http://www.jomcc.com/issues/MCC0209 by Green Hill Healthcare Communications, LLC

CLINICAL, BUSINESS, AND HEALTH ECONOMIC INSIGHTS INTO PRACTICE MANAGEMENT March/April 2009 • Volume 2 • Number 2

Clinical

IN THIS ISSUE Current and Future Therapies for Non–small-cell Lung Cancer Commentary by Konstantin H. Dragnev, MD

A Rational Approach to the Treatment of Advanced Non–small-cell Lung Cancer Report from the Scripps Cancer Center’s 29th Annual Conference on Clinical Hematology & Oncology

Business

Lung Cancer Drugs in Phase 3 and 4 Trials in the United States Multidisciplinary Cancer Clinics: A Streamlined Approach to Cancer Care in the Community Setting An interview with Mark J. Krasna, MD

Battling Reimbursement Issues to Win the War on Cancer Timothy G. Tyler, PharmD, FCSHP

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

CC ry M o JO vis 26 e d e th l A ag in ia p Jo itor el • Ed Pan

Traditional educational activities (live meetings or lectures, printed or Internetbased CME activities) may make you aware of new information, illuminate associated healthcare quality gaps, and may even provide you the rationale or evidence-based information for improving care of your multiple myeloma patients. However, they usually do not offer any further support in the successful application of the learning in your practice. MedCases brings you an innovative, multifaceted opportunity to improve the quality of care of your multiple myeloma patients. This unique initiative combines education with practice-based application. You will: N Treat virtual patients in 6 online interactive case simulations that offer up to 12 free AMA PRA Category 1 creditsâ&#x201E;˘. Learn about recent updates to the national guidelines and other current evidence, and how best to apply them in different patient scenarios. N Take the learning into your practice with the unique Performance Improvement (PI) CME activity that offers up to 20 additional free AMA PRA Category 1 creditsâ&#x201E;˘. Step through an expert-led structured mechanism to identify, implement, and evaluate specific improvements in your practice. Sponsored by

Supported by an educational grant from Millennium Pharmaceuticals, Inc.

The case simulations and PI-CME activity are now available at www.challengingcases.com

TABLE OF CONTENTS

Publisher Philip Pawelko phil@greenhillhc.com

Editorial Director Karen Rosenberg karen@greenhillhc.com

A Letter to Our Readers 6

Together We Are Stronger: Teamwork Combines the Clinical and Business Aspects of Cancer Care

Timothy G. Tyler, PharmD, FCSHP

Managing Editor Dawn Lagrosa dawn-gh@greenhillhc.com Production Manager Marie RS Borrelli

Clinical 9

Current and Future Therapies for Non–small-cell Lung Cancer Commentary by Konstantin H. Dragnev, MD

A Rational Approach to the Treatment of Advanced Non–small-cell Lung Cancer Report from the Scripps Cancer Center’s 29th Annual Conference on Clinical Hematology & Oncology

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

Directors, Client Services John W. Hennessy john@greenhillhc.com Russell Hennessy russell@greenhillhc.com Cristopher Pires cris@greenhillhc.com Business Manager Blanche Marchitto blanche@greenhillhc.com Executive Administrators Thiel Hennessy Lisa Russo

Mission Statement 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.

Multidisciplinary Cancer Care

TABLE OF CONTENTS

EDITORIAL BOARD

Business

Multidisciplinary Cancer Clinics: A Streamlined Approach to Cancer Care in the Community Setting An interview with Mark J. Krasna, MD

Battling Reimbursement Issues to Win the War on Cancer Timothy G. Tyler, PharmD, FCSHP

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

News Notes

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.

March/April 2009

John F. Aforismo, BSc, Pharm, RPh, FASCP R•J Health Systems International Oncology Pharmacy 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 Mark J. Krasna, MD St. Joseph Cancer Institute Thoracic Surgery Shaji K. Kumar, MD Mayo Clinic Hematologic Malignancies Theodore F. Logan, MD Indiana University Melanoma Beryl McCormick, MD Memorial Sloan-Kettering Cancer Center Radiation Oncology Laura L. Morris, MD Goshen Center for Cancer Care Surgical Oncology Ritu Salani, MD Ohio State University Medical Center Gynecologic Malignancies 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

GH Green Hill Healthcare Communications

, LLC ™

™

Your Innovative Partners in Medical Media

We’re here for you, so you can be there for your patients 800.564.0216

Call the ARC of Support™ Hotline at 800.564.0216 ARC of Support is a comprehensive program that provides a broad range of services for health care professionals. This resource center has experienced representatives who are available to assist you with specific questions or issues about an Abraxis Oncology product. Just call 800.564.0216 Monday through Friday to access their help. Information

Service

Support

• Safety and efficacy data • Product administration guidelines • Coverage, coding, and reimbursement information

• Assistance with claims review and appeals process • Benefit verification and prior authorization assistance • Assistance for both uninsured and insured patients through the Abraxis Patient Access Program (APAP)

• Customer service representatives • Reimbursement services representatives • Trained health care professionals • Live operators

A Letter to Our Readers Together We Are Stronger: Teamwork Combines the Clinical and Business Aspects of Cancer Care

f you are like most clinicians, you probably find yourself lagging behind in your reading and would not even consider wading into the 1800 pages of the Outpatient Prospective Payment System (OPPS) rule for 2009 or the physician fee schedule rules published in Federal Register. Also, most of us find it difficult enough to keep up with our own responsibilities, much less with things that only intersect our practice peripherally. At some point, you have to admit that you do not have the time, energy, or interest to keep up on every single aspect of care that impacts your patients. The Journal of Multidisciplinary Cancer Care is a great nod to the idea that together we are stronger; or to get biblical (or nautical), a cord of many strands is not easily broken. There are distinct advantages in the multidisciplinary approach. There are times when as a clinician you need to lean on others, sometimes very heavily. In my life, I have been leaned on by three disciplines just while trying to write this introduction. I’ve been putting the documentation in place to ensure that our patient accounting department knows that we got the replacement drug for a patient we are treating. I’ve also been working with an IT analyst on an issue with the electronic medical records system that is going live at my facility as I write. Lastly, I’ve been asked by the infectious disease physician to suggest a therapy for a chronic urinary tract infection and to explain the rationale for it to the doctor and the patient. This is a challenging time in healthcare. Healthcare expenditures are growing even as the economy tanks around us. Many eyes are focusing on our standards of practice. Now more than ever, we need to know what we do well and what we do not do well and then rely on those clinicians who know more or are better at those functions or tasks than we are. I wish I did not know anything about reimbursement, but my brain is wired for clinical outcomes and financial accountability, so I was asked to write the article on reimbursement for this issue. It is my hope that it will generate some interesting discussions among your colleagues across the healthcare spectrum. Because this issue is focusing on lung cancer, I am pleased that my colleagues in other disciplines of cancer care have written on the aspects of care that I do not know as well as they do. Our clinical articles highlight recent reports on the approved and emerging targeted therapies, as well as promising novel therapeutic agents, for non–small-cell lung cancer. Plus, for those of you thinking of implementing a multidisciplinary approach in your practice, Dr Mark Krasna, a participant in the National Cancer Institute’s National Community Cancer Center Program, explains how the approach works in his cancer center. All of us on the editorial board and staff hope you enjoy this issue. We hope to hear from you and integrate your ideas into future issues.

—Timothy G. Tyler, PharmD, FCSHP Comprehensive Cancer Institute Desert Regional Medical Center

March/April 2009

News Notes Costs May Lead Cancer Patients and Survivors to Go Without Care Two recent reports highlight the challenges cancer patients and survivors face in paying for healthcare. In a report presented at the American Association for Cancer Research’s Science of Cancer Health Disparities conference in February, National Cancer Institute researchers found that an estimated 2 million cancer survivors are going without needed medical care because of economic considerations. Nearly 10% of survivors do not fill prescriptions, nearly 8% pass on what they believe to be necessary general medical care, more than 11% skip needed dental care, and almost 3% forgo mental health services. Further, the researchers found that Hispanic and African-American survivors are twice as likely to forgo crucial care, and that financial impediments were not limited to survivors without health insurance. A Kaiser Family Foundation and American Cancer Society report, Spending to Survive: Cancer Patients Confront Holes in the Health Insurance System, highlights how many patients amass high debt, file for personal bankruptcy, or postpone or forgo necessary care. Among other factors, high cost-sharing, caps on benefits, and lifetime and annual maximums are highlighted as contributing to high out-of-pocket (OOP) costs after cancer treatments begin. Patients also face obstacles to maintain coverage after they become ill. And because many Americans depend on their employer for health insurance, patients who are unable to work may find themselves responsible for the full cost of monthly premiums as well as OOP costs, all at a time when their incomes have been reduced. After patients go into remission, they may face higher premiums even if they have a low risk of recurrence. And if patients and survivors can no longer work and qualify for Social Security Disability Insurance payments, they must wait 2 years before they are eligible for Medicare.

ASCO Guide Can Help A new American Society of Clinical Oncology (ASCO) guide, Managing the Cost of Cancer Care, can help patients and clinical staff to communicate about

the costs of cancer care. The guide can help patients understand what costs to expect, a crucial step in preparing for their disease’s financial impact. Included in the guide is a list of questions patients can ask their providers about healthcare costs, such as those associated with medication and treatment, office visits, transportation, living expenses, and long-term care. Information on resources for employment or health insurance problems is also included, along with tips for organizing bills and expenses, a list of financial resources available to people with cancer, and a glossary of cancer treatment and financial terms. The guide can be downloaded at www.cancer.net/managingcostofcare.

Seated Exercise Intervention for Lung Cancer Patients A pilot study reported at the 9th National Conference on Cancer Nursing Research sought to assess the effects of a seated exercise program on quality of life (QOL) and fatigue in lung cancer patients. Five participants randomized to the intervention group received a video of low- to moderate-intensity seated exercise programs and individualized instructions about how to modify exercise intensity. They also were encouraged to perform the exercises at least three times a week. Qualitative data of the patients’ perceptions of QOL and fatigue were assessed after 3 months. The researchers concluded that although their study group was small, their findings support the inclusion of a tailored exercise program during chemotherapy education for patients with lung cancer.

Phase 3 Study Shows Improved Progression-free Survival in Advanced NSCLC Erlotinib in combination with bevacizumab as maintenance therapy following initial treatment with bevacizumab plus chemo-therapy has been shown to extend progression-free survival significantly in advanced non–small-cell lung cancer (NSCLC) patients. A preliminary safety analysis found that adverse events were similar to those of previous bevacizumab or erlotinib studies and no new safety signals

Multidisciplinary Cancer Care

were observed. The ATLAS study was the second positive phase 3 trial of erlotinib as first-line maintenance therapy. The SATURN study previously showed that erlotinib delayed disease progression when given as a single agent following chemotherapy.

Racial Disparities Examined in Lung Cancer Patients Racial differences in the receipt of optimal therapy do not appear to affect outcomes, according to a recent study by Farjah and colleagues. Working from the hypothesis that there would be no significant evidence of racial disparities among patients with early-stage lung cancer for whom surgical therapy is recommended, the researchers analyzed data from the Surveillance,

The researchers concluded that their finding points to distrust, beliefs, and perceptions about lung cancer and its treatment, and limited access to care may play a dominant role in perpetuating racial disparities. Epidemiology, and End Resultsâ&#x20AC;&#x201D;Medicare database. They found that 14% fewer African-American patients underwent resection than their Caucasian counterparts. Further, even among patients who were recommended surgery, African-Americans underwent surgery less often than whites. Surprisingly, although unadjusted 5-year survival rates were lower for African-American patients, after adjustment, there was no significant association between race and death. The researchers concluded that their finding points to distrust, beliefs, and perceptions about lung cancer and its treatment, and limited access to care may play a dominant role in perpetuating racial disparities. (Arch Surg. 2009;144:14-18.)

New Tumor Suppressor for Lung Cancer Identified Researchers at the University of Cincinnati have found that animals that did not express the protein kinase C (PKC)-zeta gene developed more Ras-induced lung cancer. This finding suggests that this gene acts as

March/April 2009

a tumor suppressor, slowing Ras transformation and tumor development. This is significant because previous research has established that the proto-oncogene Ras is abnormally expressed in up to 25% of lung cancers. The researchers hope that this new understanding of the specific chain of events that lead to Ras-induced lung cancers will enhance the ability to develop more targeted therapies. (Galvez AS et al. Mol Cell Biol. 2009;29:104-115.)

