (the epidermal growth factor receptor [EGFR], ErbB2, ErbB3, and ErbB4) may play a role in the risk of recurrence of colorectal cancer after surgical intervention. Design: Using the tissue microarray technique, researchers assessed ErbB expression in 109 patients with high-risk stage II and stage III disease

Interestingly, adverse events other than skin toxicity were also reduced in the prophylactic arm, including diarrhea, neutropenia, hypomagnesemia, and dehydration. The reason for this is unclear, Mitchell said. “Patients in the prophylactic treatment group also reported improved quality of life, especially during weeks 2 to 3, when half the reactive treatment patients had first experienced a grade 2 or higher event,” she added. Preemptively treated patients, however, did not discontinue treatment at a lower rate than reactively treated patients, Mitchell explained. “We were seeing all patients weekly, and we think this enhanced compliance in both arms.” Robert Mayer, MD, professor of medicine at Dana-Farber Cancer Center, Boston, said the findings are important because skin toxicity is the reason that many patients discontinue treatment with EGFR inhibitors. “The antitumor response rates were the same, and there was less toxicity with preemptive treatment. That’s the good news,” he said. “The bad news is that this was not shown to impact patients in terms of therapeutic outcomes of panitumumab (ie, preemptively treated patients had no additional improvement in clinical outcomes).” n —Caroline Helwick Contributing writer

who underwent to radical surgery. Summary: Patients were found to express positive immunohistochemistry for EGFR (57.8%), ErbB2 (8.3%), ErbB3 (69.7%), ErbB4 membrane (11%), and ErbB4 cytoplasmic (19.3%). ErbB3-negative expression was associated with lymphovascular invasion. EGFR, ErbB2, and cytoplasmic ErbB4 expression was not associated with prognosis. Membranous positive ErbB4 expression was an independent prognostic factor for recurrence. ErbB3-negative expression was an independent prognostic factor for recurrence and survival in the multivariate analysis. Takeaway: The immunohistochemical expression of ErbB3 and ErbB4 may identify a subgroup of patients with stage II and stage III colorectal cancer at higher risk of recurrence. Baiocchi G, et al. Int J Colorectal Dis. April 24, 2009. Epub ahead of print. n

MultipleMyeloma_MainTherapy_King.qxp:Layout 1 5/19/09 4:11 PM Page 1

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, will proudly offer the multidisciplinary cancer team at your center a series of newsletters focusing on the challenges in treating patients with multiple myeloma.

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

# Earn Continuing Education Credits # Eight part newsletter series

CLINICAL TOPICS: • Retreatment Settings • Maintenance Therapy • Do CRs Correlate to a Clinical Benefit?

• Perspectives on Relevant End Points of Clinical Trials • Stem Cell Mobilization • Cytogenic Testing in the MM Patient

• To Transplant or Not to Transplant…That is the Question • Sequencing Strategies in MM: Treatment with Case Studies

Each newsletter will feature: • Contributions from thought-leading physicians, pharmacists, and nurses

• Continuing Education credits available to physicians, pharmacists, and nurses

TO REQUEST FREE COPIES

Call 732-992-1899 or visit www.coexm.com

Maintenance Therapy Newsletter Statement of Need

Physician Credit Designation

The purpose of this activity is to enhance knowledge concerning the treatment of patients with multiple myeloma (MM).

Global Education Group designates this educational activity for a maximum of 1.5 AMA PRA Category 1 Credit(s)TM. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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

Registered Nurse Designation

Learning Objectives

Medical Learning Institute, Inc. approved by the California Board of Registered Nursing, Provider Number 15106, for 1.5 contact hours.

At the completion of this educational activity, participants should be able to: • Define the role of posttransplant maintenance therapy in the treatment of patients with multiple myeloma (MM) • Describe how novel agents for MM can be used to sustain response and possibly delay relapse in patients with MM • Interpret new data from clinical trials of maintenance regimens for MM as reported at the 2008 ASH annual meeting • Identify the risks and benefits associated with novel agents used in the maintenance setting, including increased toxicity and acquired drug resistance

Registered Pharmacy Designation

Physician Accreditation

MLI is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. Completion of this activity provides for 1.5 contact hours (0.15 CEU) of continuing education credit. The universal program number for this activity is 468-999-09-013-H01-P. Estimated time to complete this activity: 1.5 hours Date of original release: May 11, 2009 Valid for CME credit through: May 11, 2010

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of Global Education Group (Global) and Medical Learning Institute, Inc. (MLI). Global is accredited by the ACCME to provide continuing medical education for physicians.

This activity is jointly sponsored by

This activity is supported by an educational grant from Millennium Pharmaceuticals, Inc.

New ACCC President Seeks to Shine a Light on Oncology Workforce Shortage An interview with Luana Lamkin, RN, MPH

Luana Lamkin, RN, MPH, became president of the Association of Community Cancer Centers (ACCC) at its 35th annual meeting in March. Lamkin is the administrator for St. Luke’s Mountain States Tumor Institute at St. Luke’s Boise Medical Center, Idaho. In this interview, she discusses her goals for her year as president.

Luana Lamkin, RN, MPH

ournal of Multidisciplinary Cancer Care (JOMCC): Are you the first nurse to serve as ACCC president? Luana Lamkin (LL): No, actually I’m the fifth nurse to serve as ACCC president. The presidency reflects the diverse membership of the organization. Past presidents have included physicians, a pharmacist, a social worker, and a business administrator. Of the people who attend meetings, about 50% are physicians and about 50% are nurses and other members of the oncology team. It’s a wonderful

mix from our community. What I think is particularly useful about ACCC is that the membership pretty much makes up the team of people most of us work with every day. None of us work with all physicians, all pharmacists, or all nurses. We are all part of a multidisciplinary team, and ACCC membership reflects that diversity. JOMCC: What are your goals as ACCC president? LL: Each president gets to choose a focus for the year. My personal goals have to do with shining a light

on issues of the oncology workforce. We have a shortage of physicians, nurses, and pharmacists, and we need to think about ways to succeed in the future. I am very concerned because it is estimated that between now and 2020, we will have a 55% increase in the number of cancer patients in the United Sates but just a 14% increase in the number of medical oncologists. JOMCC: What are your thoughts about how to ensure that we have an oncology workforce adequate to deal with the growing number of patients?

Join the JOMCC Editorial Advisory Panel Journal of Multidisciplinary Cancer Care is seeking oncologists, nurses, pharmacists, medical and pharmacy directors, P&T Committee members, and experts in healthcare legislation who are interested in joining our editorial advisory panel and assisting in maintaining the high quality of articles published. Panel members will occasionally be asked to contribute articles or commentaries, review manuscripts, or participate in interviews or roundtable discussions.

Articles fall into three main categories: Clinical, Business, Health Economics. These main categories are represented from the different vantage points of all stakeholders in healthcare and are divided into many subcategories, including (but not limited to): u Administration/management u Radiation oncology u Breast cancer u Other solid tumors u Finance/economics u Health policy/reform u Gastrointestinal cancers u Hematologic malignancies u Genitourinary cancers u Lung cancer u Gynecologic malignancies u Melanoma u Health information technology u Pediatric oncology u Pharmacoeconomics: cost-benefit analysis, cost-effectiveness u Reimbursement: Medicare/Medicaid, health insurance, prior authorization

To serve on the editorial advisory panel, please complete the form below and fax to 732-656-7938 or e-mail to Karen@greenhillhc.com. Advisory member information First name

Last name

Title

Company

Address E-mail

Phone

May/June 2009

Credentials

LL: The goals of the ACCC are twofold: (1) education of ourselves and our cancer team community, and (2) advocacy. First, in terms of education, in the next two ACCC meetings, we will spend considerable time on topics related to the oncology workforce. I don’t think a lot of people recognize now how difficult the situation is going to be. We have to educate ourselves on the looming crisis and begin to look at models that will help us avoid this. One thing to consider is the role of the nurse practitioner and how we can go about preparing more nurse practitioners to take on roles of midlevels in oncology practice. Another step is to work with other groups that already fund education for physicians, nurses, and pharmacists and encourage them to continue and even increase that funding. In our advocacy role, there is quite a lot we can do in terms of working with state and federal legislators on new legislation that would increase funding for education of nurses, pharmacists, and physicians, particularly in oncology and particularly in midlevel roles. One positive thing to come of the current economic situation is that it seems that more people are going into the healthcare professions. Healthcare is still a strong employer and a good business to go into. JOMCC: What factors are most important in attracting new doctors, nurses, and pharmacists to oncology? LL: I think that most people who are choosing healthcare professions are doing it because they see a stable work life ahead of them and because they want to do something that is meaningful. Those of us in oncology have not been articulate enough in

Continued on page 17

Are You Getting the Most from Your KRAS Testing? An interview with Christopher Ung, MSc, MBA

With the discovery that patients whose colorectal cancer tumors have a Kirsten rat sarcoma (KRAS) mutation do not respond to treatment with antibody-based epidermal growth factor receptor therapies, such as panitumumab and cetuximab, medical oncologists have begun to routinely send tumor samples to laboratories for KRAS-status testing. In this interview, Christopher Ung, MSc, MBA, Vice President, Strategic and Business Development, Oncology at Quintiles Transnational, explains the different types of testing available and the laboratory process involved in performing the assays. He also identifies questions oncologists should ask their laboratories to ensure they are receiving quality results. Information on sample preparation and the future of KRAS testing are discussed.

Christopher Ung, MSc, MBA

ournal of Multidisciplinary Cancer Care (JOMCC): What are the different types of assays that are available to test for Kirsten rat sarcoma (KRAS) mutation? Christopher Ung (CU): There are about 20 different ways that you can assess KRAS status. You can group these methods into two broad categories, sequencing and allele-specific polymerase chain reaction (PCR) testing. Sequencing, which is basically looking for the sequence of the gene, is considered the gold standard technology that has been around for some time. However, it suffers from a lack of sensitivity, which is why, today, the industry is talking about a new group of assays that are based on allele-specific PCR testing. These assays look at the portion of the gene where the mutation actually takes place, and the sensitivity of that technology is much higher. These assays can detect as little as 1% mutated genes in a group of normal genes. For sequencing, the numbers vary, but those assays are only about 60% to 70% sensitive.

A KRAS mutation assay is covered by every insurance company now in the United States. The DxS assay, which will be marketed by Roche and may receive approval by the US Food and Drug Administration (FDA), is in use in many US companies including ours, because it has the most clinical outcome data associated with it. The other 19 technologies available may or may not be good assays. What those assays do not have is association with clinical outcomes in colorectal cancer the way that the DxS assay does. JOMCC: If that assay is not FDAapproved, is the test covered by insurance or Medicare?

CU: A KRAS mutation assay is covered by every insurance company now in the United States. What is interesting is that starting April 1, 2009, UnitedHealthcare requires a KRAS assay to be performed before it will pay for treatment with panitumumab or cetuximab. So it is the first major payer requiring the test to be performed before it will reimburse for treatment. JOMCC: What should a medical oncologist who wants to ensure his or her samples are tested with the best assay possible, be asking the laboratory? CU: If you are a physician, I think there are a couple of things that you want to find out about the kind of test your laboratory offers. Physicians have a couple of choices, because they can either send the sample out to a central laboratory or they can call a pathology laboratory at a local hospital. But if the laboratory is using a sequencing assay, I would be concerned, because of the sensitivity issue. Physicians should also find out whether the laboratory is using a validated assay with clinical outcomes. JOMCC: If an oncologist wants to switch to one of these allele-specific PCR assays but is used to submitting samples for sequencing, is a different method of sample preparation required? CU: For allele-specific PCR assays, the specimen should be formalin-fixed and paraffin-embedded. At our laboratory, when we get a colorectal biopsy, it arrives embedded into paraffin to preserve the tissue in a block. In some instances, the local hospital refuses to part with the paraffin block and cuts off some sections, which it mounts on glass slides. Then it sends the glass slides to us. Then, from the paraffin block or the glass slides, we extract the DNA and perform the test, looking for the mutation. Whether it is sequencing or an allele-specific PCR assay, it is more or

less the same process to extract the DNA. However, with sequencing, because the sensitivity is lower, the pathologist will have to make sure there is enough tumor in the tissue before he or she can perform the sequencing aspect. The assay may require additional material. With an allele-specific PCR assay, you can probably get away with two or three

bit more data. For these clients we will provide the specific KRAS mutations (there are seven); any one of the mutations will classify the patient as positive for the KRAS mutation.

I think KRAS testing is going to become standard of care for colorectal cancer.

CU: I think KRAS testing is going to become standard of care for colorectal cancer. There is a lot of momentum, and for good reason, because if a patient has a mutation, he or she is not going to benefit from treatment with cetuximab or panitumumab, which are both used in the metastatic setting right now and increasingly used in the neoadjuvant setting as well. Only about 40% to 45% of colorectal cancer patients have the mutation. Therefore, 60% may benefit from the drugs and 40% definitely will not benefit from the drugs. If the oncologist is considering treatment with panitumumab or cetuximab and the patient is positive for the KRAS mutation, the oncologist can immediately exclude that patient from treatment with one of these agents. It is very important to say that the FDA has not approved the labeling for panitumumab or cetuximab indication to include KRAS mutation assessment. That is still being very heavily debated and there are a lot of substantiating data but the FDA has not made that decision yet.

slides, maybe three or four slides, if there is sufficient tumor in the tissue. When an oncologist calls to have a test performed, he or she should ask for specimen guidelines by the performing laboratory. If you visit our website (www.tmdlab.com), you will find our section on what kind of specimen is suitable. Ideally, the laboratory will want to make sure that the tissue has tumor in it. In our laboratory, the first thing we do when we get the tissue is to assess that there is tumor. Sometimes we get tissue with insufficient tumor or no tumor at all. So once we determine there is enough tumor, we are confident that we can run an assay that will provide a reliable result. JOMCC: With both types of testing, does the report to the oncologist just indicate whether the tissue is KRAS mutationâ&#x20AC;&#x201D;positive or negative or does it give the doctor more information? CU: Although it depends on the laboratory, oncologists will get essentially the most important information they will wantâ&#x20AC;&#x201D;whether the KRAS mutation exists or not. Essentially most laboratories will inform the oncologist if the mutation is there or it is wild-type. At our laboratory, we serve some clients in the clinical development arena who want a little

JOMCC: Do you expect these tests to be performed more frequently in the future and to be required by insurance and Medicare?