Microcoil Localization Helps in Removal of Small Lung Nodules A new technique using microcoil localization of small peripheral lung nodules enables their resection using fluoroscopically guided video-assisted thoracoscopic surgery (VATS), with a low rate of intervention for procedural complications. The technique uses computed tomography to place the fiber-coated surgical microcoil at the precise location of the nodule to guide the VATS removal. The authors propose that this technique can be used to definitively determine if a nodule is malignant or benign. Further, this procedure allows for removal of the entire nodule and only a small amount of surrounding tissue, thereby maintaining lung function and reducing recovery time. (Mayo JR et al. Radiology. 2009;250:576-585.)

Potential Biomarker Identified for Lung Diseases Linked to Smoking Researchers at Boston University have shown that microRNAs (miRNAs) regulate the smoking-induced gene-expression changes in airway epithelium. In comparing smokers with never smokers, the researchers found 28 miRNAs to be differentially expressed in smokers, with the majority being down-regulated. They also identified a number of mRNAs whose expression level is highly inversely correlated with miRNA expression in vivo. The study suggests that these changes in miRNA expression levels mediate some of the smoking-induced gene-expression changes in airway epithelium, and therefore, that miRNAs play a role in regulating host response to environmental exposures and may contribute to the pathogenesis of smoking-related lung cancer. It is hoped that these findings may lead to a new, relatively noninvasive biomarker for smoking-related lung diseases. (Schembri F et al. Proc Natl Acad Sci U S A. Epub January 23, 2009.) n

Current and Future Therapies for Nonâ&#x20AC;&#x201C;small-cell Lung Cancer With commentary by Konstantin H. Dragnev, MD (see page 14)

ne-year relative survival for lung cancer has increased slightly in the past 30 years, from 35% in 1975-1979 to 41% in 2000-2003, due largely to better surgical and pharmacologic interventions.1 However, 5-year survival for all lung cancer stages combined is just 15%.1 When lung cancer is detected while still localized, 5-year survival is better (49%), but only 16% of cases are diagnosed at this early stage.1 The World Health Organization classifies lung cancer into two main groups on the basis of biology, therapy, and prognosis: nonâ&#x20AC;&#x201C;small-cell lung cancer (NSCLC) and small-cell lung cancer (SCLC).2 NSCLC, which accounts for more than 85% of all lung cancers, includes two main types: nonsquamous carcinoma (eg, adenocarcinoma) and squamous cell carcinoma.2 SCLC accounts for the remaining 15% of lung cancers.3 This article focuses on approved and emerging therapies for NSCLC.

Prognostic Factors In patients with NSCLC, prognostic factors indicative of longer survival include early-stage disease, good performance status, no significant weight loss, and female gender; poor prognosis in NSCLC is predicted by immunohistologic factors that include mutation of the tumor suppression gene (p53) and the activation of KRAS oncogenes.2 Standard Therapy for NSCLC For patients with earlier stage (I or II) NSCLC, surgery provides the best chance of cure.2 Unfortunately, only 30% of patients are candidates for curative surgery.4 Radiation therapy is also employed in NSCLC, as is chemotherapy.2 Chemotherapy has numerous applications in NSCLC, depending on disease stage and surgical eligibility. Following surgery for early-stage disease, adjuvant chemotherapy has been shown to improve survival.2 In patients with stage III NSCLC that is not surgically resectable, concurrent chemoradiation may be superior to sequential chemotherapy.2 For stage IV disease, which is rarely treated surgically, platinum-

based chemotherapy is the standard treatment.2 Regimens include carboplatin/paclitaxel, cisplatin/ paclitaxel, cisplatin/vinorelbine, gemcitabine/cisplatin, and docetaxel/cisplatin.2 Nanoparticle-albumin-bound paclitaxel can be substituted for paclitaxel to improve therapeutic targeting. Antifolate therapy with pemetrexed may also be used in NSCLC. The Table shows chemotherapy drugs approved for NSCLC by the US Food and Drug Administration (FDA).5,6

Approved Targeted Therapies for Advanced NSCLC Specific, targeted therapies have been developed for advanced NSCLC.2 Three of these agents, bevacizumab, erlotinib, and gefitinib, are FDA approved (Table).5,6 Bevacizumab. The recombinant monoclonal antibody bevacizumab blocks vascular endothelial growth factor (VEGF). Bevacizumab was approved by the FDA in 2007 for unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC.2 Based on results from phase 2/3 clinical trials, the Eastern Cooperative Oncology Group (ECOG) recommends bevacizumab plus paclitaxel and carboplatin, provided patients meet the following selection criteria: advanced nonsquamous NSCLC, no history of hemoptysis, and no untreated central nervous system (CNS) metastasis.7 Patients treated with bevacizumab/paclitaxel/carboplatin in ECOG trials achieved higher median overall survival ([OS] 12.3 vs 10.3 months, P = .003), median progression-free survival ([PFS] 6.2 vs 4.5 months, P <.001), and response rates (35% vs 15%, P <.001) compared with paclitaxel/carboplatin.7 The three-drug combination, however, produced higher rates of clinically significant bleeding than did the two-drug regimenâ&#x20AC;&#x201D;4.4% versus 0.7% (P <.001). Bevacizumab should therefore be combined cautiously with any therapy that carries a high risk of thrombocytopenia and thus bleeding.2 Other important adverse events (AEs) include gastrointestinal (GI) perforation, non-GI fistula, esophagitis, and hypertension.7 Erlotinib. Erlotinib is an orally administered small-

Multidisciplinary Cancer Care

Table. Drugs Approved by the FDA for NSCLC Drug

Approved indication

Approval date

Chemotherapy Gemcitabine (injectable)

Vinorelbine (injectable)

Docetaxel (injectable)

Paclitaxel (injectable)

Pemetrexed (injectable)

In combination with cisplatin for the first-line treatment of patients with inoperable, locally advanced (stage IIIA or IIIB) or metastatic (stage IV) NSCLC

1998

As a single agent or in combination with cisplatin for stage IV NSCLC or first-line treatment of ambulatory patients with unresectable, advanced NSCLC; in combination with cisplatin for stage III NSCLC

1994, 2000

As a single agent for locally advanced or metastatic NSCLC after failure of prior platinum-based chemotherapy; in combination with cisplatin for unresectable, locally advanced or metastatic NSCLC not previously treated with chemotherapy

1999, 2002

In combination with cisplatin for the first-line treatment of NSCLC in patients who are not candidates for potentially curative surgery and/or radiation therapy In combination with cisplatin therapy for locally advanced or metastatic nonsquamous NSCLC; as a single agent for locally advanced or metastatic nonsquamous NSCLC after prior chemotherapy

1998

2004, 2008

Molecularly Targeted Therapy Erlotinib (tablets)

Gefitinib (tablets)

For the treatment of patients with locally advanced or metastatic NSCLC after failure of at least 1 prior chemotherapy regimen; not recommended for use with platinum-based chemotherapy As monotherapy for the continued treatment of locally advanced or metastatic NSCLC after failure of both platinumbased and docetaxel chemotherapies, for patients who are benefiting or have benefited from gefitinib*; no benefit from adding gefitinib to doublet, platinum-based chemotherapy

Bevacizumab (injectable) In combination with carboplatin and paclitaxel for first-line treatment of unresectable, locally advanced, recurrent, or metastatic nonsquamous NSCLC

2004

2003, 2005

2007

*Use other treatment options in advanced NSCLC populations that have received 1 or 2 prior chemotherapy regimens and are refractory or intolerant to their most recent regimen. NSCLC staging: stage III, locally advanced disease; stage IV, disease with distant metastases. Sources: References 5 and 6.

March/April 2009

molecule tyrosine kinase inhibitor (TKI) with specific inhibitory activity of the epidermal growth factor receptor (EGFR).2 EGFR is detectable in 80% to 85% of patients with NSCLC, at widely varying levels of expression. Inhibition of EGFR suppresses multiple tumor-cell functions, including proliferation and survival.2 Erlotinib was approved by the FDA in 2004 for patients with locally advanced NSCLC who have failed one or more prior chemotherapy regimens.2 Erlotinib may also be considered for off-label use first line, as monotherapy or in combination with chemotherapy, in a stratified subset of NSCLC patients who exhibit an active EGFR mutation or gene amplification and who have never smoked.2,8,9 However, combining erlotinib with paclitaxel and carboplatin first line in a nonstratified group of NSCLC patients did not confer a survival advantage compared with dual therapy with paclitaxel/carboplatin.10 In a phase 3 trial of NSCLC patients previously treated with one or two chemotherapy regimens,11 erlotinib monotherapy produced a response rate of 8.9% versus <1% in the placebo group (P <.001); PFS was 2.2 months and 1.8 months, respectively (P <.001), and OS was 6.7 months and 4.7 months, respectively (P <.001). Five percent of patients discontinued erlotinib because of toxic effects. Common AEs included skin rash, anorexia, nausea, and vomiting. Hepatically impaired patients taking erlotinib should be closely monitored and therapy discontinued or interrupted if changes in liver function are severe.2 Gefitinib. Gefitinib, another orally administered TKI, received accelerated approval by the FDA in 2003 as monotherapy for patients with locally advanced or metastatic NSCLC after two failed chemotherapy regimens. This approval was based on two large phase 2 studies, with tumor response rate being the surrogate end point in these trials. Subsequently, however, a phase 3 trial showed no improvement in survival with gefitinib compared with placebo, and in 2005, the FDA approved new labeling for the drug, restricting its use to patients in clinical trials or still receiving benefit from treatment already initiated.12

Updates on Emerging Targeted Therapies Numerous targeted therapies are under continued investigation for advanced NSCLC, such as monoclonal antibodies (eg, cetuximab and trastuzumab) and TKIs (eg, gefitinib, sunitinib, axitinib, and sorafenib), as well as novel combinations containing erlotinib and bevacizumab. Emerging therapies aim at various ongogenic targets, including EGFR activity, multiple tyrosine kinase receptors, EGFR2 (HER2/neu), stem-

cell factor receptor, insulin-like growth factor receptor, and VEGF. At the 2008 Annual Meeting of the American Society of Clinical Oncology (ASCO), investigators presented a number of studies on emerging NSCLC therapies, which are summarized here. Gefitinib. Lee and colleagues13 compared oral gefitinib 250 mg/day with intravenous docetaxel 75 mg/m2 every 3 weeks in 161 patients with advanced or metastatic NSCLC previously treated with platinumbased chemotherapy. Treatment with gefitinib produced significantly longer PFS than did docetaxel (P = .0441), along with a significantly improved overall response rate (28.1% vs 7.6%, P = .0007). There were no significant differences between treatments in quality of life and lung cancer symptom improvement rate. AEs, which were generally mild, were consistent with both the underlying disease and the usual toxicity profiles of the drugs. More severe AEs (grade 3/4) occurred in 21.0% and 27.6% of patients taking gefitinib and docetaxel, respectively; one possible treatment-related death occurred in the gefitinib arm. An event indicative of interstitial lung disease was observed in three patients treated with gefitinib and three treated with docetaxel. Bevacizumab. Socinski and colleagues14 studied the incorporation of bevacizumab and erlotinib into chemotherapy and radiotherapy regimens for NSCLC. Patients received induction therapy with carboplatin AUC 6, paclitaxel 225 mg/m2, and bevacizumab 15 mg/kg, on days 1 and 22. On day 43, they began receiving continuation therapy with weekly carboplatin AUC 2 x 7 and paclitaxel 45 mg/m2 x 7 with 74 Gy of thoracic radiotherapy. During this phase of therapy, cohort 1 (n = 5) received concurrent bevacizumab at 10 mg/kg every 2 weeks; cohorts 2 and 3 (both n = 5) received the same dose of concurrent bevacizumab plus oral erlotinib 100 mg and 150 mg, respectively, 4 days out of each week. As of the presentation date, an initial set of 20 patients was evaluable, with one patient experiencing grade 3/4 nonhematologic toxicity. A total of 44.4% of patients had objective responses, and none progressed during induction. Tumor volumes and volumes on positron-emission tomography significantly decreased following induction (P <.0002). Over the entire study, 33% of patients experienced grade 3 esophagitis. During the concurrent therapy phase, grade 3 AEs included one pulmonary hemorrhage requiring bevacizumab discontinuation, one case of interstitial pneumonitis, and two cases of esophagitis. One grade 5 hemorrhage occurred in a squamous cell carcinoma patient. The authors concluded that adding bevacizumab and erlotinib to chemotherapy and radio-

Multidisciplinary Cancer Care

therapy was feasible, but that esophagitis remains the primary toxicity. Dansin and colleagues15 reported preliminary results from the SAiL study, an open-label, single-arm trial evaluating the safety of first-line bevacizumab combined with standard chemotherapy regimens in 2000 patients with locally advanced, metastatic, or recurrent nonsquamous NSCLC. Patients received a standard first-line platinum-based chemotherapy regimen for up to six cycles combined with bevacizumab. There were 396 serious AEs (SAEs), of which 16% were bevacizumab-related. Most of these SAEs, (75.5%) resolved or improved. Grade 3/4 hypertension was seen in 2.7% of patients. CNS progression of disease was observed in 1.1% of patients, but no CNS hemorrhage was seen during treatment; one patient diagnosed with brain metastases after cessation of bevacizumab had a CNS hemorrhage 26 weeks after the last dose. The study demonstrated that bevacizumab-based therapy has a well-characterized safety profile in NSCLC, with no metastases-related cases of CNS hemorrhage to date. Erlotinib. Erlotinib at a dose of 150 mg/day is currently under investigation in the large-scale, openlabel, nonrandomized, global TRUST study, which includes more than 6000 patients with advanced NSCLC who have failed on or were not candidates for chemotherapy/radiotherapy. Several reports from TRUST were presented at ASCO 2008. Groen and colleagues16 reported TRUST findings for 6708 patients. Data on best tumor response were available for 5448 patients: fewer than 1% had a complete response (CR), 12% had a partial response (PR), and 56% had stable disease (SD). Median PFS was 14.1 weeks. Among 6267 safety-evaluable patients, 52% had at least one AE of any cause. Only 4% had more than one erlotinib-related SAE, of which the most common was diarrhea (1%). Erlotinib-related AEs resulted in treatment discontinuation in 5% of patients, predominantly due to rash, which was observed in 70% of patients and was primarily mild (grade 1/2). The authors concluded that erlotinib would be an effective option for patients with advanced NSCLC. Merimsky and colleagues17 assessed erlotinib in an important subgroup of the TRUST study, ie, elderly patients who had not received prior chemotherapy or radiotherapy. Such first-line use of erlotinib may be useful in an elderly population, since prognosis in this group is poor due to significant comorbidities and low performance status. At the time of reporting, interim data were available for 451 elderly patients older than 70 years. Moderate to severe AEs (grade 3 to 5) of any

March/April 2009

cause were reported by 49% of patients; however, only 7% had more than one treatment-related AE, and only three patients (<1%) died because of a treatment-related AE. Dose reductions were required in 16% of patients, CR occurred in 1%, PR in 8%, SD in 45%, and PFS of 16.4 weeks. The study authors concluded that erlotinib would be valuable as a first-line treatment in the management of advanced NSCLC in elderly patients. Crin贸 and colleagues18 presented data on quality of life, symptom control, and survival in the TRUST study. In evaluable patients who received erlotinib as second-line treatment (n = 2724), fewer than 1% had a CR, 13% had a PR, and 54% had SD. Median PFS was 13.7 weeks for all patients, but was longer or shorter depending on better or worse performance status. The safety analysis showed that only 4% of patients reported an erlotinib-related SAE. Erlotinib-related rash was reported in 71% of patients, with 84% of those cases grade 1 or 2. Interestingly, PFS was significantly longer in patients who experienced rash of any grade versus those without rash. The study also showed that patients with a good performance status had better outcomes. The authors concluded that, due to its favorable toxicity profile and efficacy, erlotinib would be a good alternative as second-line treatment in NSCLC. Cetuximab. Cetuximab, an EGFR inhibitor, is approved for the treatment of metastatic colorectal cancer and head and neck cancer, but its use in treatment of lung cancer is currently being investigated. In the phase 3 FLEX trial, Pirker and colleagues19 assessed the efficacy and safety of cetuximab in combination with cisplatin/vinorelbine (CV) compared with CV alone in 1125 patients with advanced NSCLC and detectable EGFR. Patients were randomized to two arms: patients in arm A (n = 557) received a regimen every 3 weeks of an initial dose of cetuximab 400 mg/m2 then 250 mg/m2/wk plus cisplatin 80 mg/m2 on day 1 and vinorelbine 25 mg/m2 on days 1 and 8; those in arm B (n = 568) received only the CV portion of the regimen. At the time of data presentation, median OS was significantly improved in arm A versus arm B (11.3 vs 10.1 months, respectively, P = .0441). The study authors concluded that since cetuximab plus CV showed superior survival versus CV alone, it would be a clinically relevant choice for first-line treatment of advanced NSCLC. Pirker and colleagues19 also included a preplanned racial subgroup analysis. Caucasians (n = 945) had significantly longer median OS when cetuximab was included in treatment (arm A, 10.5 months) than without cetuximab (arm B, 9.1 months, P = .0025); the

difference was observed regardless of tumor histology— adenocarcinoma or squamous cell carcinoma. In the subgroup of 121 Asian patients, median OS was 17.6 months in arm A and 20.4 months in arm B, a nonsignificant difference. Pilz and colleagues20 reported early phase 2 results on the feasibility of using cetuximab combined with common chemotherapy regimens in patients with locally advanced or metastatic NSCLC. All patients received cetuximab 400 mg/m2 as an initial dose then 250 mg/m2 weekly in combination with either (1) gemcitabine 1000 mg/m2 on days 1 and 8 for two 3-weekly cycles followed by docetaxel 75 mg/m2 on day 1 for two cycles every 3 weeks; or (2) gemcitabine 1200 mg/m2 on days 1 and 8 and carboplatin AUC 5 on day 1 for a maximum of four cycles every 3 weeks. Among 142 patients evaluable for toxicity, the addition of cetuximab did not add to the known toxicity of chemotherapy in the induction phase; cetuximab combinations were also well tolerated in the maintenance phase. The Cancer and Leukemia Group B, led by Govindan and colleagues,21 compared chemotherapy and thoracic radiation with and without cetuximab in a randomized phase 2 study. The study reported results for a total of 106 eligible patients with previously untreated stage III NSCLC. Patients were randomized to receive either thoracic radiation 70 Gy plus carboplatin AUC 5 and pemetrexed 500 mg/m2 intravenously on day 1 every 21 days for 4 cycles (arm A) or the same radiation and chemotherapy regimen plus cetuximab at a loading dose of 400 mg/m2 followed 1 week later by 250 mg/m2/wk for an additional 6 weeks (arm B). All patients then received consolidation therapy with four additional cycles of pemetrexed 500 mg/m2 every 21 days. Preliminary data show that the incidence of grade 3 or higher AEs was relatively similar for both treatment arms, except for skin rash, which was markedly higher with the addition of cetuximab. One patient died of fatal hemoptysis. The study authors concluded that combining radiation with pemetrexed/carboplatin with or without cetuximab was both feasible and well tolerated.

Conclusion Despite advances in treatment, the mortality rate for patients with lung cancer remains high, and improved treatment is a clinical priority. Molecularly targeted drug therapies, alone or in combination with chemotherapy, show promise in NSCLC. Research on targeted therapy is especially robust in advanced NSCLC, and three targeted drugs, erlotinib, gefitinib,

and bevacizumab, have been approved by the FDA for use in this type of lung cancer. It is hoped that ongoing research will continue to discover and confirm appropriate uses for targeted therapy in lung cancers. n

References 1. American Cancer Society. Cancer Facts & Figures, 2006. www.can cer.org/downloads/STT/CAFF2006PWSecured.pdf. Accessed October 29, 2008. 2. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. V.2.2009. www.nccn.org/professionals/physician_gls/PDF/nscl.pdf. Accessed October 29, 2008. 3. National Comprehensive Cancer Network. NCCN Clinical Practice Guidelines in Oncology: Small Cell Lung Cancer. V.2.2009. www.nccn.org/professionals/physician_gls/PDF/sclc.pdf. Accessed October 29, 2008. 4. Carney DN, Hansen HH. Non-small-cell lung cancer—stalemate or progress? N Engl J Med. 2000;343:1261-1262. 5. RxList: the Internet Drug Index. www.rxlist.com. Accessed December 3, 2008. 6. US Food and Drug Administration. Drugs@FDA: FDA approved drug products. www.accessdata.fda.gov/scripts/cder/drugsatfda. Accessed December 3, 2008. 7. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med. 2006;355:2542-2550. 8. Sequist LV, Joshi VA, Jänne PA, et al. Response to treatment and survival of patients with non-small cell lung cancer undergoing somatic EGFR mutation testing. Oncologist. 2007;12:90-98. 9. Eberhard DA, Johnson BE, Amler LC, et al. Mutations in the epidermal growth factor receptor and in KRAS are predictive and prognostic indicators in patients with non-small-cell lung cancer treated with chemotherapy alone and in combination with erlotinib. J Clin Oncol. 2005;23:5900-5909. 10. Herbst RS, Prager D, Hermann R, et al. TRIBUTE: a phase III trial of erlotinib hydrochloride (OSI-774) combined with carboplatin and paclitaxel chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2005;23:5892-5899. 11. Shepherd FA, Rodrigues Pereira J, Ciuleanu T, et al. Erlotinib in previously treated non-small-cell lung cancer. N Engl J Med. 2005;353: 123-132. 12. US Food and Drug Administration. FDA Alert: Gefitinib (marketed as Iressa) information. www.fda.gov/cder/drug/infopage/gefitinib/ default.htm. Accessed February 20, 2009. 13. Lee D, Kim S, Park K, et al. A randomized open-label study of gefitinib versus docetaxel in patients with advanced/metastatic nonsmall cell lung cancer (NSCLC) who have previously received platinium-based chemotherapy. J Clin Oncol. 2008;26(May 20 suppl):Abstract 8025. 14. Socinski MA, Morris DE, Stinchcombe TE, et al. Incorporation of bevacizumab (B) and erlotinib (Er) with induction (I) and concurrent (C) carboplatin (Cb)/paclitaxel (P) and 74 Gy of thoracic radiotherapy in stage III non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(May 20 suppl):Abstract 7517. 15. Dansin E, Mezger J, Isla D, et al. Safety of bevacizumab-based therapy as first-line treatment of patients with advanced or recurrent nonsquamous non-small cell lung cancer (NSCLC): MO19390 (SAiL). J Clin Oncol. 2008;26(May 20 suppl):Abstract 8085. 16. Groen H, Arrieta OG, Riska H, et al. The global TRUST study of erlotinib in advanced non-small-cell lung cancer (NSCLC). J Clin Oncol. 2008;26(May 20 suppl):Abstract 19000. 17. Merimsky O, Cheng C, Reck M, et al. Erlotinib as 1st-line therapy for elderly patients (pts) with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(May 20 suppl):Abstract 19016.

Multidisciplinary Cancer Care

18. Crinó L, Boyer M, Eberhardt WE, et al, on behalf of the TRUST investigators. Second-line erlotinib in patients with advanced nonsmall-cell lung cancer (NSCLC): results from a large, open-label study. J Clin Oncol. 2008;26(May 20 suppl):Abstract 19002. 19. Pirker R, Szczesna A, von Pawel J, et al. FLEX: a randomized, multicenter, phase III study of cetuximab in combination with cisplatin/vinorelbine (CV) versus CV alone in the first-line treatment of patients with advanced non-small cell lung cancer (NSCLC). J Clin Oncol. 2008;26(May 20 suppl):Abstract 3. 20. Pilz LR, Cicenas S, Eschbach C, et al. Feasibility of cetuximab in

combination with gemcitabine or docetaxel or carboplatin/gemcitabine for chemonaïve patients with advanced non-small cell lung cancer (NSCLC): observations from an ongoing randomized phase II/III trial (GemTax IV). J Clin Oncol. 2008;26(May 20 suppl): Abstract 19005. 21. Govindan R, Bogart J, Wang X, et al. A phase II study of pemetrexed, carboplatin and thoracic radiation with or without cetuximab in patients with locally advanced unresectable non-small cell lung cancer: CALGB 30407—early evaluation of feasibility and toxicity. J Clin Oncol. 2008;26(May 20 suppl):Abstract 7518.