JOMCC: Are there any other regulatory matters involving KRAS assays? CU: The American Society of Clinical Oncology (ASCO) released a Provisional Clinical Opinion (PCO) in January 2009, which recommends that colorectal cancer patients be screened for KRAS status. The National Comprehensive Cancer Network (NCCN) has also added these recommendations

Continued on page 28

Journal of Multidisciplinary Cancer Care

Colon and Rectal Cancers NCCN Guideline Updates H

OLLYWOOD, FL—New Kirsten rat sarcoma (KRAS) testing recommendations, survivorship protocols, and resectability criteria are the main highlights from the latest colon and rectal cancers guideline updates from the National Comprehensive Cancer Network (NCCN), as reported at the 14th Annual NCCN Conference: Clinical Practice Guidelines & Quality Cancer Care. The guidelines were presented by Paul F. Engstrom, MD, Fox Chase Cancer Center, Philadelphia, Pennsylvania, and head of the NCCN committee for colon, rectal, and anal cancer guidelines. “I think the KRAS story is probably the number one story of the guidelines,” Engstrom said during an interview. “I think the second one is the addition of the survivorship guidelines to our panel. I think other than lung cancer, really we’re the only cancer right now to have a full inclusion in the guidelines of survivorship. And then I think third is judging who’s resectable for liver metastasis.” Several studies published in 2008 demonstrated that the status of the tumor KRAS gene is highly predictive of outcome with anti–epidermal

growth factor receptor (EGFR) agents, such as cetuximab and panitumumab. However, these agents have been found to be effective only in colorectal cancer patients with tumors that express the normal (or wild-type) KRAS gene and not with tumors that express KRAS gene mutations. So the colon and rectal cancers guideline updates include the recommendation that KRAS testing should be done for all patients diagnosed with metastatic colorectal cancer before finalizing their treatment plan, with these agents used only for those who have tumors with wild-type KRAS genes. Said Engstrom, “I think the finding [from those studies] was an eye-opener to oncologists because we didn’t know why some patients didn’t respond before. Just like we have a lot of other agents that we don’t know why patients don’t respond to, such as irinotecan. Some of our patients do [respond] and some don’t. And now we’re starting to tease this apart with these molecular tests. I think this is an important new direction in the management of colorectal cancer.” The guidelines’ new section on survivorship outlines principles for long-term follow-up care for patients

in remission. In addition to monitoring these patients for disease-specific recurrence, the new guidelines stress the need for screening and monitoring for other cancers. Specifically, the guidelines state that special attention should be paid to prevention of breast and cervical cancers among women survivors, while surveillance for prostate cancer should be stressed to male cancer survivors. In addition, the survivorship section describes healthy lifestyle recommendations (especially exercise), the management of long-term treatment side effects, wellness counseling, and transferring care to a primary care physician. “There are many survivors in the group of colorectal patients, and they’re a little bit neglected,” said Engstrom. “Some of them have had colonoscopies. Many of them have had radiotherapy along with chemotherapy. I have patients that are out 20, 25, 30 years from their treatment of [colorectal] cancer and they still have some sequelae that they are living with. And nobody’s ever really talked to them about that. So I think these survivorship guidelines are important. The breast cancer patients are usually the model that we go by,

but I think there are as many survivors in colorectal cancer as there are in breast cancer.” The guideline updates also include a recommendation for the reevaluation of patients with initially unresectable metastatic colorectal disease to determine whether they would be suitable for resection following chemotherapy. Specifically, the guidelines now include the words “potentially convertible” or “unconvertible,” which have been added to the definition of unresectable disease. An up-front multidisciplinary team evaluation is now recommended, including a surgeon with resection expertise. “Before, we defined ‘resectable’ by what comes out, asking how many metastases are there and how large?” said Engstrom during his presentation. “Now we’re defining it by what stays in, such as preserving liver segments.” In addition, the guideline updates provide new data on using cetuximab in treatment of patients with metastatic colorectal cancer, including in combination with specific chemotherapy drugs as an initial therapy option. n —Deborah Brauser Contributing writer

ASCO Recommends KRAS Testing to Predict Colorectal Cancer Response to Anti-EGFR Therapy I

n the first Provisional Clinical Opinion (PCO) issued by the American Society of Clinical Oncology (ASCO), the society recommends testing for mutations in the Kirsten rat sarcoma (KRAS) gene to predict the response of patients with metastatic colorectal cancer (mCRC) to monoclonal antibody therapies directed against the epidermal growth factor receptor (EGFR). Subset analyses of results from five randomized controlled trials of cetuximab or panitumumab showed that patients with mCRC and wild-type KRAS benefit from these therapies alone or in combination with chemotherapy, whereas patients with mutations in codon 12 or 13 do not. Five additional single-arm studies retrospectively analyzed tumor response according to KRAS status. ASCO estimates that 40% of colorectal cancers have KRAS mutations.

May/June 2009

Testing of tumor-tissue DNA uses genetic probes that are specific for mutations that confer constitutive activation of Ras protein. The ASCO PCO recommends that any mCRC patient with a KRAS mutation in codon 12 or 13 should not receive an anti-EGFR antibody as part of his or her therapy. ASCO PCO’s are intended to provide the oncology community with timely, preliminary clinical direction based on the presentation or publication of potentially practice-changing data from major studies. ASCO released its PCO on KRAS testing in advance of the Gastrointestinal Cancers Symposium in January in San Francisco.

Economic Impact An analysis presented at the symposium demonstrated for the first time the potential economic benefits of personalized medicine in the management

of gastrointestinal cancers. The findings show that testing patients with mCRC for KRAS gene status before instituting first-line therapy with inhibitors of EGFR could result in an annual cost-savings of $604 million to the US healthcare system. The investigators used an economic model to determine the cost of treating patients based on KRAS status and publicly available data for laboratory and drug costs, US cancer incidence, and clinical outcomes from the cetuximab plus irinotecan in first-line therapy for mCRC trial (known as CRYSTAL). The final outcome was net dollars saved when cetuximab was used as first-line therapy for mCRC only in patients with wild-type KRAS. The cost per patient was calculated using the American Cancer Society data, including: • Estimated 28,724 annual cases of mCRC

• $452 per KRAS test (totaling $13 million) • $3986 for a loading dose • $2491 for the weekly dose of cetuximab (wholesale price), multiplied by 24 infusions per patient (in combination with the leucovorin, fluorouracil, and irinotecan [FOLFIRI] regimen). Based on these data, cost per patient was determined to be $61,279, excluding costs associated with appointments, toxicity management, and infusion time. Excluding the estimated 35.6% of patients with KRAS mutations, and treating just patients with wild-type KRAS, savings were projected to be $617 million, minus $13 million for testing, for a final annual net savings of $604 million. n This article was based on reports by Daniel M. Keller and Caroline Helwick.

Personalized Medicine Coriell Institute Makes the Genome Personally Useful

ounded in 1953, the Coriell Institute for Medical Research (www.coriell.org) is an independent nonprofit basic biomedical research institution that was and is at the forefront of biomedical research. It occupies a new five-story laboratory facility on the campus of the University of Medicine and Dentistry of New Jersey in Camden. In 1953, founder Lewis Coriell, MD, PhD, helped bring the Salk polio vaccine to the public by using cell cultures to study human viral diseases. The institute still deals in cell culture, and its biobank is the world’s largest repository of human cell cultures for research, which it distributes to laboratories worldwide. In addition, it is on the forefront of research in biomedical genetics and is the home of the

Genome Project and the Coriell Personalized Medicine Collaborative (CPMC; see accompanying article). Coriell houses a Genotyping and Microarray Center that can process up to 2000 DNA or RNA samples a month using Affymetrix GeneChip microarrays, automated processors, and chip scanners. The institute is one of the largest such facilities in the country, performing genome analyses for the CPMC, as well as receiving samples from around the world for genotyping and microarray and gene expression analyses. President and Michael Christman, PhD CEO Michael

Biobanking facility at Coriell Institute.

Christman, PhD, came to Coriell in June 2007 from the Department of Genetics and Genomics at Boston University, where has was chairman. He says, “We are trying to determine best practices in personalized medicine.” To this end, Coriell’s Genome Project involves volunteers, physicians, scientists, ethicists, and information technology experts to understand the impact of genome-informed medical practice and to formulate ethical and legal underpinnings for such practice. Already, the federal government has asked the institute to write a white paper on best practices in personalized medicine with the idea that Coriell’s approach may potentially serve as a national model for the responsible implementation of personalized medicine. The biobanking facility serves the world’s biomedical community by testing, propagating, maintaining, storing, cataloging, and distributing a tremendous variety of cell lines and other cell cultures from its large cryogenic storage facility. It has distributed more than 160,000 samples of cell lines and 50,000 DNA samples a year to 62 nations. It provided support to the Human Genome Project and the International HapMap Project, whose goal is to identify genes associated with human disease and with response to drugs. Courtney, Sill, PhD, director of communications, said that cells stored almost 40 years ago are still viable and available for research purposes. Margaret Keller, PhD, is associate director of the Cell Culture Labor-

atories and director of the New Jersey Stem Cell Resource. She says Coriell holds nearly 2 million ampoules of cells under liquid nitrogen. Besides cells, it keeps DNA from many cell lines or cultures for distribution for research purposes. It also has >20,000 blood samples from the National Institute of Neurological Diseases and Stroke, along with longitudinal medical data on many of them, for research on stroke, epilepsy, and Parkinson disease. For information on the Coriell Cell Repositories, catalogues of cells, and how to access them, visit http://ccr.coriell.org. Keller says that one of the most direct applications of Coriell’s endeavors to oncology is the study of cord blood for transMargaret Keller, plantation. AlPhD though it is easy to obtain, cord blood from any one birth is a limited resource, and more than one donor may be required to have sufficient material for transplant. The institute also has a new research study to collect materials from cancer patients as part of its personalized medicine initiative. “I think where personalized medicine will get the farthest quickest will be in the area of pharmacogenetics,” Keller says, with implications for chemotherapy drug metabolism, efficacy, and the potential for toxicity. n —Daniel M. Keller Contributing writer

Coriell Institute Aims to Give Patients “Actionable Information” From Their Genomes

hrough an ambitious study that plans to collect genetic information on 100,000 individuals, the Coriell Personalized Medicine Collaborative (CPMC) aims to determine best practices for using genetic information in medical care, truly “personalized medicine” at the genome level. This study will identify genetic variants associated with increased disease risks and give study participants information that

they may act on to help them lower their risks. Started in early 2008 and based in Camden, New Jersey, the project has recruited more than 3500 people, mainly in the Delaware Valley of eastern Pennsylvania, New Jersey, and Delaware, to allow analyses of specific regions in their genomes. It expects to enroll 10,000 participants by the end of 2009, with an ultimate goal of 100,000. The CPMC hopes to

gain a population sample ethnically representative of the region, but people anywhere in the country may enroll. The collaborative is a partnership of the Coriell Institute, Cooper University Hospital, Fox Chase Cancer Center, and Virtua Health. Coriell Institute president and CEO Michael Christman, PhD, said that only genetic variants that are “potentially actionable” will be reported to the participants, for

example, an increased risk for developing type 2 diabetes, where a person may choose to lose weight and exercise more to lower the risk. “We’ll tell them only about things that are potentially actionable, and what is potentially actionable is determined by an outside board of experts,” Christman said. This Informed Cohort Oversight Board will meet twice a year to add new actionable information as medical

Journal of Multidisciplinary Cancer Care

science uncovers it. Other examples of currently actionable items are gene variants that elevate the risk of hemochromatosis or coronary artery disease. In the future, genetic risks for certain cancers will also be available to participants, he predicted. CPMC participants may view their own genetic profiles on a secure web site, and only they can grant permission to view it to their healthcare providers, family, or friends. “The principle that we operate under is that your genome information is controlled

by you so you have to grant consent to your physician to view it,” Christman emphasized. The CPMC prepares and educates participants before they can see their results. A genetic counselor appears in a short video on the web site and provides guidance about what to expect, and individuals can elect to discuss their results with a genetic counselor in person or by phone at no cost.

New Standard of Care Medical practice today largely

Genotyping and Microarray Center performs genome analyses for the Coriell Personalized Medicine Collaborative.

“assume[s] everybody is identical genetically. We’re clearly not,” Christman said. Genetic tests “will be the standard of care...in 5 to 10 years,” he predicted. “In the future what you’ll see is patients will just have their genomes scanned, and that will be part of an electronic medical record.” At present, the CPMC study uses a “gene chip” to scan for hundreds of thousand of gene variants, which is only a sample of what is there. In the future, Christman believes, it probably will be feasible to sequence all 3 billion nucleotides in each person’s genome. Beyond the propensity for developing a disease, genetic factors influence how people react to drugs, in terms of both response to therapy and adverse reactions. According to Christman, “Many drugs that are out there on the market already probably only work in a subset of people who take them, and there may be genetic signatures that distinguish which drugs would work for some people and which would not.” Genes encoding the cytochrome system affect drug metabolism, and Christman estimated that some of them are known to affect the processing of 25% of approved drugs. He said Medicare has promulgated rules for such testing before it will reimburse for certain therapies. Oncology may be one of the first areas to capitalize on personalized medicine because “there is no blockbuster drug paradigm,” Christman said.

A patient may be tested for his or her susceptibility to a drug’s toxic effects, and the gene expression of the tumor may indicate which drugs will work best. “It’s well accepted that every cancer is different and requires a different treatment. So the idea of using personal genome information is not necessarily so foreign in thinking about oncology,” Christman explained. People wishing to participate in the CPMC study attend a brief educational session about the study and the enrollment process, read and sign a consent form, submit a saliva sample for genetic testing, and later register for a secure account on the CPMC web site. They also complete online personal and family medical histories and lifestyle questionnaires, updating them yearly. The whole process takes about 90 minutes. Besides providing genetic information to people, the CPMC eventually may mine the database to discover new medically relevant associations based on genetic variants. For information on the study, go to www.corielle.org, and click on “Enroll Now.” The CPMC plans continuing education programs for healthcare providers. “The goal is to catalyze an appreciation among medical professionals about this coming wave of genome-informed medicine because right now they don’t hear much about it,” Christman said. n —Daniel M. Keller Contributing writer

Cancer Risk Factors Folic Acid Fortification May Be Associated with Heightened Colon Cancer Risk T

here may be a rather significant downside to folic acid fortification. According to a newly released study, the rate of colorectal cancer in Chile may have increased since that country began fortifying wheat flour with folic acid. Researchers at the University of Chile in Santiago analyzed changes in colon cancer rates since the Chilean government introduced a mandatory program of folic acid fortification of wheat flour in 2000. Several countries have implemented similar policies in recent years, with the goal of prevent-

May/June 2009

ing spina bifida and other neural tube defects. In Chile, the rate of neural tube defects decreased by 40% in the first year after the start of folic acid fortification. However, there now appears to be a possible caveat to its use. The researchers compared hospital discharge data on colon cancer rates in Chile in 4-year periods before and after folic acid fortification: 1992 to 1996 versus 2001 to 2004. Although no causative relationship can be proved, the data suggested a significant relationship between folic acid supplementation and colorectal can-

cer. Reported cases of colon cancer increased by 162% in people aged 45 to 64 and by 190% in people aged 65 to 79. After adjustment for other factors, discharge diagnoses of colon cancer in these age groups were two to three times more frequent after the start of folic acid fortification. Most other diseases showed no consistent pattern of changes. There was a small increase in breast cancer, which may have been related to early detection and universal treatment programs for that disease.

Chile is the third country to report an apparent increase in colorectal cancer after introducing a national folic acid fortification program. A 2007 report suggested increases in colorectal cancer after folic acid fortification was introduced in the United States and Canada in the mid-1990s. Chile uses a higher “dose” of folic acid than the two North American countries. Folic acid fortification has not yet been introduced in Europe. n —John Schieszer Contributing writer

New ACCC President Seeks to Shine a Light on Oncology Workforce Shortage Continued from page 12 explaining to younger and middleaged students just how meaningful a

role in oncology can be. It is one of the few specialties in which you sometimes have the same patients for years and years now that cancer is

becoming a chronic disease. I am always pleased to see in organizations around the country that patient satisfaction scores are

generally higher in oncology areas than in other areas of the hospital, even in the maternity department. That is true for employee satisfaction scores as well. I think it is because we see our patients long enough to develop relationships with them. We feel a sense of family with our patients, and I think they feel that with us as well. Young healthcare practitioners who are looking for meaningful work can do no better than go into oncology. JOMCC: What are some of the other challenges that community oncology practices are facing?

makes all the difference

LL: Certainly declining Medicare reimbursement for our services is a challenge. The economy is having an interesting impact in another way as well. The number of new patients is declining. From what I am hearing, there may be as much as a 10% decline in new patients, and this has been sustained for at least 6 months. That is concerning because we know the incidence of cancer is not going down. It seems to me that people without insurance or with big gaps in their insurance are choosing not to heed the warning signals that they are getting. The lack of insurance and the perception that cancer is a very expensive disease to treat must be having an impact. We are going to see these patients eventually, but when we do, they will be much further along in their disease. JOMCC: What are your thoughts on how the healthcare system reforms proposed by the Obama administration may affect community cancer care? LL: Several things the administration is recommending could be very helpful to cancer care, including healthcare reform that would increase the number of insured patients. That should result in more people with cancer symptoms being able to seek care. Second, there is a great emphasis on higher education, and nurse practitioners and others in the healthcare professions could be assisted by that. The Kennedy-Hutchinson bill, which we hope to see introduced very soon, is reported to include provisions that would increase funding for cancer survivorship programs and patient navigator assistance, which would be very beneficial. n —Karen Rosenberg

With CancerCare, the difference comes from: • Professional oncology social workers • Free counseling • Education and practical help • Up-to-date information • CancerCare for Kids® For needs that go beyond medical care, refer your patients and their loved ones to CancerCare. CancerCare’s free services help people cope with the emotional and practical concerns arising from a cancer diagnosis and are integral to the standard of care for all cancer patients, as recommended by the Institute of Medicine.

41960ALT_ASize_v1 1

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5/13/08 10:05:24 AM

Journal of Multidisciplinary Cancer Care

Treatment of Metastatic Colon Cancer: A Multidisciplinary Approach Roseleen Charania, MD; Shubham Pant, MD; Susie Morgal, RN, MS, AOCNS; Emily Borders, PharmD In numerous institutions across the country, care of oncology patients is accomplished through a multidisciplinary approach to meet the goal of comprehensive patient care. The following case is that of a 59-year-old man who originally presented with stage I colon cancer, which had been surgically resected. Approximately 1 year later, the patient was found to have an isolated liver metastasis of colon cancer origin. The following commentaries reflect on the evidence and the thought processes behind treating this patient from the views of the physicians, the pharmacist, and the certified oncology nurse.

CASE PRESENTATION Chief complaint: Generalized fatigue for 6 months. History of present illness: The patient was a 59year-old white man who presented to his primary care physician in January 2007 with generalized fatigue for 6 months. A complete blood count revealed microcytic anemia, and his iron profile was consistent with iron deficiency. The fecal occult blood test was positive. The colonoscopy demonstrated a 5-cm frondlike, nonobstructing, villous lesion arising from the descending colon. Biopsies were positive for low-grade, moderately differentiated adenocarcinoma. Tumor marker carcinoembryonic antigen (CEA) was 80 ng/mL (normal, 0-5 ng/mL). There was no evidence of systemic disease on staging computed tomography (CT) scans. He underwent left-sided hemicolectomy and colostomy placement. Pathology findings revealed 4.5-cm, low-grade, moderately differentiated, adenocarcinoma invading into the muscularis propria, but not the subserosa. Twentyfour lymph nodes removed were negative for malignancy. The final diagnosis was stage I (pT2pN0pMx) cancer. Postoperatively, CEA decreased to <0.1 ng/mL. The patient was followed clinically and with CT scans of the chest, abdomen, and pelvis every 3 months. He remained symptom free for 10 months. A follow-up CT in December 2007 demonstrated a 4-cm solitary enhancing lesion in the right lobe of the liver. CEA was elevated at 20

ng/mL. CT-guided biopsy of the liver lesion was consistent with low-grade, moderately differentiated, adenocarcinoma, likely of colon origin. The patient was treated with modified FOLFOX-6 (5fluorouracil, oxaliplatin, leucovorin) for six cycles (1 cycle = 2 weeks), with no significant adverse events. The liver lesion was 1.0 cm in the posttherapy CT scan. He underwent surgical resection with clear margins. He was treated with an additional six cycles of mFOLFOX. He has no evidence of disease progression, 1 year after the end of therapy. Medical history: Hypertension. Surgical history: Left-sided hemicolectomy, January 2007. Family history: Mother: deceased at age 75 with myocardial infarction. Father: deceased at age 70 with congestive heart failure. No family history of any cancers. Social history: Patient has been a lifetime nonsmoker, drinks alcohol socially, and denies any drug use. He currently works as a pharmacy technician. He is married and has three children.

Ms Morgal is Research Clinical Nurse Specialist, Oklahoma University Cancer Institute, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Dr Borders is Clinical Assistant Professor, College of Pharmacy, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

May/June 2009

Vital signs: Temperature: 97.5째F; heart rate: 64 beats/min; blood pressure: 124/74 mm Hg, central venous oxygen saturation: 99%, height: 69 inches; weight: 75 kg. Head Ears Eyes Nose Throat: No pallor, icterus. Oropharynx clear. Neck: Supple, no jugular venous distention, no significant lymphadenopathy. Respiratory: Clear to auscultation. Cardiovascular: Regular rate and rhythm, no murmurs. Abdomen: Soft, nontender, ostomy site clean, normal bowel sounds, no organomegaly. Extremities: No edema, cyanosis, clubbing. Laboratory values:

6.0

13.4 38.2

295

Segs 73/lymphs 21/Eos 2/Monos 4

Medications: Atenolol 50 mg by mouth once a day. Allergies: No known drug allergies.

146 3.9

106 24

0.9

117

CEA: 0.4 ng/mL

Physician Commentary

Dr Charania is Fellow, Division of Hematology/Oncology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma. Dr Pant is Assistant Professor, Division of Hematology/Oncology, Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma.

Physical examination: General: Thinly built white male, well dressed and well nourished, in no acute distress.

Roseleen Charania, MD

Shubham Pant, MD

This patient initially presented with adenocarcinoma of the colon that was surgically resected. There was no lymph node involvement. Current guidelines and evidencebased medicine indicate the benefit of adjuvant therapy is limited to stage III patients and select high-risk stage II patients. This recommendation is

based on numerous studies, including the Multicenter International Study of Oxaliplatin/5-fluorouracil/Leucovorin (MOSAIC), which demonstrated 3year disease-free survival of 73% in patients with resected stage II and III colon cancer.1 Most of the benefit was limited to patients with stage III disease. This study established 5-fluorouracil (FU), oxaliplatin, leucovorin (FOLFOX) as the standard of care in stage III colon cancer. Because this patient presented with stage I disease, adjuvant chemotherapy was not indicated. Ten months later, when the patient presented with isolated liver metasta-

sis, options available were surgery or perioperative chemotherapy. The choice of therapy in metastatic colon cancer is influenced by several factors, such as the extent of metastasis, functional status, prior exposure to chemotherapeutic agents, and hepatic and renal function. More than 50% of patients diagnosed with colon cancer develop liver metastasis during the course of their disease. Surgical resection of the metastasis can be curative and offers long-term survival in 25% to 40% of resectable patients.2 However, unresectable patients who are treated with

palliative chemotherapy alone have a median survival of 12 to 20 months and a 5-year survival rate of less than 5%. Neoadjuvant chemotherapy has been demonstrated to render unresectable metastasis resectable in small studies. For patients with resectable metastasis, neoadjuvant chemotherapy can potentially eliminate micrometastatic disease and shrink the tumor preoperatively, decreasing the extent and morbidity of the surgical procedure.3 In the large phase 3 European Organization for Research and Treatment of Cancer (EORTC) 40983 trial, researchers administered 12 cycles of perioperative FOLFOX, six cycles before and six cycles after surgery. There was improvement in resectability rates and progressionfree survival. Overall survival data are maturing.2 Preoperative chemotherapy is associated with a unique set of side effects. It can induce pathologic changes in the liver parenchyma and potentially increase operative complications. Oxaliplatin has been associated with sinusoidal dilation; hepatic venous congestion; and perisinusoidal fibrosis mimicking venoocclusive disease, which can increase

the risk of intraoperative bleeding and need for transfusions, whereas irinotecan has been implicated in the development of steatohepatitis, with a higher risk of postoperative infections, morbidity, and mortality. However, multiple studies have demonstrated the safety of six cycles of preoperative chemotherapy, with no increase in perioperative morbidity or mortality.4

We recommended a short course of perioperative FOLFOX followed by six cycles of postoperative chemotherapy. Combination chemotherapy with targeted agents, such as the vascular endothelial growth factor inhibitor bevacizumab, has demonstrated improved response rates and overall survival in metastatic colon cancer.5 Perioperative therapy with bevacizumab, however, is associated with risk of organ perforation, bleeding, delayed wound healing, and impaired liver regeneration.5 At the American

Pharmacist Commentary Infusional FOLFOX often is used in the treatment of both adjuvant and metaEmily Borders, static colon canPharmD cer. Pharmacists must consider several issues when treating a patient with this regimen. These issues include proper dosing and preparation, prevention and management of drug-associated adverse effects, screening for drug interactions, and comprehensive patient education. Addressing each of these areas helps achieve the overall goal of obtaining a maximum therapeutic response with the least possible interference in the patientâ&#x20AC;&#x2122;s quality of life. The successful achievement of this goal most often occurs when the pharmacist collaborates with other members of the healthcare team. The pharmacist must provide both the healthcare team and the patient with his or her knowledge of the drugs used in the FOLFOX regimen and how these agents relate to issues described. Before dispensing 5-FU and oxali-

platin, it is important to determine the correct dose for the patient involved and the proper fluids needed to deliver the drugs. FOLFOX is administered over the course of 2 days every 2 weeks and is typically given in the outpatient setting. This necessitates the use of an ambulatory infusion device. The dose of 5-FU is 400 mg/m2 intravenous (IV) bolus on day 1, followed by 2400 mg/m2 IV over 46 hours. Oxaliplatin is given at a dose of 85 mg/m2 IV on day 1 over 2 hours. Dose adjustments for organ dysfunction should be considered only in patients with severe hepatic or renal impairment for 5-FU,8,9 and oxaliplatin should be used with caution in patients with preexisting renal impairment.10 Because our patient had normal hepatic and renal function, it was appropriate to give the patient full doses of each drug. The patient also had no other causes for dose reductions or delay, such as reduced blood counts, drug interactions, a preexisting infection, or toxicity. While 5-FU is compatible with most available solutions, oxaliplatin should only be mixed in 5% dextrose injection.11

Society of Clinical Oncology Gastrointestinal Cancers Symposium held in January 2009, data presented by Zorzi and colleagues from M.D. Anderson Cancer Center suggested that the combination of preoperative chemotherapy with FOLFOX and bevacizumab had significantly higher rates of complete response compared with FOLFOX alone, 58% versus 43%. Complete or major pathologic response was similar in the two groups, 57% for patients receiving fewer than eight cycles of preoperative chemotherapy and 55% in patients receiving more than eight cycles. The incidence of adverse events was not significantly increased in patients receiving fewer than eight cycles of FOLFOX in combination with bevacizumab as compared with FOLFOX alone.6 Use of preoperative cetuximab in combination with cytotoxic chemotherapy has been demonstrated to increase response and resectability rates in patients with Kirsten rat sarcoma (KRAS) wild-type tumors.7 These data look promising, but longer follow-up and multi-institutional studies will help define the role of bevacizumab and cetuximab in this subgroup of patients.

Our patient presented with isolated liver metastasis and, based on the existing randomized phase 3 data, was treated with perioperative FOLFOX. We recommended a short course (ideally six cycles) of perioperative FOLFOX followed by six cycles of postoperative chemotherapy because this patient was a candidate for curative surgical resection. Adjuvant chemotherapy with 12 cycles of FOLFOX in patients who undergo upfront surgical resection of the metastasis is also appropriate, although no data from randomized phase 3 trials are currently available to support this approach. Additionally, irinotecanbased regimens (eg, leucovorin, fluorouracil, and irinotecan [FOLFIRI]) have also been demonstrated to allow for surgical resection of liver metastasis. Although no direct randomized studies have been designed to answer this question, FOLFIRI-based regimens appear to have lower resection rates than oxaliplatin-based regimens, which led to our choice of FOLFOX for this case. Appropriately selected patients may gain additional benefit from neoadjuvant chemotherapy when combined with targeted agents.