Commentary

Current and Future Therapies for Non–small-cell Lung Cancer: The Clinician’s Perspective By Konstantin H. Dragnev, MD*

ew technology, the explosion of biological and genetic information, and the development of novel therapeutic agents have significantly impacted the treatment of cancer. The survival of patients with advanced non–small-cell lung cancer (NSCLC) has increased in recent years. This is attributed to improved cytotoxic chemotherapy, better supportive care, and the introduction of targeted agents. Many more treatment options are available, and the challenge is the selection of the most appropriate regimen for each patient. Tumor histology is one easily obtainable characteristic that can be used to select chemotherapy. For example, pemetrexed is more effective than gemcitabine in patients with nonsquamous carcinoma of the lung. Molecular markers to assist in the selection of chemotherapy are also being studied, such as ERCC1 to predict sensitivity to cisplatin, or RRM1 for gemcitabine. The results have not yet been validated, and these remain a research tool, rather than a clinically useful aid. Targeted agents are developed based on improved understanding of the molecular mechanisms of cancer. The target is a molecule that should be critical for the survival or proliferation of cancer cells and should be expendable for the normal cells. This is straightforward in theory, but finding such unique targets has not been easy. Current targeted agents are not effective in all patients, and they all affect to some degree noncancerous cells and tissues, causing toxicities. Ideally, therapies for individual patients should be selected based on the presence of the target in their tumors. For the available targeted agents for NSCLC,

March/April 2009

however, there are no markers ready for use in the clinic. For antiangiogenic drugs, for example, the selection is based on risks for toxicities. Ongoing studies may expand the range of patients who can receive regimens containing these agents. Even for drugs targeting wellstudied molecules, such as the epidermal growth factor receptor, there are no agreed upon markers that the clinician can use in everyday practice. With the availability of many regimens, more patients will be offered several lines of therapy. It may be more important that patients are exposed to all these agents at some point in the course of their treatment rather than the precise sequence of regimens. The economic impact of the high cost of the novel treatments will invariably influence the choice of therapy. Although the well-being of the patient remains the primary focus of the oncology team, economic realities will change our practice. It is likely that more regulation by payers—insurance companies and federal agencies—may soon affect our ability to select therapy. As more targeted agents are developed, it is imperative that treatment choices become individualized and regimens are tailored to the specific molecular characteristics of the tumor. Thus, an expensive new drug will be used only in a patient who is likely to benefit from it. A patient whose tumor has different characteristics will be offered another regimen. This will improve the cost/benefit ratio of novel therapies and will ensure that all patients continue to receive high-quality cancer care. *Norris Cotton Cancer Center, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire

A Rational Approach to the Treatment of Advanced Non–small-cell Lung Cancer Report from Scripps Cancer Center’s 29th Annual Conference on Clinical Hematology & Oncology Kristina Rebelo

AN DIEGO—A leading expert in the treatment of advanced lung cancer recently described some promising novel therapeutic agents that when combined could potentially improve upon the current standard chemotherapeutics by triggering apoptosis and slowing down tumor progression. Ronald B. Natale, MD, gave this year’s Longmire Lecture at the Scripps Cancer Center’s 29th Annual Conference on Clinical Hematology & Oncology. Natale is the senior research advisor and national director of the Lung Cancer Research Program for Aptium Oncology and an attending physician at the CedarsSinai Outpatient Cancer Center in Los Angeles. The lecture, which each year honors Dr William P. Longmire Jr, the surgeon who helped found the University of California at Los Angeles School of Medicine, was titled, “Treatment of Advanced NSCLC: Chemotherapy, Biological Agents, and a New Hypothesis Regarding Their Interaction.” Natale’s review first looked back to what worked and then forward to what improvements can be made in synergistic drug therapy for non–small-cell lung cancer (NSCLC). In the lecture, he touched on emerging agents for the treatment of NSCLC and included combination regimens that are currently approved by the US Food and Drug Administration (FDA); a review of the Eastern Cooperative Oncology Group (ECOG) 4599 trial; the subsequent Avastin in Lung (AVAiL) trial; and data supporting the use of molecularly targeted therapies for NSCLC, such as the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) gefitinib and erlotinib, which Natale said represent “a new hypothesis and maybe a new paradigm that can produce an apoptotic response in patients” (Table).

Combination Regimens in NSCLC Currently, the FDA-approved combination regimens for first-line treatment of advanced NSCLC are carboplatin + paclitaxel + bevacizumab for patients with no brain metastases and cisplatin/carboplatin + paclitaxel/ docetaxel/gemcitabine for those with brain metastases. Natale presented a chart showing that the 1-year survival rates for cytotoxic, alkylating agents pre-1980 were 12% to 15%; from 1980 to 1990, the cisplatinbased treatment increased the survival rate to 25%, and from 1990 to 2000, it increased further to 35% or more with cisplatin + carboplatin-based treatments. The ECOG Trial: Questions Remain Based on the findings of the ECOG 4599 trial, bevacizumab was approved in 2006 as a component of firstline therapy for patients with unresectable, locally advanced, recurrent or metastatic, nonsquamous NSCLC.1,2 Bevacizumab is a monoclonal antibody made partially of murine protein from Chinese hamster ovary cells. It works by blocking the action of vascular endothelial growth factor (VEGF). Natale said that patients with “undifferentiated NSCLC” or “NSCLC not otherwise specified” were included in ECOG 4599 and that the trial also included patients with adenocarcinoma of the lung; large-cell undifferentiated carcinoma of the lung; poorly differentiated or undifferentiated carcinoma; carcinoma not otherwise specified; and a large number of elderly subjects. This study showed statistically significant progression-free survival (PFS) and overall survival benefits when 15 mg/kg of bevacizumab was added to the standard regimen of carboplatin + paclitaxel every 3 weeks compared with chemotherapy alone (25% improvement; hazard ratio, 0.80).

Multidisciplinary Cancer Care

Table. Generating a New Hypothesis of NSCLC Treatment • EGFR-TKIs can produce an “apoptotic” response (>30% rapid, measurable tumor regression) in NSCLC. ~10% of unselected patients ~50% of never smokers (or “light” former smokers >15-year interval) ~70% of patients with EGFR mutations • EGFR-TKIs (gefitinib/erlotinib) can produce an “antiproliferative” effect in NSCLC. ~40%-60% of unselected patients ~30% of never smokers (or “light” former smokers >15-year interval) ~10%-20% of patients with EGFR mutations • EGFR-TKIs induce apoptotic effects that may be synergistic with chemotherapy; the antiproliferative effects are probably antagonistic. NSCLC indicates non–small-cell lung cancer; EGFR, epidermal growth factor receptor; TKI, tyrosine kinase inhibitor.

Natale, however, cited several problems with the trial. “This trial started off ambitiously, but left many questions remaining.” He said the trial has been “debated and debated, but the primary problem with the study was that clinicians knew which patients were getting what drugs.” Other important questions raised were (a) whether a lower dose of bevacizumab would have provided similar efficacy; and (b) whether bevacizumab could have also enhanced the activity of other chemotherapy regimens besides carboplatin + paclitaxel. Natale said that, despite its reported flaws, the ECOG 4599 trial has led to changes in the standard of patient care in the United States. The AVAiL study3 addressed some of the issues raised by ECOG 4599 by randomizing 1043 patients with NSCLC to gemcitabine + cisplatin, with or without either high-dose (15 mg/kg) or low-dose (7.5 mg/kg) bevacizumab; this study confirmed that bevacizumab improves PFS in patients with advanced, nonsquamous NSCLC. According to Natale, however, the AVAiL study raised questions too, such as whether a higher dose of bevacizumab is needed for lung cancer. He also urged treating oncologists to utilize pathology findings. “We need to talk to pathologists and get more patient tissue to try to nail down a diagnosis, and we need more molecular studies for more valid parameters, not just histology.”

The Rationale for EGFR Inhibitors Natale explained that despite the importance of chemotherapy in lung cancer treatment, it can be expected that patients with advanced lung cancer will eventually reach the “chemotherapy plateau,” and he stressed

March/April 2009

the importance of adding novel agents at that point. He presented slides elucidating the basic concepts of EGFR signaling pathways and how EGFR, a protein with a critical role in cell division that is often mutated in tumors, is overexpressed in many solid tumors, including NSCLC,4 definitively documenting its role in the pathogenesis of some lung cancers. He said that tumor heterogeneity is a hallmark of lung cancer and “patients may require multiple drugs to attack multiple targets.” Natale reviewed studies of the EGFR-TKIs, which include gefitinib and erlotinib. He explained that these molecularly targeted agents provide a different mechanism of action from chemotherapy that can be much more specific in treatment of patients with NSCLC who have EGFR mutations.5 “Gefitinib and erlotinib work very differently than standard chemotherapy and have a very different toxicity profile,” he said, and therefore adding one of these agents to standard chemotherapy should improve patient survival. He noted too that “taking a pill once a day that causes a mild-to-moderate skin rash and mild diarrhea may be at least as good as receiving toxic intravenous chemotherapy in some patients. Let’s test this strategy in patients who are so debilitated from their lung cancer that chemotherapy may not be the best choice.” He discussed two phase 2 trials in patients with previously treated advanced NSCLC that suggested gefitinib is efficacious and less toxic than chemotherapy. A recently reported phase 3 study of patients with previously treated advanced NSCLC showed that gefitinib was noninferior in overall survival compared with docetaxel.6

Another Novel Agent Shows Promise Natale next discussed studies of vandetanib, a oncedaily oral agent that selectively inhibits VEGF receptor, EGFR, and rearranged during transfection (RET) signaling.7 Improved PFS with vandetanib has been shown in three phase 2 studies of patients with advanced NSCLC. Two of these studies were in previously treated patients (vandetanib 300 mg vs gefitinib; vandetanib 100 mg ± docetaxel vs docetaxel), and in one, it was used as first-line therapy (vandetanib 300 mg ± paclitaxel + carboplatin vs paclitaxel + carboplatin). Another study, however, found poorer PFS with vandetanib 300 mg monotherapy compared with pacitaxel + carboplatin. Results of an exploratory analysis reported at the 2008 annual meeting of the American Society of Clinical Oncology suggest that low baseline levels of circulating VEGF may be predictive of a PFS advantage in patients with NSCLC who receive vandetanib monotherapy. n

References 1. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006;355:2542-2550. 2. Cohen MH, Gootenberg J, Keegan P, et al. FDA drug approval summary: bevacizumab (Avastin) plus carboplatin and paclitaxel as firstline treatment of advanced/metastatic recurrent nonsquamous nonsmall cell lung cancer. Oncologist. 2007;12:713-718. 3. Reck M, von Pawel J, Zatloukal P, et al. Phase III trial of cisplatin plus gemcitabine with either placebo or bevacizumab as first-line therapy for non-squamous non–small-cell lung cancer: AVAiL. J Clin Oncol. 2009 Feb 2;Epub ahead of print. 4. Perez-Soler R, Chachoua A, Huberman M, et al. A phase II trial of the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor OSI-774, following platinum-based chemotherapy, in patients (pts) with advanced, EGFR-expressing, non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol. 2001;20(suppl):Abstract 1235. 5. Comis RL. The current situation: erlotinib (Tarceva) and gefitinib (Iressa) in non-small cell lung cancer. Oncologist. 2005;10:467-470. 6. Kim ES, Hirsh V, Mok T, et al. Gefitinib versus docetaxel in previously treated non-small-cell lung cancer (INTEREST): a randomised phase III trial. Lancet. 2008;372:1809-1818. 7. Heymach JV, Hanrahan EO, Mann P, et al. Baseline VEGF as a potential predictive biomarker of vandetanib clinical benefit in patients with advanced NSCLC. J Clin Oncol. 2008;26(May 20 suppl):Abstract 8009.