After determining the proper dose for this patient, the prevention of regimen-specific adverse effects was addressed. When given as a continuous infusion, 5-FU is associated with toxicities, such as hand-foot syndrome, diarrhea, and mucositis. Prevention strategies for 5-FU toxicities are limited and, thus, close monitoring for the development of each toxicity is vital so that the patient can be treated at symptom onset. Cryotherapy is a common practice used to reduce the incidence and severity of mucositis with many regimens but is not an option when 5-FU is given with oxaliplatin. Oxaliplatin is associated with a unique toxicity profile, which includes two distinct types of neurotoxicities: acute-phase and chronic-phase neuropathy.11 The acute neuropathy is generally characterized as a reversible, primarily peripheral, sensory neuropathy, which is often exacerbated by exposure to cold temperatures. Because of this, cryotherapy should not be used as a mucositis prevention strategy. Calcium gluconate and magnesium sulfate infusions have commonly been used before and after treatment with oxaliplatin to prevent the manifestations of the acute neuropathy. The development of the

acute neuropathy is likely due to the effects of oxalate, a neurotoxic oxaliplatin metabolite. It is hypothesized that by giving calcium and magnesium infusions around oxaliplatin administration, neurotoxicity is prevented through their ability to chelate oxalate, thus inhibiting its neurotoxic effects.10,12,13 Recently this practice has been called into controversy because of a possible deleterious effect on efficacy.14 However, the validity of these data has been called into question,13,15 and many practitioners are choosing to continue to use calcium and magnesium with oxaliplatin, especially in the metastatic setting. FOLFOX is commonly associated with neutropenia; however, the incidence of neutropenic fever is low, and thus routine primary prophylaxis with granulocyte colony-stimulating factors is not recommended in low-risk patients, such as the patient presented in the case.16 Primary prophylaxis can be considered in patients age 65 years and older, as well as patients with poor performance status, organ dysfunction, or preexisting conditions such as neutropenia or infection.16 FOLFOX is categorized as a moderate emetogenic risk and proper prophylaxis with a serotonin antagonist and break-

Journal of Multidisciplinary Cancer Care

through antiemetic, such as promethazine or prochlorperazine, is recommended.17 Dexamethasone is also typically included as an emesis prevention strategy.18 Aprepitant can be considered in subsequent cycles for patients who experience a higher amount of nausea and vomiting with an earlier cycle. Toxicity management is crucial to

avoid dose reductions, delays, and maintenance of the patient’s quality of life. Diarrhea often can be controlled with over-the-counter antidiarrheals, such as loperamide, and patients should be educated on the appropriate dosing. Pain management and good hygiene to prevent infections are important in patients with mucositis. Occasionally, these

Nurse Commentary Oncology nurses are crucial to the comprehensive care of the cancer patient, Susie Morgal, RN, MS, AOCNS regardless of the specific type of cancer, stage of disease, treatment regimen(s) used, or therapeutic response. The nursing role is multifaceted in that the nurse must view each patient in a holistic fashion that encompasses the physical, emotional, spiritual, and economic dimensions unique to the patient and his or her significant relationships. Nurses function as the primary contact for consistency of care and work to build the trust-based relationship crucial to quality care throughout the disease continuum.19 The primary focus for the patient in this case was disease eradication; the nurse’s goal was to maintain quality of life during and after treatment, with emphasis on the lack of disruption of lifestyle, family/social activities, societal responsibilities, and physical and/or emotional functioning.19 The nurse’s role in the care of a colon cancer patient receiving a FOLFOX regimen is not in isolation, but depends on the interaction between patient, physician, pharmacist, and other specialists consulted for their specific area of expertise. Responsibilities of the nurse on the multidisciplinary team include, but are not limited to, patient/family education, treatment administration, adverse event prevention, early detection of symptoms through systematic assessment, referral to additional specialists (eg, physical therapy), and facilitation of the lines of communication among all members of the team.20 Patients often express concern as to how cancer treatment, the schedule of events, and the symptoms of the therapy will affect their day-to-day lives. They question how they will continue to work, support their families financially and emotionally, and not be a burden on employers or family. For patients in the adjuvant setting with a

May/June 2009

good pretreatment performance status and absence of other comorbid conditions affecting their general health, this is a reasonable goal.19 The nurse fulfills this critical role, as well as coordinates teamwork and timing of infusion, and discusses the overall timeframe of the planned course of medical treatment, which gives the patient and his or her family some control of an aspect of the care and allows the patient to become an active member of the multidisciplinary team. Before the actual administration of antitumor therapy, education of the patient and caregiver is essential to comprehensive, quality oncology care. This can be accomplished through various formats, from oneon-one educational time, group classes before the start of the treatment, or in the infusion room/at the chairside the first day of therapy. Regardless of when initial education occurs, it is an ongoing event that is reinforced throughout the course of therapy and will continue into survivorship for proper follow-up and management of any late effects of treatment.19 The patient in this case received FOLFOX after completion of prescribed antinausea prophylaxis. Oxaliplatin and leucovorin calcium were given concurrently over 2 hours via IV infusion, followed by a 5-FU bolus over 5 minutes. Once the bolus was completed, a continuous infusion of 5-FU over 46 hours was begun, via an ambulatory infusion pump as recommended in the literature.21 This patient was treated in the outpatient setting; however, in some cases an extenuating circumstance can require a patient to be admitted to the hospital for chemotherapy administration. Regardless of physical location, the nurse must be attentive to the use of an exclusive dextrose solution for flush and agent suspension, use of all solutions at room temperature, correct connection of the concurrent oxaliplatin and leucovorin solutions (usually through a y-connection) and

conditions may necessitate closer monitoring or IV medications in a hospital setting. Treatment delays and dose reductions are often needed to effectively manage hand-foot syndrome. Other options include the use of topical emollients and creams, systemic and topical corticosteroids, or vitamin E–based products. Many products have been investigated to

manage the neuropathies associated with oxaliplatin. The data on these strategies are limited, and often a dose reduction or cessation of therapy is needed to alleviate the neuropathy. Comprehensive patient education is mandatory to ensure the patient’s ability to recognize these toxicities and take the appropriate steps to minimize their negative effects.

completeness of tubing flush between the oxaliplatin and 5-FU bolus, as these agents are incompatible.22 Additionally, cryotherapy was avoided during the 5-FU bolus due to the acute, cold-initiated sensory neuropathy associated with oxaliplatin. Before the first course of FOLFOX, a central line for IV administration of the chemotherapeutic agents was inserted. An indwelling venous access device (VAD) is preferred for patient convenience and lack of need for daily care when not in use. In certain circumstances (patient preference, other

known to be effective for the FOLFOX regimen.19,22,23 CINV remains one of the most distressing adverse events of cancer treatment, despite effective antiemetic agents. Interventions that are likely to be effective include acupuncture, acupressure, guided imagery, music therapy, progressive muscle relaxation, and psychoeducational support.24 Cancer- and treatment-related fatigue is widely reported and can be a pervasive problem that traverses the disease continuum. Moderate exercise is recommended as well as energy conservation, activity management, relaxation, measures to enhance sleep quality, massage, and healing touch.25 Dermatologic toxicities of treatment include mucositis, hand-foot syndrome, and photosensitivityinduced skin rashes. Mucositis can occur throughout the gastrointestinal tract, but interventions have been studied more frequently for the oral cavity. Various treatments have been identified but lack established effectiveness. An oral care protocol including assessment, education, toothbrushing, flossing, and bland oral rinses is the most widely accepted.26 Hand-foot syndrome (also known as palmar-plantar erythrodysesthesia) has been reported with infusional 5-FU. Patients should be educated to avoid increased heat exposure, sun exposure, and repeated rubbing, friction, or prolonged pressure to the hand and feet during the 5-FU infusion. The use of emollient creams to moisturize the skin and sunscreens with a sun protection factor of at least 15 is recommended.19,20 Patients should also be counseled on strategies to prevent acute oxaliplatininduced neuropathy. Interventions include education of the patient about the signs and symptoms of CIPN, avoidance of cold exposure and use of gloves/scarf during possible exposure to environmental elements. Nurses should conduct a baseline assessment before the first cycle of oxaliplatin therapy and each subsequent cycle, noting any changes in functional ability.19,23,27

The primary focus for the patient in this case was disease eradication; the nurse’s goal was to maintain quality of life during and after treatment. comorbid condition[s] that precludes the use of an indwelling device), a peripherally inserted central line (PICC) will be placed.22 A referral to home health nurse can be made for care of the PICC in the home setting and troubleshooting of the continuous ambulatory infusion device should the need occur.23 Systematic assessment of the patient before, during, and after completion of therapy is crucial. Information gathered from a nursing assessment can identify potential issues or early signs of drug toxicity and guide the patient and team to balance toxicity of treatment against benefit derived.21 Early reporting of signs and symptoms of adverse effects are critical to both symptom management and patient safety. Chemotherapy-induced nausea and vomiting (CINV), mucositis, dermatologic issues (hand-foot syndrome), myelosuppression, chemotherapy-induced peripheral neuropathy (CIPN), and fatigue are toxicities that can be minimized through proper education and early interventions

Continued on page 23

Personalized Medicine for Metastatic Colorectal Cancer: The Role of KRAS Testing and Its Impact on Clinical Decisions A free CME/CE initiative for physicians and nurses Register online at www.questmeded-kras.com

Participate in the Essentialsâ&#x201E;˘ Series: On-site Webcast: Wednesday, June 24, 2009 12:00 NOON - 1:00 PM ET OR 12:00 NOON - 1:00 PM PT

Engage your team in a dialogue about KRAS testing and colorectal cancer within the convenience of your practice setting! Interact with the experts and share your insights with other practices.

On-demand Activity: Launching July 20, 2009 (1 credit hour)

Expert Faculty Axel Grothey, MD, chair Professor of Oncology Mayo Clinic Rochester, Minnesota Neal J. Meropol, MD Director, GI Cancer Program Director, Gastrointestinal Tumor Risk Assessment Program Fox Chase Cancer Center Philadelphia, PA Jointly sponsored by University of California, Irvine School of Medicine and Quest MedEd, LLC

Supported by an educational grant from

Personalized Medicine for Metastatic Colorectal Cancer: The Role of KRAS Testing and Its Impact on Clinical Decisions Statement of Need: The recent, broad introduction of KRAS testing has been hailed as a practice-changing event in colorectal cancer. Many questions remain about the optimal incorporation of testing into practice. This initiative is designed to ensure that the practicing oncology healthcare provider understands the basics of KRAS testing so that he/she can effectively incorporate the test into a strategy for personalizing therapy for patients with mCRC. By using an interactive format in which the learner is questioned about essential information, exposed to expert commentary on that topic, and then given the opportunity to discuss the practical information with the experts/colleagues, the Essentials method provides key information in relevant formats for the learner in two distribution platforms: in either the context of his/her practice environment (Essentials On-site) or via the web as part of self-directed learning (Essentials On-demand). Who Should Participate: The educational series is intended for medical oncologists and other physicians, nurse practitioners, physician assistants, oncology nurses, investigators, and fellows in training with research and management interests in colorectal cancer care throughout the United States. Learning Objectives: At the end of this initiative, the participant should be able to: • Evaluate the data surrounding KRAS testing and outcomes for targeted therapies in mCRC • Define the appropriate use of KRAS testing in mCRC • Identify strategies to overcome the barriers to appropriate use of KRAS testing in the community

Essentials™ On-site Description

Essentials On-Demand Description

Date: Wednesday, June 24, 2009 12:00 PM ET (webcast 1), 12:00 PM PT (webcast 2): Core Content (~35 minutes)* KRAS Testing: What, Why, Who, When, and How? • Data on KRAS as a response marker and as a prognostic marker • Brief review of data for different regimens stratified by KRAS status • Current recommendations on KRAS testing and impact on first-line and subsequent therapy recommendations • Review of options for testing (academic and standardized commercial) • Reimbursement barriers and methods to overcome them 12:35 PM: Open Discussion (~25 minutes) Practices interact with each other and the faculty host in a live Q/A session via telephone Voice Bridge 1:00 PM: Conclusion

Format: 1-hr, interactive, self-study activity with video clips and text-based summaries of the Q/A from the Essentials On-site activity Release Date: July 20, 2009 Expiration Date: July 19, 2010

Registration for all Activities: www.questmeded-kras.com

Accreditation Statement This activity has been planned and implemented in accordance with the Essential Areas and policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint sponsorship of the University of California, Irvine School of Medicine (UCI) and Quest MedEd, LLC. The University of California, Irvine School of Medicine is accredited by the ACCME to provide continuing medical education for physicians. Credit Designation Statement The University of California, Irvine School of Medicine designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. General Disclosure Statement It is the policy of the University of California, Irvine School of Medicine and the University of California CME Consortium to ensure balance, independence, objectivity, and scientific rigor in all CME activities. Full disclosure of conflict resolution will be made in writing via handout materials or syllabus. This activity is in compliance with California Assembly Bill 1195, which requires continuing medical education components to include curriculum in the subjects of cultural and linguistic competency. For specific information regarding Bill 1195 and definitions of cultural and linguistic competency, please visit the CME Web site at http://www.healthaffairs.uci.edu/som/meded/CME/CME-H-AB1195.htm. Nurses: Contact hours for registered nurses are provided by the University of California, Irvine College of Health Sciences, Program in Nursing Science as approved by the California Board of Registered Nursing, Provider Number 11349 for 1.0 contact hours.

Conclusion At the University of Oklahoma, our main goal is to provide cancer patients with the best chance of long-term survival without decreasing our patients’ quality of life. In patients with colon cancer, such as the presented case, care involves surgical resection of isolated liver metastasis after neoadjuvant chemotherapy (most often followed by adjuvant chemotherapy). The physicians, pharmacists, and nurses, each providing core clinical services, work together so our patients can receive all of the chemotherapy needed in this intense approach. Our multidisciplinary system affords our patients the best chance to achieve long-term survival. n

References 1. de Gramont A, Boni C, Navarro M, et al. Oxaliplatin/5FU/LV in adjuvant colon cancer: updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years. J Clin Oncol. 2007;25 (18S):Abstract 4007. 2. Nordlinger B, Sorbye H, Glimelius B, et al; for EORTC Gastro-Intestinal Tract Cancer Group; Cancer Research UK; Arbeitsgruppe Lebermetastasen und-tumoren in der Chirurgischen Arbeitsgemeinschaft Onkologie (ALMCAO); Australasian Gastro-Intestinal Trials Group (AGITG); Fédération Francoph-one de

Cancérologie Digestive (FFCD). Perioperative chemotherapy with FOLFOX4 and surgery versus surgery alone for resectable liver metastases from colorectal cancer (EORTC Intergroup trial 40983): a randomised controlled trial. Lancet. 2008;371:1007-1016. Nordlinger B, Benoist S. Neoadjuvant chemotherapy before resection of colorectal cancer liver metastases. In: ASCO Education Book 2007. Alexandria, VA: American Society of Clinical Oncology; 2007. Aloia T, Sebagh M, Plasse M, et al. Liver histology and surgical outcomes after preoperative chemotherapy with fluorouracil plus oxaliplatin in colorectal cancer liver metastases. J Clin Oncol. 2006;24:4983-4990. Giantonio BJ, Catalano PJ, Meropol NJ, et al; for Eastern Cooperative Oncology Group Study E3200. Bevacizumab in combination with oxaliplatin, fluorouracil, and leucovorin (FOLFOX4) for previously treated metastatic colorectal cancer: results from the Eastern Cooperative Oncology Group Study E3200. J Clin Oncol. 2007;25:1539-1544. Zorzi D, Kishi Y, Maru DM, et al. Effect of extended preoperative chemotherapy on pathologic response and postoperative liver insufficiency after hepatic resection for colorectal liver metastasis. Presented at: ASCO Gastrointestinal Cancers Symposium; 2009. Abstract 295. Tan BR, Zubal B, Hawkins W, et al. Preoperative FOLFOX plus cetuximab or panitumab therapy for patients with potentially resectable hepatic colorectal metastases. Presented at: ASCO Gastrointestinal Cancers Symposium; 2009. Abstract 497. Aronoff GR, Bennett WM, Berns JS, et al. Drug Prescribing in Renal Failure: Dosing Guidelines for Adults and Children. 5th ed. Philadelphia, PA: American College of

Physicians; 2007:100. 9. Koren G, Beatty K, Seto A, et al. The effects of impaired liver function on the elimination of antineoplastic agents. Ann Pharmacother. 1992;26:363-371. 10. Gamelin L, Boisdron-Celle M, Delva R, et al. Prevention of oxaliplatin-related neurotoxicity by calcium and magnesium infusions. Clin Cancer Res. 2004;10(12 Pt 1):4055-4061. 11. Eloxatin (oxaliplatin for injection) [package insert]. Bridgewater, NJ: sanofi-aventis; 2002. 12. Hochster H, Grothey A, Childs BH. Use of calcium and magnesium salts to reduce oxaliplatin-related neurotoxicity. J Clin Oncol. 2007;25:4028-4029. 13. Grolleaus F, Gamelin L, Boisdron-Celle M, et al. A possible explanation for a neurotoxic effect of the anticancer agent oxaliplatin on neuronal voltage-gated sodium channels. J Neurophysiol. 2001;85:2293-2297. 14. Gamelin L, Boisdron-Celle M, Morel A, et al. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy. J Clin Oncol. 2008;26:1188-1189. 15. Hochster H, Grothey A. Oxaliplatin-related neurotoxicity: interest of calcium-magnesium infusion and no impact on its efficacy [authors’ reply]. J Clin Onocol. 2008;26:1189. 16. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Myeloid Growth Factors. V.1.2009. www.nccn. org/professionals/physician_gls/PDF/myeloid_ growth.pdf. Accessed April 13, 2009. 17. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Antiemesis. V.3.2009. www.nccn. org/professionals/physician_gls/PDF/antieme sis.pdf. Accessed April 13, 2009. 18. Kris MG, Hesketh PJ, Somerfield MR, et al. American Society of Clinical Oncology guideline for antiemetics in oncology: update

2006. J Clin Oncol. 2006;24:2932-2947. 19. Viale PH, Sommers R. Nursing care of patients receiving chemotherapy for metastatic colorectal cancer: implications of the treatment continuum concept. Sem Oncol Nurs. 2007;23(suppl 1):22-35. 20. Polvovich M, Whitford JM, Olsen M, eds. Chemotherapy and Biotherapy Guidelines and Recommendations for Practice. 3rd ed. Pittsburgh, PA: Oncology Nursing Society; 2009. 21. Wilkes GM. Therapeutic options in the management of colon cancer: 2005 update. Clin J Oncol Nurs. 2005;9:31-44. 22. Sorich J, Taubes B, Wagner A, Hochester H. Oxaliplatin: practical guidelines for administration. Clin J Oncol Nurs. 2004;8:251-256. 23. Viale PH. Expanded treatment options in the adjuvant therapy of colon cancer: implications for oncology nurses. Oncol Nurs Forum. 2006;33:81-90. 24. Tipton JM, McDaniel RW, Barbour L, et al. Putting evidence into practice: evidencebased interventions to prevent, manage, and treat chemotherapy-induced nausea and vomiting. Clin J Oncol Nurs. 2007; 11:69-78. 25. Mitchell SA, Beck SL, Hood LE, Moore K, Tanner ER. Putting evidence into practice: evidence-based interventions for fatigue during and following cancer and its treatment. Clin J Oncol Nurs. 2007;11:99-113. 26. Harris DJ, Eilers J, Harriman A, Cashavelly BJ, Maxwell C. Putting evidence into practice: evidence-based interventions for the management of oral mucositis. Clin J Oncol Nurs. 2008;12:141-152. 27. Visovsky C, Collins M, Abbott L, Aschenbrenner J, Hart C. Putting evidence into practice: evidence-based interventions for chemotherapy-induced peripheral neuropathy. Clin J Oncol Nurs. 2007;11:901-913.

Reimbursement Support Information for Colorectal Cancer Drugs Many pharmaceutical manufacturers provide clinical information and financial support assistance for patients receiving their drugs. Support lines and websites for colorectal cancer agents are listed below.

Drug

Manufacturer

Support service

Contact data

Vectibix (panitumumab)

Amgen

Reimbursement Connection

800.272.9376 www.amgen.com/reimbursement_connection/vectibix_ using_reimbursement.html

Erbitux (cetuximab)

Bristol-Myers Squibb/ ImClone Systems

Destination Access

800.681.0048 www.destinationaccess.com/index.aspx?bmscontentpg=erbitux

Xeloda (capecitabine)

Roche Laboratories

Oncoline Reimbursement Support

800.443.6676 www.rochereimbursement.com/xeloda/patientassistance

Eloxatin (oxaliplatin)

sanofi-aventis

PACT+ Program

800.996.6626 www.eloxatin.com/support/patient_support/financial_issues.aspx

Avastin (bevacizumab)

Genentech

Access Solutions

888.249.4918 www.genentechaccesssolutions.com/avastin/professional/index.jsp

Camptosar (irinotecan)

Pfizer Oncology

FirstRESOURCE

877.744.5675 www.pfizeroncology.com/reimbursement/first-resource-overview.jsp

Journal of Multidisciplinary Cancer Care

Recent Advances in Treatment of Colorectal Cancer Deena Damsky Dell, MSN, RN-C, AOCN

In the United States, colorectal cancer (CRC) remains the third most common cancer and the third leading cause of cancer deaths for both men and women. When the final numbers come in for 2008, it is expected there will have been 148,810 new cases of CRC and 49,960 deaths. If diagnosed early, the 5-year survival rate for the disease is approximately 93%; however, 20% of patients present with stage IV disease, for which the 5-year survival rate decreases to about 10%. Wider adoption of available effective screening methods should lead to earlier diagnosis and increased survival. In the meantime, surgery and several active agents can be used to manage this disease.1

Deena Damsky Dell, MSN, RN-C, AOCN

Principles of Surgery Before discussing the adjuvant agents used in the treatment of CRC, it must be emphasized that surgery still offers the greatest potential for cure. The goals of surgery are to maintain bowel continuity and anal continence, as well as bladder and sexual functioning. For patients with colon cancer, the surgical standard is a colectomy with en bloc resection of lymph nodes. At least 12 lymph nodes must be resected for adequate staging.2 The value of sentinel lymph node (SLN) biopsy is still under investigation. Studies have shown high falsenegative rates and lack of correlation with outcome when sentinel nodes are examined by immunohistochemistry. Some researchers think that focused examination (ultrastaging) of the SLN to identify micrometastases might help to better identify which stage II patients would benefit from adjuvant therapy.3 The standard surgical procedure for rectal cancer is a sharp dissection of the mesorectum en bloc, which is done with either a low anterior resection or an anterior-posterior resection. Before any surgery, however, it is essential that an endorectal ultrasound be done to ensure correct local staging.4 If the primary tumor has been resected for cure and there are resectable liver or lung metastases, these should also be resected to increase the chance of survival.2 For example, a 5-year survival rate of 30% to 40% can be achieved if liver metastases can be successfully resected.5

Table 1. Level of Evidence and Classification of Recommendations

Principles of Adjuvant Chemotherapy

Class 1:

Benefit >>> Risk

Class 2a:

Benefit >> Risk

Adjuvant chemotherapy is not recommended for stage I colon cancer patients. About 5% of stage II

Class 2b:

Benefit ≥ Risk

Class 3:

Risk ≥ Risk

Ms Dell is Director of the Graduate Nurse Transition Program, Fox Chase Cancer Center, Philadelphia, Pennsylvania.

patients will benefit from adjuvant chemotherapy; the problem is identifying who will benefit. To decide which stage II patients might be high risk, consideration must be given to number of lymph nodes analyzed, tumor size, presence of close or positive margins, presence of perforation and/or peritumoral lymphovascular invasion, grade, and presence of bowel obstruction on presentation.2 Adjuvant!Online is a computerbased program that helps healthcare professionals predict the net benefit of adjuvant treatment for colon cancer based on population data (www. adjuvantonline.com). In addition, Genomic Health, Inc (genomic health.com) is conducting clinical validation studies of a genomic assay to predict individual recurrence and treatment response in early-stage patients following a path similar to that used for OncotypeDX in breast cancer patients. Sargent and associates have suggested that physicians consider testing stage II patients for mismatch repair (MMR) proteins before treating them with 5-fluorouracil (5-FU)-based chemotherapy. They found that patients with defective MMR achieved better results without chemotherapy, and 5FU may actually be detrimental to patients in this group.6 For stage III colon cancer patients, the National Comprehensive Cancer

May/June 2009

Source: Handbook of Emergency Cardiovascular Care for Healthcare Providers. Dallas, TX: American Heart Association; 2008:ii.

Network (NCCN) guidelines recommend 6 months of adjuvant therapy.4 According to the NCCN guidelines, stage II and III rectal cancer patients should receive preoperative concurrent radiation and continuous infusion 5-FU. This is one reason that a staging endorectal ultrasound is so important. Surgery should be followed by 3 to 4 months of adjuvant therapy.

For stage III colon cancer patients, the National Comprehensive Cancer Network guidelines recommend 6 months of adjuvant therapy. The standard of care for adjuvant therapy, established by the Multicenter International Study of Oxaliplatin/ 5-Fluorouracil/Leucovorin in the Adjuvant Treatment of Colon Cancer (MOSAIC) trial, is infusional 5-FU with leucovorin (LV) and oxaliplatin (FOLFOX).7 This is considered a class 1 recommendation for stage III cancer patients, class 2a for high-risk stage II, and class 2b for good or average stage II (Table 1). Bolus 5-FU/LV/oxaliplatin is an alternative regimen but results in more grade 3 and 4 diarrhea. Singleagent capecitabine or 5-FU and LV is considered a class 2a recommendation for stage III and high-risk stage II patients and class 2b for non–high-risk stage II patients. Bolus 5-FU/LV/ irinotecan is not recommended for adjuvant therapy; there is no improvement in overall survival or failure-free survival compared with 5-FU/LV, but there is more neutropenia, neutropenic fever, and death.2,4 If oxaliplatin is used, it should be stopped (with other drugs maintained) after 3 months or sooner if greater than grade 3 neurotoxicity

develops. It may be reintroduced if the tumor progresses. This “stop-andgo” approach results in less toxicity without affecting overall survival in patients with advanced CRC. The NCCN recommends that calcium (Ca) and magnesium (Mg) infusions not be used to prevent neurotoxicity, because studies have shown that the infusions decrease the response to FOLFOX. However, new data from Hochster,8 Grothey,9 and colleagues reveal that Ca/Mg infusions are safe, although their use is questionable because the “stop-and-go” approach is effective. It is important to remember that most trials with capecitabine were done in Europe, and North Americans may not be able to tolerate the same dosage, probably because of genomic differences. The efficacy of lower doses has not been evaluated. Patients who are scheduled to receive irinotecan should be tested for the uridine diphosphate glycuronyltransferase (UGT) 1A1 allele, an enzyme that metabolizes this agent. Patients with the allele have decreased levels of this enzyme and do not metabolize irinotecan as well as those without the allele. Starting doses need to be reduced in these patients to avoid increased toxicity, which manifests as diarrhea, dehydration, and severe neutropenia.2 Three studies are exploring the adjuvant use of bevacizumab with chemotherapy for CRC. Two of these studies have reported initial safety data. The National Surgical Adjuvant Breast and Bowel Project and the National Cancer Institute study C-08 showed more grade 3 or higher adverse advents in the combination arm but no increase in bevacizumab-associated toxicities, such as gastrointestinal perforations, hemorrhage, and peripheral artery or cardiac ischemia.10 The AVANT study confirmed that the overall mortality in the combination arms was consistent with

Table 2. Possible Choices for Systemic Therapy Based on NCCN Guidelines Initial therapy

Progression

Next progression

• FOLFIRI or irinotecan

• Cetuximab plus irinotecan or

Able to tolerate intensive therapy • FOLFOX4 or mFOLFOX6 with bevacizumab or • CapeOX with bevacizumab • FOLFIRI with bevacizumab

(if cannot tolerate) single-agent

• FOLFIRI plus cetuximab (2b) or cetuximab plus irinotecan (2b) • FOLFOX or CapeOX or

cetuximab or panitumumab • Clinical trial or best supportive care • Irinotecan or cetuximab plus

• Cetuximab plus irinotecan or

irinotecan or single-agent cetuximab

single-agent cetuximab or panitumumab

or panitumumab • FOLFOX or CapeOX

Not able to tolerate intensive therapy • 5-FU/LV plus bevacizumab (2b)

• Irinotecan or FOLFIRI

• Cetuximab plus irinotecan or (if cannot tolerate), single-agent cetuximab or panitumumab

• Infusional 5-FU plus LV plus bevacizumab

• Initially unable to tolerate

• If improved, consider intensive

intensive therapy

therapy • No improvement, best supportive care

5-FU indicates 5-fluorouracil; CapeOX, oxaliplatin plus capecitabine; FOLFIRI, irinotecan with 5-FU and LV; FOLFOX, 5-FU with LV and oxaliplatin; LV, leucovorin; mFOLFOX, modified FOLFOX; NCCN, National Comprehensive Cancer Network.

that in other early-stage colon cancer trials.11 Eastern Cooperative Oncology Group E5202 will compare 3-year disease-free survival in high-risk stage II patients randomized to FOLFOX + bevacizumab.