Upcoming Meetings APRIL

JUNE

April 30-May 3 Oncology Nursing Society 34th Annual Congress San Antonio, TX www.ons.org

17-20 HOPA 2009: Hematology/Oncology Pharmacy Association 5th Annual Conference Miami, FL www.hoparx.org

MAY

17-20 10th International Lung Cancer Congress Kohala Coast, HI www.cancerlearning.com

3-6 12th World Congress on Cancer of the Skin 2009 Tel Aviv, Israel Wccs2009@kenes.com 13-14 4th Annual Oncology Economics Forum: Access to Innovative Cancer Therapies in 2009 Washington, DC www.conferagroup.com May 29-June 2 2009 ASCO Annual Meeting Orlando, FL www.asco.org

22-26 2009 Pan Pacific Lymphoma Conference Kohala Coast, HI bram@unmc.edu 24-26 VIII Madrid Breast Cancer Conference Madrid, Spain www.madridbreastcancer2009.com 25-27 Supportive Care in Cancer MASCC/ISOO 2009 International Symposium Rome, Italy www.mascc.org

Multidisciplinary Cancer Care

She’s still fighting after surgery, radiation, and chemotherapy. How can you respond when she asks what’s next?

ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) is indicated for the treatment of breast cancer after failure of combination chemotherapy for metastatic disease or relapse within 6 months of adjuvant chemotherapy. Prior therapy should have included an anthracycline unless clinically contraindicated. WARNING: ABRAXANE for Injectable Suspension (paclitaxel proteinbound particles for injectable suspension) (albumin-bound) should be administered under the supervision of a physician experienced in the use of cancer chemotherapeutic agents. Appropriate management of complications is possible only when adequate diagnostic and treatment facilities are readily available. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. In order to monitor the occurrence of bone marrow suppression, primarily neutropenia, which may be severe and result in infection, it is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE. Note: An albumin form of paclitaxel may substantially affect a drug’s functional properties relative to those of drug in solution. DO NOT SUBSTITUTE FOR OR WITH OTHER PACLITAXEL FORMULATIONS.

IMPORTANT SAFETY INFORMATION The use of ABRAXANE has not been studied in patients with hepatic or renal dysfunction. In the randomized controlled trial, patients were excluded for baseline serum bilirubin >1.5 mg/dL or baseline serum creatinine >2 mg/dL. ABRAXANE can cause fetal harm when administered to a pregnant woman. Women of childbearing potential should be advised to avoid becoming pregnant while receiving treatment with ABRAXANE. Men should be advised to not father a child while receiving treatment with ABRAXANE. It is recommended that nursing be discontinued when receiving ABRAXANE therapy. ABRAXANE contains albumin (human), a derivative of human blood. Caution should be exercised when administering ABRAXANE concomitantly with known substrates or inhibitors of CYP2C8 and CYP3A4. ABRAXANE therapy should not be administered to patients with metastatic breast cancer who have baseline neutrophil counts of less than 1,500 cells/mm3. It is recommended that frequent peripheral blood cell counts be performed on all patients receiving ABRAXANE.

give her

In a pivotal phase III trial 速

ABRAXANE delivered nearly double the overall response rate vs solvent-based paclitaxel1 The albumin-bound paclitaxel, ABRAXANE, eliminates the need for Cremophor 速 EL,* allowing delivery of a 49% higher dose vs solvent-based paclitaxel1

for efficacy

21.5% vs 11.1% (P=.003) for all study patients.1 95% CI, 16.2% to 26.7% for ABRAXANE.1 95% CI, 6.9% to 15.1% for solvent-based paclitaxel.1

15.5% vs 8.4% (P=NS) for study patients who failed combination chemotherapy or relapsed within 6 months of adjuvant chemotherapy.1 95% CI, 9.3% to 21.8% for ABRAXANE.1 95% CI, 3.9% to 12.9% for solvent-based paclitaxel.1

BOUND AND DETERMINED

Patients should not be retreated with subsequent cycles of ABRAXANE until neutrophils recover to a level >1,500 cells/mm3 and platelets recover to a level >100,000 cells/mm3. In the case of severe neutropenia (<500 cells/mm3 for 7 days or more) during a course of ABRAXANE therapy, a dose reduction for subsequent courses is recommended. Sensory neuropathy occurs frequently with ABRAXANE. If grade 3 sensory neuropathy develops, treatment should be withheld until resolution to grade 1 or 2 followed by a dose reduction for all subsequent courses of ABRAXANE. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema, thrombosis, pulmonary thromboembolism, pulmonary embolism, and hypertension. In the randomized metastatic breast cancer study, the most important adverse events included alopecia (90%), neutropenia (all cases 80%; severe 9%), sensory neuropathy (any symptoms 71%; severe 10%), asthenia (any 47%; severe 8%), myalgia/arthralgia (any 44%; severe 8%), anemia (all 33%; severe 1%), infections (24%), nausea (any 30%;

severe 3%), vomiting (any 18%; severe 4%), diarrhea (any 27%; severe <1%), and mucositis (any 7%; severe <1%). Other adverse reactions have included ocular/visual disturbances (any 13%; severe 1%), fluid retention (any 10%; severe 0%), hepatic dysfunction (elevations in bilirubin 7%, alkaline phosphatase 36%, AST [SGOT] 39%), renal dysfunction (any 11%; severe 1%), thrombocytopenia (any 2%; severe <1%), hypersensitivity reactions (any 4%; severe 0%), cardiovascular reactions (severe 3%), and injection site reactions (<1%). During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. To learn more about ABRAXANE, visit our Web site at www.abraxane.com Please see the Brief Summary of the ABRAXANE full prescribing information (including boxed WARNING) on the next page. *Cremophor EL (polyoxyethylated castor oil) is a registered trademark of BASF Aktiengesellschaft. Reference: 1. ABRAXANE [prescribing information]. Los Angeles, Calif: Abraxis Oncology, a division of Abraxis BioScience, Inc; August 2007. ABRAXANE is a registered trademark of Abraxis BioScience, LLC. Abraxis Oncology速 is a division of Abraxis BioScience, LLC. 息2008 Abraxis BioScience, LLC All Rights Reserved. AO 1127 12/08

Rx Only

Table 1: Frequencya of Important Treatment Emergent Adverse Events in the Randomized Study on an Every-3-Weeks Schedule (Continued) Percent of Patients ABRAXANE Paclitaxel Injection 260/30minb 175/3hc,d (n=229) (n=225)

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

80 9

82 22

2 <1

3 <1

33 1 24 2 2

25 <1 20 1 2 (Continued)

Hypersensitivity Reactione All 4 12 Severef 0 2 Cardiovascular Vital Sign Changesg Bradycardia <1 <1 Hypotension 5 5 Severe Cardiovascular Eventsf 3 4 Abnormal ECG All patients 60 52 Patients with Normal Baseline 35 30 Respiratory Cough 7 6 Dyspnea 12 9 Sensory Neuropathy Any Symptoms 71 56 Severe Symptomsf 10 2 Myalgia/Arthralgia Any Symptoms 44 49 8 4 Severe Symptomsf Asthenia Any Symptoms 47 39 Severe Symptomsf 8 3 Fluid Retention/Edema Any Symptoms 10 8 Severe Symptomsf 0 <1 Gastrointestinal Nausea Any symptoms 30 22 Severe symptomsf 3 <1 Vomiting Any symptoms 18 10 4 1 Severe Symptomsf Diarrhea Any Symptoms 27 15 Severe Symptomsf <1 1 Mucositis Any Symptoms 7 6 <1 0 Severe Symptomsf Alopecia 90 94 Hepatic (Patients with Normal Baseline) Bilirubin Elevations 7 7 Alkaline Phosphatase Elevations 36 31 AST (SGOT) Elevations 39 32 Injection Site Reaction <1 1 a Based on worst grade b ABRAXANE dose in mg/m2/duration in minutes c 2 paclitaxel injection dose in mg/m /duration in hours d paclitaxel injection pts received premedication e Includes treatment-related events related to hypersensitivity (e.g., flushing, dyspnea, chest pain, hypotension) that began on a day of dosing. f Severe events are defined as at least grade 3 toxicity g During study drug dosing. Myelosuppression and sensory neuropathy were dose related. Adverse Event Experiences by Body System Unless otherwise noted, the following discussion refers to the primary safety database of 229 patients with metasttatic breast cancer treated with single-agent ABRAXANE in the randomized controlled trial. The frequency and severity of important adverse events for the study are presented above in tabular form. In some instances, rare severe events observed with paclitaxel injection may be expected to occur with ABRAXANE. Hematologic Neutropenia, the most important hematologic toxicity, was dose dependent and reversible. Among patients with metastatic breast cancer in the randomized trial, neutrophil counts declined below 500 cells/mm3 (Grade 4) in 9% of the patients treated with a dose of 260 mg/m2 compared to 22% in patients receiving paclitaxel injection at a dose of 175 mg/m2. In the randomized metastatic breast cancer study, infectious episodes were reported in 24% of the patients treated with a dose of 260 mg/m2 given as a 30-minute infusion. Oral candidiasis, respiratory tract infections and pneumonia were the most frequently reported infectious complications. Febrile neutropenia was reported in 2% of patients in the ABRAXANE arm and 1% of patients in the paclitaxel injection arm. Thrombocytopenia was uncommon. In the randomized metastatic breast cancer study, bleeding episodes were reported in 2% of the patients in each treatment arm. Anemia (Hb <11 g/dL) was observed in 33% of patients treated with ABRAXANE in the randomized trial and was severe (Hb <8 g/dL) in 1% of the cases. Among all patients with normal baseline hemoglobin, 31% became anemic on study and 1% had severe anemia. Hypersensitivity Reactions (HSRs) In the randomized controlled metastatic breast cancer study, Grade 1 or 2 HSRs occurred on the day of ABRAXANE administration and consisted of dyspnea (1%) and flushing, hypotension, chest pain, and arrhythmia (all <1%). The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. During postmarketing surveillance, rare occurrences of severe hypersensitivity reactions have been reported with ABRAXANE. The use of ABRAXANE in patients previously exhibiting hypersensitivity to paclitaxel injection or human albumin has not been studied. Patients who experience a severe hypersensitivity reaction to ABRAXANE should not be rechallenged with the drug. Cardiovascular Hypotension, during the 30-minute infusion, occurred in 5% of patients in the randomized metastatic breast cancer trial. Bradycardia, during the 30-minute infusion, occurred in <1% of patients. These vital sign changes most often caused no symptoms and required neither specific therapy nor treatment discontinuation. Severe cardiovascular events possibly related to single-agent ABRAXANE occurred in approximately 3% of patients in the randomized trial. These events included chest pain, cardiac arrest, supraventricular tachycardia, edema,thrombosis, pulmonary thromboembolism, pulmonary emboli, and hypertension. Cases of cerebrovascular attacks (strokes) and transient ischemic attacks have been reported rarely. Electrocardiogram (ECG) abnormalities were common among patients at baseline. ECG abnormalities on study did not usually result in symptoms, were not dose-limiting, and required no intervention. ECG abnormalities were noted in 60% of patients in the metastatic breast cancer randomized trial. Among patients with a normal ECG prior to study entry, 35% of all patients developed an abnormal tracing while on study. The most frequently reported ECG modifications were non-specific repolarization abnormalities, sinus bradycardia, and sinus tachycardia. Respiratory Reports of dyspnea (12%) and cough (6%) were reported after treatment with ABRAXANE in the randomized trial. Rare reports (<1%) of pneumothorax were reported after treatment with ABRAXANE. Rare reports of interstitial pneumonia, lung fibrosis, and pulmonary embolism have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of radiation pneumonitis have been received in paclitaxel injection patients receiving concurrent radiotherapy. There is no experience with the use of ABRAXANE with concurrent radiotherapy. Neurologic The frequency and severity of neurologic manifestations were influenced by prior and/or concomitant therapy with neurotoxic agents. In general, the frequency and severity of neurologic manifestations were dose-dependent in patients receiving single-agent ABRAXANE. In the randomized trial, sensory neuropathy was observed in 71% of patients (10% severe) in the ABRAXANE arm and in 56% of patients (2% severe) in the paclitaxel injection arm. The frequency of sensory neuropathy increased with cumulative dose. Sensory neuropathy was the cause of ABRAXANE discontinuation in 7/229 (3%) patients in the randomized trial. In the randomized comparative study, 24 patients (10%) treated with ABRAXANE developed Grade 3 peripheral neuropathy; of these patients, 14 had documented improvement after a median of 22 days; 10 patients resumed treatment at a reduced dose of ABRAXANE and 2 discontinued due to peripheral neuropathy. Of the 10 patients without documented improvement, 4 discontinued the study due to peripheral neuropathy. No incidences of grade 4 sensory neuropathies were reported in the clinical trial. Only one incident of motor neuropathy (grade 2) was observed in either arm of the controlled trial. Reports of autonomic neuropathy resulting in paralytic ileus have been received as part of the continuing surveillance of paclitaxel injection safety. Cranial nerve palsies have been reported during postmarketing surveillance of ABRAXANE. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Ocular/visual disturbances occurred in 13% of all patients (n=366) treated with ABRAXANE in single arm and randomized trials and 1% were severe. The severe cases (keratitis and blurred vision) were reported in patients in a single arm study who received higher doses than those recommended (300 or 375 mg/m2). These effects generally have been reversible. However, rare reports in the literature of abnormal visual evoked potentials in patients treated with paclitaxel injection have suggested persistent optic nerve damage. Arthralgia/Myalgia Forty-four percent of patients treated in the randomized trial experienced arthralgia/myalgia; 8% experienced severe symptoms. The symptoms were usually transient, occurred two or three days after ABRAXANE administration, and resolved within a few days. Hepatic Among patients with normal baseline liver function treated with ABRAXANE in the randomized trial, 7%, 36%, and 39% had elevations in bilirubin, alkaline phosphatase, and AST (SGOT), respectively. Grade 3 or 4 elevations in GGT were reported for 14% of patients treated with ABRAXANE and 10% of patients treated with paclitaxel injection in the randomized trial.

Rare reports of hepatic necrosis and hepatic encephalopathy leading to death have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Renal Overall 11% of patients experienced creatinine elevation, 1% severe. No discontinuations, dose reductions, or dose delays were caused by renal toxicities. Gastrointestinal (GI) Nausea/vomiting, diarrhea, and mucositis were reported by 33%, 27%, and 7% of ABRAXANE treated patients in the randomized trial. Rare reports of intestinal obstruction, intestinal perforation, pancreatitis, and ischemic colitis have been received as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment. Rare reports of neutropenic enterocolitis (typhlitis), despite the coadministration of G-CSF, were observed in patients treated with paclitaxel injection alone and in combination with other chemotherapeutic agents. Injection Site Reaction Injection site reactions have occurred infrequently with ABRAXANE and were mild in the randomized clinical trial. Recurrence of skin reactions at a site of previous extravasation following administration of paclitaxel injection at a different site, i.e., “recall”, has been reported rarely. Rare reports of more severe events such as phlebitis, cellulitis, induration, skin exfoliation, necrosis, and fibrosis have been received as part of the continuing surveillance of paclitaxel injection safety. In some cases the onset of the injection site reaction in paclitaxel injection patients either occurred during a prolonged infusion or was delayed by a week to ten days. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Asthenia Asthenia was reported in 47% of patients (8% severe) treated with ABRAXANE in the randomized trial. Asthenia included reports of asthenia, fatigue, weakness, lethargy and malaise. Other Clinical Events Rare cases of cardiac ischemia/infarction and thrombosis/embolism possibly related to ABRAXANE treatment have been reported. Alopecia was observed in almost all of the patients. Nail changes (changes in pigmentation or discoloration of nail bed) were uncommon. Edema (fluid retention) was infrequent (10% of randomized trial patients); no patients had severe edema. The following rare adverse events have been reported as part of the continuing surveillance of paclitaxel injection safety and may occur following ABRAXANE treatment: skin abnormalities related to radiation recall as well as reports of Stevens-Johnson syndrome, toxic epidermal necrolysis, conjunctivitis, and increased lacrimation. As part of the continuing surveillance of ABRAXANE, skin reactions including generalized or maculo-papular rash, erythema, and pruritis have been observed. Additionally, there have been case reports of photosensitivity reactions, radiation recall phenomenon, and in some patients previously exposed to capecitabine, reports of palmar-plantar erythrodysaesthesiae. Because these events have been reported during clinical practice, true estimates of frequency cannot be made and a causal relationship to the events has not been established. Accidental Exposure No reports of accidental exposure to ABRAXANE have been received. However, upon inhalation of paclitaxel, dyspnea, chest pain, burning eyes, sore throat, and nausea have been reported. Following topical exposure, events have included tingling, burning, and redness. OVERDOSAGE: There is no known antidote for ABRAXANE overdosage. The primary anticipated complications of overdosage would consist of bone marrow suppression, sensory neurotoxicity, and mucositis. DOSAGE AND ADMINISTRATION: After failure of combination chemotherapy for metastatic breast cancer or relapse within 6 months of adjuvant chemotherapy, the recommended regimen for ABRAXANE for Injectable Suspension (paclitaxel protein-bound particles for injectable suspension) is 260 mg/m2 administered intravenously over 30 minutes every 3 weeks. Hepatic Impairment The appropriate dose of ABRAXANE for patients with bilirubin greater than 1.5 mg/dL is not known. Dose Reduction Patients who experience severe neutropenia (neutrophil <500 cells/mm3 for a week or longer) or severe sensory neuropathy during ABRAXANE therapy should have dosage reduced to 220 mg/m2 for subsequent courses of ABRAXANE. For recurrence of severe neutropenia or severe sensory neuropathy, additional dose reduction should be made to 180 mg/m2. For grade 3 sensory neuropathy hold treatment until resolution to grade 1 or 2, followed by a dose reduction for all subsequent courses of ABRAXANE. Preparation and Administration Precautions ABRAXANE is a cytotoxic anticancer drug and, as with other potentially toxic paclitaxel compounds, caution should be exercised in handling ABRAXANE. The use of gloves is recommended. If ABRAXANE (lyophilized cake or reconstituted suspension) contacts the skin, wash the skin immediately and thoroughly with soap and water. Following topical exposure to paclitaxel, events may include tingling, burning and redness. If ABRAXANE contacts mucous membranes, the membranes should be flushed thoroughly with water. Given the possibility of extravasation, it is advisable to closely monitor the infusion site for possible infiltration during drug administration. Limiting the infusion of ABRAXANE to 30 minutes, as directed, reduces the likelihood of infusion-related reactions (see PRECAUTIONS: Injection Site Reaction). No premedication to prevent hypersensitivity reactions is required prior to administration of ABRAXANE. Preparation for Intravenous Administration ABRAXANE is supplied as a sterile lyophilized powder for reconstitution before use. AVOID ERRORS, READ ENTIRE PREPARATION INSTRUCTIONS PRIOR TO RECONSTITUTION. Each mL of the reconstituted formulation will contain 5 mg/mL paclitaxel. 1. Aseptically, reconstitute each vial by injecting 20 mL of 0.9% Sodium Chloride Injection, USP. 2. Slowly inject the 20 mL of 0.9% Sodium Chloride Injection, USP, over minimum of 1 minute, using the sterile syringe to direct the solution flow onto the INSIDE WALL OF THE VIAL. 3. DO NOT INJECT the 0.9% Sodium Chloride Injection, USP, directly onto the lyophilized cake as this will result in foaming. 4. Once the injection is complete, allow the vial to sit for a minimum of 5 minutes to ensure proper wetting of the lyophilized cake/powder. 5. Gently swirl and/or invert the vial slowly for at least 2 minutes until complete dissolution of any cake/powder occurs. Avoid generation of foam. 6. If foaming or clumping occurs, stand solution for at least 15 minutes until foam subsides. Calculate the exact total dosing volume of 5 mg/mL suspension required for the patient: Dosing volume (mL) = Total dose (mg)/5 (mg/mL). The reconstituted suspension should be milky and homogenous without visible particulates. If particulates or settling are visible, the vial should be gently inverted again to ensure complete resuspension prior to use. Discard the reconstituted suspension if precipitates are observed. Discard any unused portion. Inject the appropriate amount of reconstituted ABRAXANE into an empty, sterile IV bag (plasticized polyvinyl chloride (PVC) containers, PVC or non PVC type IV bag). The use of specialized DEHP-free solution containers or administration sets is not necessary to prepare or administer ABRAXANE infusions. The use of an in-line filter is not recommended. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration whenever solution and container permit. Stability Unopened vials of ABRAXANE are stable until the date indicated on the package when stored between 20°C to 25°C (68°F to 77°F), in the original package. Neither freezing nor refrigeration adversely affects the stability of the product. Stability of Reconstituted Suspension in the Vial Reconstituted ABRAXANE should be used immediately, but may be refrigerated at 2°C to 8°C (36°F to 46°F) for a maximum of 8 hours if necessary. If not used immediately, each vial of reconstituted suspension should be replaced in the original carton to protect it from bright light. Discard any unused portion. Stability of Reconstituted Suspension in the Infusion Bag The suspension for infusion prepared as recommended in an infusion bag should be used immediately, but may be stored at ambient temperature (approximately 25°C) and lighting conditions for up to 8 hours. HOW SUPPLIED: Product NDC No. No. 103450 68817-134-50 100 mg of paclitaxel in a single use vial, individually packaged in a carton. Storage Store the vials in original cartons at 20°C to 25°C (68°F to 77°F). Retain in the original package to protect from bright light. Handling and Disposal Procedures for proper handling and disposal of anticancer drugs should be considered. Several guidelines on this subject have been published.1-8 There is no general agreement that all of the procedures recommended in the guidelines are necessary or appropriate. U.S. Patent Numbers: 5,439,686; 5,498,421; 6,096,331; 6,506,405; 6,537,579; 6,749,868; 6,753,006 REFERENCES: 1. Recommendations for the Safe Handling of Parenteral Antineoplastic Drugs. Publication No. 83-2621. For sale by the Superintendent of Documents, US Government NIH Printing Office, Washington, DC 20402. 2. AMA Council Report. Guidelines for Handling Parenteral Antineoplastics. JAMA, 1985; 253(11):1590-1592. 3. National Study Commission on Cytotoxic Exposure Recommendations for Handling Cytotoxic Agents. Available from Louis R Jeffrey, ScD, Chairman, National Study Commission on Cytotoxic Exposure. Massachusetts College of Pharmacy and Allied Health Sciences. 179 Longwood Avenue, Boston, Massachusetts 02115. 4. Clinical Oncology Society of Australia. Guidelines and Recommendations for Safe Handling of Antineoplastic Agents. Med J Australia, 1983; 1:426-428. 5. Jones RB, et al: Safe Handling of Chemotherapeutic Agents: A Report from the Mount Sinai Medical Center. CA-A Cancer Journal for Clinicians, 1983; (Sept/Oct) 258-263. 6. American Society of Hospital Pharmacists Technical Assistance Bulletin on Handling Cytotoxic and Hazardous Drugs. Am J Hosp Pharm, 1990; 47:1033-1049. 7. Controlling Occupational Exposure to Hazardous Drugs. (OSHA WORK-PRACTICE GUIDELINES.) Am J Health-Syst Pharm, 1996; 53:1669-1686. 8. ONS Clinical Practice Committee. Cancer Chemotherapy Guidelines and Recommendations for Practice. Pittsburgh, Pa: Oncology Nursing Society; 1999:32-41.

Lung Cancer Drugs in Phase 3 and 4 Trials in the United States New drugs and combinations are being studied for the treatment of non–small-cell and small-cell lung cancer. Ongoing trials and those currently recruiting patients are listed below.