Principles of Systemic Therapy for Advanced and Metastatic Disease The choice of systemic therapy for advanced or metastatic disease depends on the type of prior therapy and the time since initial therapy. Table 2 provides possible options for first and second progressions. The evidence does not support the use of either cetuximab or panitumumab with chemotherapy and bevacizumab. In both the Panitumumab Advanced Colorectal Cancer Evaluation (PACCE) study and CAIRO2 study, there was a significant decrease in progression-free survival when either of these epidermal growth factor receptor (EGFR) inhibitors was added to chemotherapy and bevacizumab.12,13

The Move to Individualized Treatment KRAS status. The anti-EGFR monoclonal antibodies cetuximab and panitumumab are known to be active agents in patients with CRC. Not all patients respond to these drugs, however, and of those who do, not all benefit equally. In 2008, several studies presented at the American Society of Clinical Oncology (ASCO) annual meeting confirmed that 30% to 40% of CRC patients

have a mutant form of the Kirsten rat sarcoma (KRAS) gene (KRAS mt) in their tumors; these patients are unlikely to benefit from these monoclonal antibodies and, therefore, should be saved the cost and toxicity of treatment. In January 2009, ASCO, in its first Provisional Clinical Opinion, recommended routine KRAS testing in patients with metastatic CRC to predict response to EGFR inhibitors.14 The landmark trial in this area was presented by van Cutsem and associates.15 They examined the genomic DNA from archived tissue of 587 patients. Sixty-four percent had wildtype KRAS (KRAS wt), and 36% had KRAS mt. Patients with KRAS mt did not benefit from cetuximab. Bokemeyer and associates examined genomic DNA in 233 patients from the phase 2 OPUS trial and found KRAS mt in 42%. They observed that there was no benefit in adding cetuximab to chemotherapy in patients with KRAS mt, and there was a suggestion that EGFR inhibitors may even be detrimental in patients with this mutation.16 Tejpar and colleagues explored the idea of escalating cetuximab doses in patients who had grade 0/1 skin reactions after 22 days of chemotherapy plus cetuximab. They analyzed archived tissue from 77 of the 89 patients for KRAS mutations. They found that patients with KRAS mt had no benefit from the addition of cetuximab to chemotherapy even with dose escalations of this agent.17 In a retrospective study of 89

irinotecan-refractory patients who were treated with cetuximab, Lièvre and colleagues found that none of the KRAS mt patients responded to cetuximab, whereas 40% of the KRAS wt did respond.18 Amado and associates evaluated KRASstatus as it relates to the efficacy of panitumumab. They compared best supportive care with and without panitumumab. Patients with KRAS mt had a shorter overall survival in both arms of the study, and the incidence of disease progression after panitumumab was nearly two times higher in patients with KRAS mt. The researchers concluded that panitumumab monotherapy appears to be effective only in patients with KRAS wt, and they recommended that KRASgenotyping be performed in all patients with metastatic CRC.19 Baker and colleagues sought to validate biomarkers to further narrow down which patients would respond to EGFR inhibitors. They analyzed tissue samples from 226 patients with advanced CRC from three separate cetuximab monotherapy trials. They looked at not only KRAS mt and wt, but also at the qualitative expression of 102 other candidate genes. Similar to other studies, 32% of patients had KRAS mt. The researchers then studied disease control and overall response rate based on KRAS status. Sixty percent of patients with KRAS wt had disease control compared with 23% of those with KRAS mt. Twenty-two percent of patients with KRAS wt had an overall response rate versus only 1% with KRAS mt. The

researchers concluded that KRAS mutation status identifies 53% of patients who do not benefit from treatment with cetuximab and 42% of patients who are nonresponders. They then chose four genes from the 102 candidate genes to create a final model. With the addition of these four genes to KRAS status, they could identify 58% of the KRAS wt patients who would be candidates for cetuximab therapy, estimating that 85% of these would have true disease control. They concluded that further study was warranted regarding the applicability of multigene models to cetuximab combination therapy.20 Circulating tumor cells. Another exciting development is the identification of the possible predictive role of circulating tumor cells (CTCs) in patients with metastatic CRC. In a prospective multicenter study, CTCs were measured in the peripheral blood of 430 patients at baseline and after starting first-, second-, and third-line therapy. Patients were divided into two groups: those with three or more CTCs (unfavorable group) and those with less than three CTCs (favorable group). The authors found that CTCs provide additional prognostic information to that obtained from imaging studies and that the number of CTCs before and after treatment is an independent predictor of overall and progressionfree survival in metastatic CRC patients. More research is needed, but interesting questions arise. Could CTCs be used for early detection of a need for a different therapy? Could they predict which patients can safely have a treatment break or which ones need targeted therapy?21

Summary We are moving toward individualized treatment for CRC. We know KRAS status can identify patients in whom EGFR may be beneficial. CTCs may help us determine earlier whether a therapy is working. A new assay is on the horizon to provide objective evidence as to which stage II patients will benefit from chemotherapy and which may safely avoid the toxicity and expense. Ongoing clinical trials will give us even more information on the use of targeted chemotherapies in patients with CRC. n

References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2008. CA Cancer J Clin. 2008;58:71-96. 2. National Comprehensive Cancer Network. Practice Guidelines in Oncology: Colon Cancer. V.2.2008. www.nccn.org/professionals/physi cian_gls/PDF/colon.pdf. Accessed October 15, 2008.

Journal of Multidisciplinary Cancer Care

3. Nicholl M, Bilchik AJ. Is routine use of senfor patients with unresectable liver metastases tinel node biopsy justified in colon cancer? from colorectal carcinoma. J Clin Oncol. Ann Surg Oncol. 2008;15:1-3. 2005;23:2038-2048. 4. National Comprehensive Cancer Network. 6. Sargent DJ, Marsoni S, Thibodeau SN, et al. Practice Guidelines in Oncology: Rectal Cancer. Confirmation of deficient mismatch repair 2008. www.nccn.org/professionals/physcian_gls/ (dMMR) as a predictive marker for lack of PDF/rectal.pdf. Accessed October 15, 2008. benefit from 5-FU based chemotherapy in 5. Leonard G, Brenner B, Kemeny NE. Neostage II and III colon cancer (CC); a pooled CoeTOPHouseAd_OnDemand_A:House Page 1 reanalysis of randomized chemoadjuvant chemotherapy beforeAd liver5/19/09 resection3:47 PMmolecular

therapy trials. J Clin Oncol. 2008;26(suppl 20):Abstract 4008. 7. André T, Boni C, Mounedji-Boudiaf M, et al. Oxaliplatin, fluorouracil, and leucovorin as adjuvant treatment for colon cancer. N Engl J Med. 2004;350:2343-2351. 8. Hochster HS, Grothey A, Shpisky A, Childs BH. Effect of intravenous (IV) calcium and magnesium (Ca/Mg) versus placebo on

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May/June 2009

response to FOLFOX + bevacizumab (BEV) in the CONcePT trial. J Clin Oncol. 2008;26(suppl 20):Abstract 280. 9. Grothey A, Hart LL, Rowland KM, et al. Intermittent oxaliplatin (oxali) administration and time-to-treatment failure (TTF) in metastatic colorectal cancer (mCRC): final results of the phase III CONcePT trial. J Clin Oncol. 2008;26(suppl 20):Abstract 4010. 10. Allegra CJ, Yothers G, O’Connell MJ, et al. Initial safety report of NSAPB C-08, a randomized phase III study of modified 5-fluorouracil (5-FU)/leucovorin (LCV) and oxaliplatin (OX) (mFOLFOX6) with or without bevacizumab (bev) in the adjuvant treatment of patients with stage II/III colon cancer. J Clin Oncol. 2008;26(suppl 20):Abstract 4006. 11. Roche Pharmaceuticals. Recruitment planned to resume in AVANT international phase III trial in post-surgical adjuvant colon cancer. Investor Update. 2006. www.roche.com/ investors/ir_update/inv-update-2006-0523.htm. Accessed October 16, 2008. 12. Hecht R, Mitchell E, Chidiac T, et al. An updated analysis of safety and efficacy of oxaliplatin (Ox)/bevacizumab (bev) +/- panitumumab (pmab) for first-line treatment (tx) of metastatic colorectal cancer (mCRC) from a randomized, controlled trial (PACCE). J Clin Oncol. 2008;26(suppl 20):Abstract 273. 13. Punt CJ, Tol J, Rodenburg CJ, et al. Randomized phase III study of capecitabine, oxaliplatin, and bevacizumab with or without cetuximab in advanced colorectal cancer (ACC), the CAIRO2 study of the Dutch Colorectal Cancer Group (DCCG). J Clin Oncol. 2008;26(suppl 20):Abstract LBA4011. 14. Allegra CJ, Jessup JM, Somerfield MR, et al. American Society of Clinical Oncology Provisional Clinical Opinion: Testing for KRAS gene mutations in patients with metastatic colorectal carcinoma to predict response to anti-epidermal growth factor receptor monoclonal antibody therapy. J Clin Oncol. 2009;27:2091-2096. 15. van Cutsem E, Lang I, D’haens G, et al. KRAS status and efficacy in the first-line treatment of patients with metastatic colorectal cancer (mCRC) treated with FOLFIRI with or without cetuximab: the CRYSTAL experience. J Clin Oncol. 2008;26(suppl 20):Abstract 2. 16. Bokemeyer C, Bondarenko I, Hartmann JT, et al. KRAS status and efficacy of first-line treatment of patients with metastatic colorectal cancer (mCRC) with FOLFOX with or without cetuximab: the OPUS experience. J Clin Oncol. 2008;26(suppl 20):Abstract 4000. 17. Tejpar S, Peeters M, Humblet Y, et al. Relationship of efficacy with KRAS status (wild type versus mutant) in patients with irinotecan-refractory metastatic colorectal cancer (mCRC) treated with irinotecan (q2w) and escalating doses of cetuximab (q1w): the EVEREST experience (preliminary data). J Clin Oncol. 2008;26(suppl 20):Abstract 4001. 18. Lièvre A, Bachet JB, Boige V, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374-379. 19. Amado RG, Wolf M, Freeman D, et al. Panitumumab (pmab) efficacy and patientreported outcomes (PRO) in metastatic colorectal cancer (mCRC) patients (pts) with wild-type (WT) KRAS tumor status. J Clin Oncol. 2008;26(suppl 20):Abstract 278. 20. Baker JB, Dutta D, Watson D, et al. Evaluation of tumor gene expression and KRas mutations in FFPE tumor tissue as predictors of response to cetuximab in metastatic colorectal cancer. J Clin Oncol. 2008;26(suppl 20):Abstract 3512. 21. Cohen S, Punt CJ, Iannotti N, et al. Relationship of circulating tumor cells to tumor response, progression-free survival, and overall survival in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:3213-3221.

Colorectal Cancer Drugs in Phase 3 and 4 Trials in the United States New drugs and combinations are being studied for the treatment of colorectal cancer (CRC). Selected ongoing trials and those currently recruiting patients are listed below.

Drug name, developer(s)

Study

Status

5-FU; l-leucovorin Tegafur; uracil; leucovorin (new combinations)

• Comparing adjuvant oral tegafur/uracil/levcovorin to 5-fluorouracil/l-leucovorin in stage III CRC

Active

Aflibercept (VEGF trap) Regeneron, sanofi-aventis

• Afilbercept vs placebo in combination with irinotecan/5-fluorouracil in metastatic CRC after failure of an oxaliplatin-based regimen

Recruiting

Avastin (bevacizumab) Genentech

• Combination chemotherapy/bevacizumab with/without erlotinib in metastatic CRC that cannot be removed by surgery

Recruiting

• Avastin/chemotherapy for CRC and non–small-cell lung cancer

Recruiting

• Avastin/Xeloda in elderly patients with metastatic CRC

Recruiting

• Avastin/crossover fluoropyrimidine-based chemotherapy in metastatic CRC

Recruiting

Brivanib (VEGFR/FGFR kinase inhibitor) Bristol-Myers Squibb

• Cetuximab with/without brivanib in metastatic CRC

Recruiting

Celebrex (celecoxib) Pfizer

• Celecoxib to prevent CRC in patients who have undergone surgery to remove polyps • Combination chemotherapy with/without celecoxib in metastatic CRC • Celecoxib combined with fluorouracil/leucovorin in resected stage III adenocarcinoma of the colon • Prevention of progression of duodenal adenomas in patients with familial adenomatous polyposis

Active Active Active

Erbitux (cetuximab) Bristol-Myers Squibb, ImClone Systems

• Cetuximab and/or bevacizumab combined with combination chemotherapy in metastatic CRC • FOLFIRI plus cetuximab vs FOLFIRI plus bevacizumab in first-line treatment of CRC • Combination chemotherapy with/without cetuximab before/after surgery in patients with resectable liver metastases caused by CRC • Comparing combination chemotherapy regimens with/without cetuximab in patients who have undergone surgery for stage III colon cancer • Combination chemotherapy with/without cetuximab in patients with stage III colon cancer completely removed by surgery

Recruiting Recruiting Recruiting

Recruiting

Recruiting Recruiting

Litx (talaporfin) Light Sciences Oncology

• Litx plus chemotherapy vs chemotherapy only in CRC patients with recurrent liver metastases

Recruiting

NKTR 102 Nektar Therapeutics

• NKTR-102 vs irinotecan in second-line, irinotecan-naïve, KRAS mutant, CRC

Recruiting

S-1 sanofi-aventis

• S-1/oxaliplatin vs capecitabine/oxaliplatin in advanced CRC

Recruiting

Sutent (sunitinib) Pfizer

• FOLFIRI chemotherapy with/without sunitinib in metastatic CRC

Recruiting

Tarceva (erlotinib) Genentech, OSI Pharmaceuticals

• Combination chemotherapy and bevacizumab with/without erlotinib in metastatic CRC that cannot be removed by surgery • Chemotherapy and Avastin followed by maintenance with Avastin with/without Tarceva

Recruiting Recruiting

Tegafur; uracil (new combination) Merck KGaA

• Tegafur/uracil or observation in stage II CRC completely removed by surgery

Recruiting

Vectibix (panitumumab) Amgen

• Irinotecan with/without panitumumab or cyclosporine in advanced or metastatic CRC that did not respond to fluorouracil • ABX-EGF plus best supportive care vs best supportive care in metastatic CRC • Efficacy of panitumumab in combination with chemotherapy in metastatic CRC • Comparing chemotherapy with panitumumab to chemotherapy alone • Fluorouracil/oxaliplatin with/without panitumumab in high-risk colon cancer that can be removed by surgery

Recruiting

Xeloda (capecitabine) Roche

Active Active Active Recruiting

• Xeloda/eloxatin for advanced or metastatic CRC • Two schedules of Xeloda as first-line therapy in metastatic CRC • Adjuvant Xeloda/eloxatin with/without Avastin after radical resection of liver metastasis of CRC

Active Active Recruiting

• Xeloda as adjuvant monotherapy in patients with colon cancer

Recruiting

FOLFIRI indicates 5-fluorouracil/folinic acid/irinotecan; KRAS, Kirsten rat sarcoma.