Drug name, developer(s)

Study

Status

Abraxane (paclitaxel proteinbound particles); Abraxis Bioscience

• Abraxane/carboplatin vs Taxol/carboplatin as first-line therapy in advanced NSCLC

Recruiting

Affinitak Isis Pharmaceuticals, Eli Lilly

• Chemotherapy/carboplatin/paclitaxel vs carboplatin/ paclitaxel/Affinitak in advanced, previously untreated NSCLC

Active

Aflibercept sanofi-aventis

• Aflibercept vs placebo in patients treated with second-line docetaxel after failure of one platinum-based therapy for locally advanced/metastatic NSCLC

Recruiting

AG3340 Agouron Pharmaceuticals

• Prinomastat in combination with gemcitabine/cisplatin in advanced NSCLC

Active

Alimta (pemetrexed) Eli Lilly

• Pemetrexed/carboplatin/bevacizumab followed by maintenance pemetrexed/bevacizumab vs paclitaxel/ carboplatin/bevacizumab followed by maintenance bevacizumab in stage IIIB or IV nonsquamous NSCLC • Maintenance pemetrexed/best supportive care vs best supportive care immediately following induction treatment for advanced NSCLC • Pemetrexed/cisplatin/radiotherapy followed by consolidation pemetrexed vs etoposide/cisplatin/radiotherapy followed by consolidation cytotoxic chemotherapy of choice in unresectable, locally advanced, stage III NSCLC other than predominantly squamous cell histology

Recruiting

Active

Recruiting

Amrubicin Pharmion

• Comparing amrubicin vs topotecan in extensive/limited and sensitive/refractory SCLC after failure of first-line chemotherapy

Recruiting

Avastin (bevacizumab) Genentech

• Comparing bevacizumab therapy with/without erlotinib after completion of chemotherapy with bevacizumab for the firstline treatment of locally advanced/recurrent/metastatic NSCLC • Bevacizumab/Tarceva compared with Tarceva alone for treatment of advanced NSCLC after failure of standard first-line chemotherapy • Avastin/chemotherapy for treatment of metastatic, locally advanced, and unresectable colorectal cancer and locally advanced/ metastatic NSCLC (excluding predominant squamous cell histology)

Active

Recruiting

Multidisciplinary Cancer Care

Drug name, developer(s)

Study

Status

Genasense (oblimersen); Genta

• Docetaxel vs docetaxel/Genasense in previously treated NSCLC

Active

Mage-3 recombinant pharmaccine GlaxoSmithKline

• Cancer immunotherapeutic GSK1572932A as adjuvant therapy Recruiting for mage-A3-positive NSCLC • GSK1572932A antigen-specific cancer immunotherapeutic as Recruiting adjuvant therapy in patients with resectable mage-A3-positve NSCLC

NOV-002 Novelos Therapeutics

• NOV-002/paclitaxel/carboplatin vs paclitaxel/carboplatin alone for advanced NSCLC

Recruiting

Onconase (ranpirnase) Alfacell

• Onconase/doxorubicin vs doxorubicin for malignant pleural/ peritoneal mesothelioma with no more than one prior chemotherapy regimen

Active

Stimuvax; Merck, EMD Serono

• Cancer vaccine Stimuvax in unresectable stage III NSCLC

Recruiting

Sutent (sunitinib) Pfizer

• Efficacy/safety study of sunitinib in advanced/metastatic NSCLC treated with erlotinib

Recruiting

Tarceva (erlotinib) Genentech, OSI Pharmaceuticals

• Bevacizumab/Tarceva compared with Tarceva alone for advanced Active NSCLC after failure of standard first-line chemotherapy • Comparing bevacizumab therapy with/without erlotinib after Active completion of chemotherapy with bevacizumab for the first-line treatment of locally advanced/recurrent/metastatic NSCLC • Erlotinib or placebo following concurrent docetaxel/ Recruiting carboplatin/thoracic radiotherapy in inoperable stage III NSCLC

Taxotere (docetaxel) sanofi-aventis

• RRM1/ERCC1 directed customized chemotherapy vs standard of care for first-line treatment of advanced NSCLC

Recruiting

Thalomid (thalidomide) Celgene

• Carboplatin/paclitaxel/thoracic radiotherapy with/ without thalidomide in stage III NSCLC

Active

Xyotax (polyglutamate paclitaxel) Cell Therapeutics

• Paclitaxel poliglumex/carboplatin vs paclitaxel/carboplatin for chemonaïve advanced NSCLC in women with estradiol >30 pg/mL • CT-2103 vs docetaxel for the second-line treatment of NSCLC • CT-2103 vs gemcitabine or vinorelbine for PS = 2 patients with chemonaïve advanced NSCLC • CT-2103/carboplatin vs paclitaxel/carboplatin for PS = 2 patients with chemonaïve advanced NSCLC • Paclitaxel poliglumex/carboplatin vs paclitaxel/carboplatin for chemonaïve advanced NSCLC in women with estradiol >25 pg/mL

Recruiting

Zactima (vandetanib) AstraZeneca

Zolinza (vorinostat) Merck

• Zactima/pemetrexed vs pemetrexed alone in locally advanced/metastatic NSCLC • Zactima vs Tarceva in locally advanced/metastatic NSCLC after failure of at least one chemotherapy

March/April 2009

Active Recruiting Active Active

• Oral suberoylanilide hydroxamic acid in advanced malignant pleural Recruiting mesothelioma previously treated with systemic chemotherapy

NSCLC indicates non–small-cell lung cancer; PS, performance status; SCLC, small-cell lung cancer.

Active Active

Multidisciplinary Cancer Clinics: A Streamlined Approach to Cancer Care in the Community Setting An interview with Mark J. Krasna, MD

Mark J. Krasna, MD

Patients with cancer often require treatment by medical, surgical, and radiation oncologists. Those treated in the community setting—as the vast majority of patients are today—usually have to schedule individual appointments with these specialists at their separate offices. In this interview, Mark J. Krasna, MD, explains the advantages of multidisciplinary cancer clinics, in which medical, surgical, and radiation oncologists work as a team in one facility and together develop a consensus on a patient’s treatment plan. He illustrates this approach with a description of how a patient with lung cancer would be treated in a multidisciplinary clinic.

ournal of Multidisciplinary Cancer Care (JOMCC): What are the advantages of a multidisciplinary treatment approach for patients with cancer and their healthcare providers?

Mark J. Krasna (MJK): The major advantage of multidisciplinary care for patients is that they have a true one-stop shopping approach. They no longer have to go from physician office to physician office, which can take anywhere from weeks to months and cover a huge geographic distance, which obviously is very difficult for the patient. Besides convenience, this approach also has advantages in terms of quality of care. If the patient is seen at one time, in one place, by one team of physicians, that patient now has access to all the specialties he or she needs and gets all of the input at one place. That means that the patient knows that the entire medical team has a consensus on what is the right care and that there is one treatment plan that can be delivered in a timely fashion. JOMCC: With all its advantages, why hasn’t the multidisciplinary approach been more widely adopted? Dr Krasna is Medical Director of St. Joseph Cancer Institute in Towson, MD, and principal investigator, Catholic Health Initiatives National Community Cancer Center Program sites.

MJK: The number one limitation is simply the lack of a physical facility that would allow all the providers to meet in one place. Number two is the lack of the infrastructure in terms of how to house doctors and make sure that everyone can do the appropriate billing. Number three is how to get everybody on the same page to do what’s right for the patient. Obviously, everyone wants to do that, but the challenge is how to facilitate it. Cancer centers, whether they be academic or in the community, generally have a hard time answering those needs. You need to build a cancer center that not only has the physical space but also has the infrastructure to provide all the necessary support. There are significant reimbursement issues as well. You have to make sure that patients are getting the approvals for consultations with more than one physician. Let’s say, for example, that they are going to see a medical, surgical, and radiation oncologist for lung cancer. They have to get a preauthorization for consultation for all three of those specialists. That is definitely doable, but it’s another challenge that has to be taken into consideration by the administrators who are running that cancer center to make sure that they are adhering to all the appropriate Medicare guidelines and still able to do what they need to do. JOMCC: Please explain how a patient with lung cancer, for example, would be treated in a multidisciplinary clinic.

Multidisciplinary Cancer Care

MJK: In the current era, about 90% of patients with lung cancer will get multimodality therapy. For stage IB patients or higher, there is a role for chemotherapy after surgery. Stage III patients who have local, regional tumors that are potentially resectable will get chemotherapy, radiation therapy, and surgery, whereas for those with stage III tumors that are not resectable, there’s a role for chemotherapy and radiation. Today, even 50% of patients with stage IV disease who are getting chemotherapy will eventually get radiation too

The best approach for every patient is to see the entire team before any therapy has begun so that there is a true prospective evaluation of the patient. because they have a brain or bone metastasis that needs palliation. So of the 190,000 patients who will be diagnosed with lung cancer this year, 150,000 to 170,000 will get more than one type of therapy. Therefore, the best approach for every patient is to see the entire team before any therapy has begun so that there is a true prospective evaluation of the patient, and the patient gets an opinion from each of the specialists before any therapy is started. That should be the standard of care in both community and academic medical centers. At St. Joseph Cancer Institute, all the team members typically see every new patient with lung cancer. The unique approach is that we all, as a team, give our input upfront. This approach couldn’t work without what I call a nurse coordinator, or what others may call a navigator. Each of our disease sites has a nurse coordinator who helps patients coordinate their medical, radiation, and surgical oncology visits and treatments. We have navigators as well, but they are more focused on the survivorship or the palliative side of cancer care. JOMCC: Please describe your cancer center and how it works. MJK: The Cancer Institute at St. Joseph Medical Center, a member of Catholic Health Initiatives, was designed specifically to provide multidisciplinary cancer care with facilities for all the different specialties. It was truly built around the patient experience. In addition to the thoracic oncology center, there are centers specializing in breast, hepatobiliary, colorectal, gynecologic, and urologic oncology as well as a medical oncol-

March/April 2009

ogy center and a radiation oncology center. Taking lung cancer as an example, a patient newly diagnosed with what is thought to be stage III disease is first seen by a nurse technician, who gets the patient’s vital signs and brings the patient into one of the multidisciplinary clinic rooms. The patient stays in the same room the whole time of their visit and the physician team rotates around the patient. The medical oncologist sees the patient first with the nurse coordinator. Then the nurse brings in the radiation oncologist followed by the surgical oncologist. So during that one visit, the patient sees three medical specialists plus the nurse coordinator plus the navigator, plus the dietitian if necessary. A patient who is considered a potential clinical trial candidate will also see the research nurse. By the time the patient leaves, follow-up appointments and any additional tests have been scheduled. That same day, we have a multidisciplinary conference and discuss every single patient before any treatment is begun. The advantages for the patient are huge. Not only does he or she, in one visit, experience this consensus approach, but the amount of time saved for the patient is immeasurable. The best part is that when the consensus is reached, we can then initiate treatment, usually within 2 weeks from the date of their first visit. That kind of multidisciplinary approach is very hard to replicate without the commitment of the physicians, the staff, and a committed nurse coordinator, but if it can be done, it really takes multidisciplinary care to the next level. It is because of this model that St. Joseph Cancer Institute was chosen by the National Cancer Institute (NCI) to be part of the National Community Cancer Centers Program (NCCCP) pilot [see sidebar, page 25]. The NCCCP is an opportunity to demonstrate that you don’t have to be an NCI-designated cancer center to deliver high-quality cancer care. The basics that are necessary to define your ability to function like an NCCCP site are multidisciplinary care as a paradigm, outreach to minority populations, and enrollment of patients in clinical trials. JOMCC: It has been said that doctors in community practice may be reluctant to refer their patients to clinical trials because they would lose that patient. Have you found that to be the case, and, if so, what can be done about it? MJK: It is one of the main barriers to enrollment in clinical trials in community settings. If a medical oncologist is treating a patient in his or her private office setting, that physician not only has a personal interest in and relationship with the patient, but also a financial

NCI Community Cancer Centers Program Pilot: A 1-Year Update

he National Cancer Institute (NCI) Community Cancer Centers Program (NCCCP) is a proposed national network of community cancer centers designed to bring the latest scientific advances and the highest level of innovative and integrated, multispecialty care to many more cancer patients in the communities where they live. The goals of the program are as follows: • Draw more patients into clinical trials in community-based settings • Reduce cancer healthcare disparities • Explore standards for collecting and storing cancer research specimens • Link to national computer networks for conducting research and sharing results. Approximately 85% of American cancer patients are diagnosed at community hospitals and physician offices. For most, especially senior citizens and minorities, treatment at a major cancer center is unrealistic because of location/travel, distance from family and other support systems, or economic reasons. Currently in the pilot stage, this program provides state-of-theart cancer care to patients in 16 community hospitals in 14 states, with the goal of expanding nationwide after successful completion in 2010. NCCCP was established to encourage collaboration between private-practice medical, surgical, and radiation oncologists and NCI research and NCI-designated cancer centers, which are based at large research universities. Currently, pilot program sites are exploring ways to share information, via electronic medical records, to improve patient care. These sites also are researching new and enhanced ways to assist, educate, and better treat the needs of underserved populations, including elderly, rural, innercity, and low-income patients as well as racial and ethnic groups with unusually high cancer rates. In addition, NCCCP pilot sites have been tasked to study how community hospitals nationwide could most effectively develop and implement a national database of voluntarily provided electronic medical records accessible to cancer researchers. The sites also are studying methods of expanding and standardizing the collection of blood and tissue specimens voluntarily obtained. Begun in 2007, considerable progress has been

made to date. Sites have launched an effort focused on three phase 3 clinical trials—breast, colorectal, and lung—that has increased the patient accrual rate to each. Further, many pilot sites have created collaborations with NCI-designated cancer centers and other academic biomedical research institutions. Formal agreements have been made with NCI’s Community Networks Program, reducing disparities among racial and ethnic minorities as well as underserved populations through community-based education, training, and research.