Journal of Multidisciplinary Cancer Care

Are You Getting the Most from Your KRAS Testing? Continued from page 13 into its guideline update5/19/09 (see page 14). thing—that NurseNavigAd_Asize:NurseNavigatorAd 3:28 PM Page 1 ASCO has also released a second PCO, that basically says the same

physicians should be screening for KRAS status. And then you have UnitedHealthcare, from a

payer perspective, saying that physicians should be screening also. The FDA is the only group that is holding

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AONN membership is for Oncology Nurses—AND all Oncology Caregivers, including Nurse Navigators, Practice Managers, Patient Care Coordinators, and Nursing Administrators, devoted to the complexities of the cancer care treatment continuum. Information on patient care and treatment strategies, side effect management, patient outreach, navigation programs, and much more is thoroughly covered in AONN’s vast resources. AONN membership provides you with: • A subscription to the journal, The Oncology Nurse (TON) (a $150 value), and the bimonthly Journal of Multidisciplinary Cancer Care.

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Join a network of individuals dedicated to enhancing the lives of Cancer Patients. Join AONN. May/June 2009

CU: Our laboratory is looking at KRAS mutations for the development of drugs, because we feel it is important to select the right patient for the right drugs. Therefore, we are very committed to that process. Not all KRAS wildtype patients respond to panitumumab or cetuximab, and we would like to understand why. If there is a yet unidentified marker like KRAS (perhaps BRAF) that can do an even better job, that is what we would like to discover and test. n —Dawn Lagrosa

• Free patient brochures on a range of issues impacting cancer patients (eg, Treatment Guidelines, CINV, Pain Management, DVT, Chemotherapy Toxicities, Skin Reactions, Reimbursement Information, Coding Updates) will soon be available.

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steady, which is understandable. The available analysis for KRAS was not done prospectively. It was done retrospectively. The study indicated that the response rate in KRAS mutationexpressing patients would be zero. Whereas if oncologists would only treat patients with wild-type KRAS, there would be a much better response rate, in some cases, even as high as 70%. The FDA is taking a very conservative approach by saying that it is not going to immediately make a decision based only on a retrospective clinical trial. It would prefer collaborative data from a prospective study.

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Medications Used for the Treatment of Colorectal Cancer

olorectal cancer is a term used to refer to cancer that starts in either the colon or the rectum. Colon cancer and rectal cancer have many features in common. The following sections will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of colorectal cancer.

The following sections include: • Associated ICD-9-CM codes used for the classification of colorectal cancer • Drugs that have been FDA-approved in the treatment of colorectal cancer 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 colorectal cancer. 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 Colorectal Cancer 153

Malignant neoplasm of colon Excludes: benign carcinoid tumor of colon (209.50-209.56) malignant carcinoid tumor of colon (209.10-209.16) 153.0 Hepatic flexure 153.1 Transverse colon 153.2 Descending colon Left colon 153.3 Sigmoid colon Sigmoid (flexure) Excludes: rectosigmoid junction (154.0) 153.4 Cecum Ileocecal valve 153.5 Appendix 153.6 Ascending colon Right colon 153.7 Splenic flexure 153.8 Other specified sites of large intestine Malignant neoplasm of contiguous or overlapping sites of colon whose point of origin cannot be determined Excludes: ileocecal valve (153.4) rectosigmoid junction (154.0) 153.9 Colon, unspecified Large intestine NOS

154

Malignant neoplasm of rectum, rectosigmoid junction, and anus Excludes: benign carcinoid tumor of rectum (209.57) malignant carcinoid tumor of rectum (209.17) 154.0 Rectosigmoid junction Colon with rectum Rectosigmoid (colon) 154.1 Rectum Rectal ampulla 154.2 Anal canal Anal sphincter Excludes: skin of anus (172.5, 173.5) 154.3 Anus, unspecified Excludes: anus: margin (172.5, 173.5) skin (172.5, 173.5) perianal skin (172.5, 173.5) 154.8 Other Anorectum Cloacogenic zone Malignant neoplasm of contiguous or overlapping sites of rectum, rectosigmoid junction, and anus whose point of origin cannot be determined

Journal of Multidisciplinary Cancer Care

FDAapproved for colorectal cancer

Generic (brand) name

HCPCS code: code description

bevacizumab (Avastin)

J9035: injection bevacizumab, 10 mg

capecitabine (Xeloda)

J8520: capecitabine, oral, 150 mg

capecitabine (Xeloda)

J8521: capecitabine, oral, 500 mg

cetuximab (Erbitux)

J9055: injection, cetuximab, 10 mg

floxuridine (FUDR)

J9200: injection, floxuridine, 500 mg

fluorouracil (Adrucil)

J9190: injection, fluorouracil, 500 mg

irinotecan (Camptosar)

J9206: injection, irinotecan, 20 mg

leucovorin calcium

J0640: injection, leucovorin calcium, per 50 mg

oxaliplatin (Eloxatin)

J9263: injection, oxaliplatin, 0.5 mg

panitumumab (Vectibix)

J9303: injection, panitumumab, 10 mg

NCCN Drugs and Biologics Compendium off-label use for colorectal cancer

Current code price (AWPbased pricing)

Medicare allowable (ASP + 6%), effective 4/1/09-6/30/09

CPT administration codes

$68.75

$57.40

$7.35

$5.28

N/A

$24.50

$17.51

N/A

$60.00

$49.73

96413, 96415

$121.50

$58.08

96422, 96423, 96425

$3.44

$1.55

$32.82

$18.30

96413, 96415

$3.75

$0.87

96372, 96374, 96409

$12.26

$9.54

96413, 96415

$106.09

$84.29

96413, 96415

96409

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 2; RJ Health Systems International LLC; 2nd Quarter 2009 • FDA-approved indication (from products’ prescribing information) • NCCN • American Cancer Society • www.ReimbursementCodes.com powered by RJ Health Systems International, LLC., Wethersfield, Connecticut • CMS-Medicare allowable 2nd Quarter 2009 (effective dates 4/1/096/30/09). Prices listed herein are effective as of May 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:

The Most Comprehensive HCPCS/CPT Drug and Product Reimbursement Coding and Pricing Service Available! ReimbursementCodes.com is an online HCPCS/CPT reimbursement coding and pricing service that provides up-to-date reimbursement information. You have the ability to accurately match reimbursement to the corresponding date of service for every claim! • Drugs which are injected subcutaneously, intramuscularly, or intravenously • Selected orally administered chemotherapeutic and antiemetic agents • Nutritional agents and ostomy care products • Drugs administered via nebulizers or other DME equipment • Radiopharmaceuticals Plus a fast and efficient avenue to HCPCS/CPT coding and reimbursement information! • In billable units matching the CMS- and AMA-established reimbursement code description • A validated pricing methodology • Includes all price changes that have occurred for each code, along with the effective date of the change(s)

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RITUXAN® (Rituximab) Brief summary—Please consult full prescribing information. WARNING: FATAL INFUSION REACTIONS, TUMOR LYSIS SYNDROME (TLS), SEVERE MUCOCUTANEOUS REACTIONS, and PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY (PML) Infusion Reactions: Rituxan administration can result in serious, including fatal infusion reactions. Deaths within 24 hours of Rituxan infusion have occurred. Approximately 80% of fatal infusion reactions occurred in association with the first infusion. Carefully monitor patients during infusions. Discontinue Rituxan infusion and provide medical treatment for Grade 3 or 4 infusion reactions [see Warnings and Precautions, Adverse Reactions]. Tumor Lysis Syndrome (TLS): Acute renal failure requiring dialysis with instances of fatal outcome can occur in the setting of TLS following treatment of non-Hodgkin’s lymphoma (NHL) patients with Rituxan [see Warnings and Precautions, Adverse Reactions]. Severe Mucocutaneous Reactions: Severe, including fatal, mucocutaneous reactions can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions]. Progressive Multifocal Leukoencephalopathy (PML): JC virus infection resulting in PML and death can occur in patients receiving Rituxan [see Warnings and Precautions, Adverse Reactions].

INDICATIONS AND USAGE Non-Hodgkin’s Lymphoma (NHL) Rituxan® (rituximab) is indicated for the treatment of patients with: Relapsed or refractory, low-grade or follicular, CD20-positive, B-cell NHL as a single agent; Previously untreated follicular, CD20-positive, B-cell NHL in combination with CVP chemotherapy; Non-progressing (including stable disease), low-grade, CD20positive B-cell NHL, as a single agent, after first-line CVP chemotherapy; Previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens. WARNINGS AND PRECAUTIONS Infusion Reactions Rituxan can cause severe, including fatal, infusion reactions. Severe reactions typically occurred during the first infusion with time to onset of 30–120 minutes. Rituxan-induced infusion reactions and sequelae include urticaria, hypotension, angioedema, hypoxia, bronchospasm, pulmonary infiltrates, acute respiratory distress syndrome, myocardial infarction, ventricular fibrillation, cardiogenic shock, or anaphylactoid events. Premedicate patients with an antihistamine and acetaminophen prior to dosing. Institute medical management (e.g., glucocorticoids, epinephrine, bronchodilators, or oxygen) for infusion reactions as needed. Depending on the severity of the infusion reaction and the required interventions, consider resumption of the infusion at a minimum 50% reduction in rate after symptoms have resolved. Closely monitor the following patients: those with preexisting cardiac or pulmonary conditions, those who experienced prior cardiopulmonary adverse reactions, and those with high numbers of circulating malignant cells (≥25,000/mm3). [See Boxed Warning, Warnings and Precautions, Adverse Reactions.] Tumor Lysis Syndrome (TLS) Rapid reduction in tumor volume followed by acute renal failure, hyperkalemia, hypocalcemia, hyperuricemia, or hyperphosphatemia, can occur within 12–24 hours after the first infusion. Fatal TLS cases have occurred after administration of Rituxan. A high number of circulating malignant cells (≥25,000/mm3) or high tumor burden confers a greater risk of TLS after rituximab. Consider prophylaxis for TLS in patients at high risk. Correct electrolyte abnormalities, monitor renal function and fluid balance, and administer supportive care, including dialysis as indicated. [See Boxed Warning.] Severe Mucocutaneous Reactions Mucocutaneous reactions, some with fatal outcome, can occur in patients treated with Rituxan. These reactions include paraneoplastic pemphigus, Stevens-Johnson syndrome, lichenoid dermatitis, vesiculobullous dermatitis, and toxic epidermal necrolysis. The onset of these reactions has varied from 1–13 weeks following Rituxan exposure. Discontinue Rituxan in patients who experience a severe mucocutaneous reaction. The safety of readministration of Rituxan to patients with severe mucocutaneous reactions has not been determined. [See Boxed Warning, Adverse Reactions.] Progressive Multifocal Leukoencephalopathy (PML) JC virus infection resulting in PML and death can occur in Rituxan-treated patients with hematologic malignancies or with autoimmune diseases. The majority of patients with hematologic malignancies diagnosed with PML received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. The patients with autoimmune diseases had prior or concurrent immunosuppressive therapy. Most cases of PML were diagnosed within 12 months of their last infusion of Rituxan. Consider the diagnosis of PML in any patient presenting with new-onset neurologic manifestations. Discontinue Rituxan and consider discontinuation or reduction of any concomitant chemotherapy or immunosuppressive therapy in patients who develop PML. [See Boxed Warning, Adverse Reactions.] Hepatitis B Virus (HBV) Reactivation Hepatitis B Virus (HBV) reactivation with fulminant hepatitis, hepatic failure, and death can occur in patients with hematologic malignancies treated with Rituxan. The median time to the diagnosis of hepatitis was approximately 4 months after the initiation of Rituxan and approximately one month after the last dose. Screen patients at high risk of HBV infection before initiation of Rituxan. Closely monitor carriers of hepatitis B for clinical and laboratory signs of active HBV infection for several months following Rituxan therapy. Discontinue Rituxan and any concomitant chemotherapy in patients who develop viral hepatitis, and institute appropriate treatment including antiviral therapy. Insufficient data exist regarding the safety of resuming Rituxan in patients who develop hepatitis subsequent to HBV reactivation. [See Adverse Reactions.] Other Viral Infections The following additional serious viral infections, either new, reactivated, or exacerbated, have been identified in clinical studies or postmarketing reports. The majority of patients received Rituxan in combination with chemotherapy or as part of a hematopoietic stem cell transplant. These viral infections included cytomegalovirus, herpes simplex virus, parvovirus B19, varicella zoster virus, West Nile virus, and hepatitis C. In some cases, the viral infections occurred as late as one year following discontinuation of Rituxan and have resulted in death. [See Adverse Reactions.] Cardiovascular Discontinue infusions for serious or life-threatening cardiac arrhythmias. Perform cardiac monitoring during and after all infusions of Rituxan for patients who develop clinically significant arrhythmias or who have a history of arrhythmia or angina. [See Adverse Reactions.] Renal Severe, including fatal, renal toxicity can occur after Rituxan administration in patients with hematologic malignancies. Renal toxicity has occurred in patients with high numbers of circulating malignant cells (≥25,000/mm3) or high tumor burden who experience tumor lysis syndrome and in patients with NHL administered concomitant cisplatin therapy during clinical trials. The combination of cisplatin and Rituxan is not an approved treatment regimen. Use extreme caution if this non-approved combination is used in clinical trials and monitor closely for signs of renal failure. Consider discontinuation of Rituxan for patients with a rising serum creatinine or oliguria. Bowel Obstruction and Perforation Abdominal pain, bowel obstruction and perforation, in some

cases leading to death, can occur in patients receiving Rituxan in combination with chemotherapy. In postmarketing reports, the mean time to documented gastrointestinal perforation was 6 (range 1–77) days in patients with NHL. Perform a thorough diagnostic evaluation and institute appropriate treatment for complaints of abdominal pain, especially early in the course of Rituxan therapy. [See Adverse Reactions.] Immunization The safety of immunization with live viral vaccines following Rituxan therapy has not been studied and vaccination with live virus vaccines is not recommended. For NHL patients, the benefits of primary or booster vaccinations should be weighted against the risks of delay in initiation of Rituxan therapy. Laboratory Monitoring Because Rituxan binds to all CD20positive B lymphocytes (malignant and non-malignant), obtain complete blood counts (CBC) and platelet counts at regular intervals during Rituxan therapy and more frequently in patients who develop cytopenias [see Adverse Reactions]. The duration of cytopenias caused by Rituxan can extend months beyond the treatment period. ADVERSE REACTIONS The most common adverse reactions of Rituxan (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia. The most important serious adverse reactions of Rituxan are infusion reactions, tumor lysis syndrome, mucocutaneous toxicities, hepatitis B reactivation with fulminant hepatitis, PML, other viral infections, cardiac arrhythmias, renal toxicity, and bowel obstruction and perforation. Clinical Trials Experience Non-Hodgkin’s Lymphoma Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in practice. The data described below reflect exposure to Rituxan in 1606 patients, with exposures ranging from a single infusion up to 6–8 months. Rituxan was studied in both single-agent and active-controlled trials (n = 356 and n = 1250). These data were obtained in adults with low-grade, follicular, or DLBCL NHL. Most patients received Rituxan as an infusion of 375 mg/m2 per infusion, given as a single agent weekly for up to 8 doses, in combination with chemotherapy for up to 8 doses, or following chemotherapy for up to 16 doses. Infusion Reactions In the majority of patients with NHL, infusion reactions consisting of fever, chills/rigors, nausea, pruritus, angioedema, hypotension, headache, bronchospasm, urticaria, rash, vomiting, myalgia, dizziness, or hypertension occurred during the first Rituxan infusion. Infusion reactions typically occurred within 30 to 120 minutes of beginning the first infusion and resolved with slowing or interruption of the Rituxan infusion and with supportive care (diphenhydramine, acetaminophen, and intravenous saline). The incidence of infusion reactions was highest during the first infusion (77%) and decreased with each subsequent infusion. [See Boxed Warning, Warnings and Precautions.] Infections Serious infections (NCI CTCAE Grade 3 or 4), including sepsis, occurred in less than 5% of patients with NHL in the single-arm studies. The overall incidence of infections was 31% (bacterial 19%, viral 10%, unknown 6%, and fungal 1%). [See Warnings and Precautions.] In randomized, controlled studies where Rituxan was administered following chemotherapy for the treatment of follicular or low-grade NHL, the rate of infection was higher among patients who received Rituxan. In diffuse large B-cell lymphoma patients, viral infections occurred more frequently in those who received Rituxan. Cytopenias and hypogammaglobulinemia In patients with NHL receiving rituximab monotherapy, NCI-CTC Grade 3 and 4 cytopenias were reported in 48% of patients. These included lymphopenia (40%), neutropenia (6%), leukopenia (4%), anemia (3%), and thrombocytopenia (2%). The median duration of lymphopenia was 14 days (range, 1–588 days) and of neutropenia was 13 days (range, 2–116 days). A single occurrence of transient aplastic anemia (pure red cell aplasia) and two occurrences of hemolytic anemia following Rituxan therapy occurred during the single-arm studies. In studies of monotherapy, Rituxan-induced B-cell depletion occurred in 70% to 80% of patients with NHL. Decreased IgM and IgG serum levels occurred in 14% of these patients. Single-Agent Rituxan Adverse reactions in Table 1 occurred in 356 patients with relapsed or refractory, lowgrade or follicular, CD20-positive, B-cell NHL treated in single-arm studies of Rituxan administered as a single agent. Most patients received Rituxan 375 mg/m2 weekly for 4 doses. Table 1 Incidence of Adverse Events in ≥5% of Patients with Relapsed or Refractory, LowGrade or Follicular NHL, Receiving Single-agent Rituxan (N = 356)a,b

Chemotherapy for DLBCL In Studies 6 and 7, the following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs. 46%), lung disorder (31% vs. 24%), cardiac disorder (29% vs. 21%), and chills (13% vs. 4%). Detailed safety data collection in these studies was primarily limited to Grade 3 and 4 adverse reactions and serious adverse reactions. In Study 7, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs. 1.0% for CHOP). The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs. 7%) and lung disorder (6% vs. 3%). Other Grade 3 or 4 adverse reactions occurring more frequently among patients receiving R-CHOP were viral infection (Study 7), neutropenia (Studies 7 and 8), and anemia (Study 8). Immunogenicity As with all therapeutic proteins, there is a potential for immunogenicity. The observed incidence of antibody (including neutralizing antibody) positivity in an assay is highly dependent on several factors including assay sensitivity and specificity, assay methodology, sample handling, timing of sample collection, concomitant medications, and underlying disease. For these reasons, comparison of the incidence of antibodies to Rituxan with the incidence of antibodies to other products may be misleading. Using an ELISA assay, antihuman anti-chimeric antibody (HACA) was detected in 4 of 356 (1.1%) patients with low-grade or follicular NHL receiving single-agent Rituxan. Three of the four patients had an objective clinical response. The clinical relevance of HACA formation in rituximab treated patients is unclear. Postmarketing Experience The following adverse reactions have been identified during postapproval use of Rituxan in hematologic malignancies. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Decisions to include these reactions in labeling are typically based on one or more of the following factors: (1) seriousness of the reaction, (2) frequency of reporting, or (3) strength of causal connection to Rituxan. Hematologic: prolonged pancytopenia, marrow hypoplasia, and late-onset neutropenia, hyperviscosity syndrome in Waldenstrom’s macroglobulinemia. Cardiac: fatal cardiac failure. Immune/Autoimmune Events: uveitis, optic neuritis, systemic vasculitis, pleuritis, lupus-like syndrome, serum sickness, polyarticular arthritis, and vasculitis with rash. Infection: viral infections, including progressive multifocal leukoencephalopathy (PML), increase in fatal infections in HIV-associated lymphoma, and a reported increased incidence of Grade 3 and 4 infections in patients with previously treated lymphoma without known HIV infection. Neoplasia: disease progression of Kaposi’s sarcoma. Skin: severe mucocutaneous reactions. Gastrointestinal: bowel obstruction and perforation. Pulmonary: fatal bronchiolitis obliterans and pneumonitis (including interstitial pneumonitis). DRUG INTERACTIONS Formal drug interaction studies have not been performed with Rituxan. USE IN SPECIFIC POPULATIONS Pregnancy Category C: There are no adequate and well-controlled studies of rituximab in pregnant women. Postmarketing data indicate that B-cell lymphocytopenia generally lasting less than six months can occur in infants exposed to rituximab in-utero. Rituximab was detected postnatally in the serum of infants exposed in-utero. Non-Hodgkin’s lymphoma is a serious condition that requires treatment. Rituximab should be used during pregnancy only if the potential benefit to the mother justifies the potential risk to the fetus. Reproduction studies in cynomolgus monkeys at maternal exposures similar to human therapeutic exposures showed no evidence of teratogenic effects. However, B-cell lymphoid tissue was reduced in the offspring of treated dams. The B-cell counts returned to normal levels, and immunologic function was restored within 6 months of birth. Nursing Mothers It is not known whether Rituxan is secreted into human milk. However, Rituxan is secreted in the milk of lactating cynomolgus monkeys, and IgG is excreted in human milk. Published data suggest that antibodies in breast milk do not enter the neonatal and infant circulations in substantial amounts. The unknown risks to the infant from oral ingestion of Rituxan should be weighed against the known benefits of breastfeeding. Pediatric Use The safety and effectiveness of Rituxan in pediatric patients have not been established. Geriatric Use Diffuse Large B-Cell NHL Among patients with DLBCL evaluated in three randomized, activecontrolled trials, 927 patients received Rituxan in combination with chemotherapy. Of these, 396 (43%) were age 65 or greater and 123 (13%) were age 75 or All Grades (%) Grade 3 and 4 (%) All Grades (%) Grade 3 and 4 (%) greater. No overall differences in effectiveness were observed between these Respiratory System Any Adverse Events 99 57 38 4 patients and younger patients. Cardiac adverse reactions, mostly supraventricular Body as a Whole Increased Cough 13 1 86 10 Rhinitis 12 1 Fever 53 1 arrhythmias, occurred more frequently among elderly patients. Serious pulmonary Bronchospasm 8 1 Chills 33 3 adverse reactions were also more common among the elderly, including Dyspnea 7 1 Infection 31 4 Sinusitis 6 0 Asthenia 26 1 pneumonia and pneumonitis. Low-Grade or Follicular Non-Hodgkin’s Metabolic and Nutritional Headache 19 1 Lymphoma Clinical studies of Rituxan in low-grade or follicular, CD20-positive, Abdominal Pain 14 1 Disorders 38 3 Pain 12 1 Angioedema 11 1 B-cell NHL did not include sufficient numbers of patients aged 65 and over to Back Pain 10 1 Hyperglycemia 9 1 Throat Irritation 9 0 Peripheral Edema 8 0 determine whether they respond differently from younger subjects. Flushing 5 0 LDH Increase 7 0 OVERDOSAGE There has been no experience with overdosage in human clinical Heme and Lymphatic System 67 Digestive System 48 37 2 Lymphopenia 48 40 Nausea 23 1 trials. Single doses of up to 500 mg/m2 have been given in dose-escalation Leukopenia 14 4 Diarrhea 10 1 Neutropenia 14 6 Vomiting 10 1 clinical trials. NONCLINICAL TOXICOLOGY Carcinogenesis, Mutagenesis, Thrombocytopenia 12 2 Nervous System 32 1 Impairment of Fertility No long term animal studies have been performed to Anemia 8 3 Dizziness 10 1 Skin and Appendages Anxiety 5 1 44 2 establish the carcinogenic or mutagenic potential of Rituxan or to determine Musculoskeletal System Night Sweats 15 1 26 3 Rash 15 1 Myalgia 10 1 potential effects on fertility in males or females. PATIENT COUNSELING Pruritus 14 1 Arthralgia 10 1 INFORMATION Patients should be provided the Rituxan Medication Guide and Urticaria 8 1 Cardiovascular System 25 3 Hypotension 10 1 provided an opportunity to read prior to each treatment session. Because caution Hypertension 6 1 should be exercised in administering Rituxan to patients with active infections, it is a Adverse reactions observed up to 12 months following Rituxan. bAdverse reactions graded for severity by important that the patient’s overall health be assessed at each visit and any NCI-CTC criteria. questions resulting from the patient’s reading of the Medication Guide be In these single-arm Rituxan studies, bronchiolitis obliterans occurred during and discussed. Rituxan is detectable in serum for up to six months following up to 6 months after Rituxan infusion. Rituxan in Combination With completion of therapy. Individuals of childbearing potential should use effective Chemotherapy Adverse reactions information below is based on 1250 patients contraception during treatment and for 12 months after Rituxan therapy. who received Rituxan in combination with chemotherapy or following chemotherapy. Rituxan in Combination With Chemotherapy for Low-Grade NHL In Study 4, patients in the R-CVP arm experienced a higher incidence of infusional toxicity and neutropenia compared to patients in the CVP arm. The following adverse reactions occurred more frequently (≥5%) in patients receiving R-CVP compared to CVP alone: rash (17% vs. 5%), cough (15% vs. 6%), flushing (14% vs. 3%), rigors (10% vs. 2%), pruritus (10% vs. 1%), neutropenia (8% vs. 3%), and chest tightness (7% vs. 1%). In Study 5, the following adverse reactions Revised 9/2008 (4835505) were reported more frequently (≥5%) in patients receiving Rituxan following CVP Jointly Marketed by: compared to patients who received no further therapy: fatigue (39% vs. 14%), Biogen Idec Inc. 5200 Research Place San Diego, CA 92122 anemia (35% vs. 20%), peripheral sensory neuropathy (30% vs. 18%), infections Genentech USA, Inc. 1 DNA Way South San Francisco, CA 94080-4990 (19% vs. 9%), pulmonary toxicity (18% vs. 10%), hepato-biliary toxicity (17% vs. 7%), rash and/or pruritus (17% vs. 5%), arthralgia (12% vs. 3%), and weight gain (11% vs. 4%). Neutropenia was the only Grade 3 or 4 adverse reaction that occurred more frequently (≥2%) in the Rituxan arm compared with those who received no further therapy (4% vs. 1%). Rituxan in Combination With ©2008 Biogen Idec Inc. and Genentech, Inc. 7140917 October 2008

Journal of Multidisciplinary Cancer Care

For previously untreated diffuse large B-cell, CD20-positive NHL in combination with CHOP or other anthracycline-based chemotherapy regimens

When planning a treatment course for DLBCL

Take the essential path toward improved survival

Cumulative Cumulative Proportion Proportion Surviving Surviving

RITUXAN+CHOP is proven to prolong survival in DLBCL

47% INCREASE

1.0

in 7-year OS in GELA* trial 1,2

0.8 0.6 0.4 R-CHOP (n=202) CHOP† (n=197) p =0.0004

0.2 0 0 Years

• At 7 years, 8 cycles of RITUXAN+ CHOP increased overall survival (OS) from 36% to 53% compared with CHOP alone1 • At 5 years, 8 cycles of RITUXAN+ CHOP increased OS from 46% to 58% compared with CHOP alone5

BOXED WARNINGS and Additional Important Safety Information The most important serious adverse reactions of RITUXAN are fatal infusion reactions, tumor lysis syndrome (TLS), severe mucocutaneous reactions, progressive multifocal leukoencephalopathy (PML), hepatitis B reactivation with fulminant hepatitis, other viral infections, cardiovascular events, renal toxicity, and bowel obstruction and perforation. The most common adverse reactions of RITUXAN (incidence ≥25%) observed in patients with NHL are infusion reactions, fever, chills, infection, asthenia, and lymphopenia.5 RITUXAN in Combination with CHOP Chemotherapy for DLBCL: The following adverse reactions, regardless of severity, were reported more frequently (≥5%) in patients age ≥60 years receiving R-CHOP as compared to CHOP alone: pyrexia (56% vs 46%), lung disorder (31% vs 24%), cardiac disorder (29% vs 21%), and chills (13% vs 4%). In the GELA LNH 98-5 study, a review of cardiac toxicity determined that supraventricular arrhythmias or tachycardia accounted for most of the difference in cardiac disorders (4.5% for R-CHOP vs 1.0% for CHOP).5 The following Grade 3 or 4 adverse reactions occurred more frequently among patients in the R-CHOP arm compared with those in the CHOP arm: thrombocytopenia (9% vs 7%) and lung disorder (6% vs 3%). Other Grade 3 or 4 adverse reactions reported more frequently among patients receiving R-CHOP were viral infection (GELA LNH 98-5 study), neutropenia (GELA LNH 98-5 and MInT studies), and anemia (MInT study).5

Please see brief summary of prescribing information on adjacent page. Attention Healthcare Provider: Provide Medication Guide to patient prior to RITUXAN infusion. *GELA (Groupe d’Etude des Lymphomes de l’Adulte) LNH 98-5 trial: A Phase III trial of 399 previously untreated elderly (age ≥60 years) DLBCL patients.3,4 †CHOP: Cyclophosphamide, doxorubicin, vincristine, and prednisone. References: 1. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. J Clin Oncol. 2007;25(suppl 18S):443s. Abstract 8009. 2. Coiffier B, Feugier P, Mounier N, et al. Long-term results of the GELA study comparing R-CHOP and CHOP chemotherapy in older patients with diffuse large B-cell lymphoma show good survival in poor-risk patients. Paper presented at: 43rd American Society of Clinical Oncology Annual Meeting; June 1-5, 2007; Chicago, Ill. Abstract 8009. 3. Coiffier B, Lepage E, Brière J, et al. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002;346:235-242. 4. Data on file, Genentech, Inc. 5. RITUXAN® (Rituximab) full prescribing information, Genentech, Inc., 2008.

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