Pilot program sites are exploring ways to share information, via electronic medical records, to improve patient care. NCCCP pilot sites are implementing NCI recommendations for snap-frozen and formalin-fixed tissues and other samples, which should improve the quality of specimens used in research. Five pilot sites have applied to The Cancer Genome Atlas Prospective Specimen Collection initiative, which should help accelerate the large-scale genome sequencing of cancers. Four pilot sites have begun use of electronic records, seven sites are adopting caBIG clinical trials tools, and one site is adopting caTissue. NCI’s caBIG (cancer Biomedical Informatics Grid) is an information network that enables researchers, physicians, and patients to share data and knowledge. caTissue is caBIG’s tissue bank repository tool for biospecimen inventory, tracking, and basic annotation. For community practitioners, NCCCP offers online tools to enhance clinical practice and research. A multidisciplinary care assessment tool describes case planning, physician engagement, coordination of care, infrastructure, and financial considerations for care in the community setting. A uniform chemotherapy consent form template is available for modification for individual practice use. And a genetic counseling assessment tool defines the minimal genetic counseling service requirements to guide improvements. These tools can be downloaded at http://ncccp.cancer.gov/index.htm.

Multidisciplinary Cancer Care

incentive to keep all the patient’s therapy at that center. If the patient is enrolled in the clinical trial but that requires the patient to be referred elsewhere, that’s a disincentive. I think it’s probably the number one barrier,

One of the main goals of NCCCP is to increase accrual in clinical trials and specifically to increase accrual of minorities and disparate populations into clinical trials. but it’s one that can be overcome. There are many clinical trials that can be opened in the private practice or community cancer setting, which should obviate that issue. In addition, there are many private and oncology group practices that do encourage patient participation

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.

in clinical trials and actively recruit. One of the main goals of NCCCP is to increase accrual in clinical trials and specifically to increase accrual of minorities and disparate populations into clinical trials. Again that can only be done by the community medical oncologist working with the community cancer center. It’s very hard for a single practice to do that on its own. As part of this NCCCP pilot, there are 16 hospitals as part of 10 programs and they are actually accruing more patients now on clinical trials than before, because they’ve all made a conscious effort to do so and to enlist community oncologists’ help to accrue these patients. The way to do that is to open more clinical trials in the community setting so that you don’t necessarily need to refer all the patients out to an NCI-designated cancer center. The benefit for the patients is they’re still getting access to clinical trials but may not have to travel to a facility farther from their homes. n

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

Credentials

FREE • ACCREDITED • EVIDENCE-BASED • CLINICALLY RELEVANT • INSTANT CERTIFICATION

ON DEMAND FREE CONTINUING EDUCATION CREDITS www.COEXM.com strives to provide the most up-to-date clinical information that will improve cancer care and outcomes for patients through specialty products, across multimedia platforms, reaching multiple stakeholders and customers.

Current activities at www.COEXM.com include: • Considerations in Multiple Myeloma: Health Economics • Perspectives on the Treatment of Colorectal Cancer • Perspectives on the Treatment of CTCL and PTCL • Developments in the Treatment of Metastatic Breast Cancer • Perspectives on the Treatment of Lung Cancer FREE CE newsletters at www.COEXM.com

Interactive online presentations with polling questions at www.COEXM.com

FREE CE newsletters at www.COEXM.com December 2008 • Vol. 1 • No. 8

A Supplement to

Visit us at: www.coexm.com

Colorectal Cancer Update: New Strategies in Supportive Care

Publisher Philip Pawelko phil@coexm.com Editorial Director Susan Berry susan@coexm.com

IN THIS ISSUE:

Copy Editor Bonnie Nickel

• Metastatic Colorectal Cancer Update: Reports from the 2008 Gastrointestinal Cancers Symposium

Senior Production Manager Alaina Pede

• Supportive Care Strategies for Patients with Chemotherapy-Induced Neuropathy

Directors of Client Services John W. Hennessy john@coexm.com

Virginia Chih-Yi Sun, RN, MSN, ANP Nursing and Research Education Division of Population Sciences, City of Hope, Duarte, CA

Russell Hennessy russell@coexm.com

INTRODUCTION

Circulation Department n the United States, colorectal cancer cases, chemotherapy can be used to shrink circulation@coexm.com (CRC) is estimated to be the third most unresectable tumors to facilitate surgery. diagnosed cancer and the third It also remains the mainstay of treatment Business November/December 2008Manager • Volume 1 • Numbercommonly 5 most common cause of cancer death for patients with inoperable CRC. Blanche Marchitto among both men and women.1 The inciOver the past decade, therapeutic dence rates of CRC have declined by near- options for patients with metastatic colExecutive Administrators ly 26% from 1984 to 2004, mainly due to orectal cancer (MCRC) have expanded, Thiel Hennessy early detection of polyps before progres- due in large part to the development and Lisa Russo sion to cancer.2 Surgery can cure about 90% approval of more effective chemotheraof CRCs when the disease is found early, peutic agents and new biologic therapies. and 5-year survival rates have risen from However, these novel treatments are asso51% (1975-1977) to 65% (1996-2003).1 ciated with unique toxicity profiles that About 50% to 60% of patients diagnosed pose distinct nursing management chalwith CRC will develop metastatic disease, lenges. As integral members of the cancer Supported by most commonly in the liver or lung.3 Five- care team, oncology nurses must remain year survival rates in patients with cognizant of effective strategies for managan educational grant from metastatic liver disease who do not under- ing specific treatment-related toxicities, so go surgery approach zero. With resection that patients with MCRC are better able to of liver metastases, 5-year survival rates are continue with appropriate treatments Editor in Chief approximately 25% to 50%.3,4 In some while maintaining quality of life. Sagar Lonial, MD Jointly sponsored by M edical L earning Institute, Inc. and Center of Excellence M edia, L L C Emory University

www.coexm.com

Considerations in Multiple Myeloma: Side Effect Management

MULTIDISCIPLINARY TEAM PRESENTATIONS BY Lillian Chou, PharmD NewYork-Presbyterian Hospital

Charise Gleason, MSN, ANP-BC, AOCNP Emory University

Cindy Ippoliti, PharmD Cornell Medical Center

Lisa C. Smith, MSN, FNP, AOCN Cancer Center of the Carolinas

its ed d Cr ere ff O

LETTER TO OUR READERS D ear Colleague: It is my distinct pleasure to offer this newsletter entitled “ Considerations in M ultiple M yeloma: Side Effect M anagement,” the fifth issue in a series of newsletters featuring topics relevant to your multidisciplinary team approach to caring for patients with multiple myeloma (M M ). Together with a faculty of hematologists/oncologists, oncology nurses, and oncology pharmacists, we focus our discussion on one topic for each newsletter. Previous issues focused on patients with renal dysfunction, treatment-naive patients, difficult-to-treat populations of M M patients, and health economics. T his issue will focus on the side effects associated with various agents and treatment regimens used to treat M M . It is our sincere hope that the information presented here is of value to you in your care of patients with M M . Sincerely, Sagar L onial, M D Associate Professor of H ematology and Oncology Emory U niversity

Supported by an educational grant from

Millennium Pharmaceuticals, Inc.

Jointly sponsored by CM E Consultants and Center of Excellence M edia.

its ed Cr d CE re E/ ffe O

Registered participants will receive email announcements as new educational activities become available.

Oncology

The Official Newspaper of Record for the Hem/Onc Pharmacist

Pharmacist

™

Battling Reimbursement Issues to Win the War on Cancer Timothy G. Tyler, PharmD, FCSHP

mid uncertain financial markets and record housing foreclosures, what will happen to cancer care reimbursement is not the issue foremost in most minds. The war on cancer has been waging by presidential decree since 1971 when President Nixon issued the famous proclamation that made cancer public enemy number one and created the National Cancer Institute to combat it. There were decidedly few effective drug therapies at that time and, although surgery and radiation were available, the modern clinician would cringe at the often excessive techniques used. We have come a long way since then—most, but not all of it good. Surgical techniques have improved, and

Pharmacists, who used to be employed exclusively in the hospital basement, have been migrating to outpatient clinics and are now beginning to be found even in larger private physician practices. technology is available throughout the surgical suite, from robotic assistance to laparoscopic interventions. Radiation has dramatically improved delivery and protection with intensity-modulated radiation therapy (IMRT) and 3-D conformal imaging. We not only have more effective chemotherapy agents, we have monoclonal antibodies and advanced supportive care medications. There are even oral therapies effective in targeting certain cancers. All major pharmaceutical companies have cancer as a focus and invest billions in

Dr Tyler is Director of Pharmacy Services for the Comprehensive Cancer Center, Desert Regional Medical Center, Palm Springs, CA.

March/April 2009

trying to find the next edge in fighting this collection of diseases called “the big C,” as John Wayne once remarked. Patients no longer need to anticipate long and dreary hospital stays to receive chemotherapy. The vast majority are treated as outpatients in doctors’ offices or in hospital outpatient clinics. Arguably, all of the above allow for the best and most advanced cancer care provided on the planet. It only takes money—lots and lots of money. The two most expensive line items for any oncology practice or hospital cancer clinic are drugs and people. Good people are essential. In oncology, the more training an individual has, the higher the pay grade. Pharmacists, who used to be employed exclusively in the hospital basement, have been migrating to outpatient clinics and are now beginning to be found even in larger private physician practices. Physician practices too are morphing and either becoming larger or closing their doors. By and large, gone is the time of a successful one- or two-physician practice. The economies of scale needed to compete are forcing smaller practices to band together or enter into a service agreement with area hospital providers. Some office practices are dividing sites of care, keeping reasonably profitable third-party payers and sending HMO or Medicaid patients to the local hospital. Not every physician practice is doing this, but the financial pressures will force a reduction in profit or quality, or both, if some solution is not found. Hospitals too are forced to undergo cost cutting or find some means of remaining solvent. For nonprofit hospitals, the opportunity to purchase drugs under 340B or disproportionate share pricing makes a tremendous difference. If a hospital qualifies, they can buy oncology drugs at the same low price as the federal government, which, by law, automatically gets the best price. If a hospital cannot qualify for 340B pricing, cost cuts or added revenue streams must be found.

The government as the largest payer did some maneuvering and through legislation (Omnibus Budget Reconciliation Act of 1997 and Medicare Modernization Act of 2003) created a fee schedule for Medicare Part B (the physician office setting) and an outpatient prospective payment system (OPPS) for Medicare Part A (the hospital outpatient clinic). The OPPS or Ambulatory Payment Classification (APC) system can be thought of as generally similar to when the Centers for Medicare & Medicaid Services (CMS) introduced diagnosis-related groups to hospitals. The idea was that an admitting diagnosis would have a set reimbursement. If the hospital could treat and discharge that patient for less than that predetermined rate, they made money; if not, they lost money. The OPPS-APC system is similar in that it establishes buckets or ranges and procedures; drugs get assigned into like categories and that becomes the reimbursement rate. Once the outliers are removed, the claims submitted to CMS are used to populate a database. A hospital’s cost report is then applied to this database, and CMS claims it can determine that hospital’s costs. This is contentious at present, and many groups have been working to convince CMS that their formulas have been flawed since the program’s inception. The consensus is that since any costs lower than the $60 threshold are bundled (in the OPPS system but not the physician’s fee schedule) and not separately payable, the overhead associated with each “bundled” item is not represented. The result is that CMS grossly underestimates the overhead needed to provide these drugs in a hospital outpatient setting. This appears complex but, in reality, it is quite simple. At the end of the day—regardless of where you practice—all your expenses must be less than all your revenue. If not, the practice must find other solutions or the hospital must determine to subsidize care or eventually discontinue that service line. All clinicians should keep in mind that they can affect the bottom line. By that I mean that every nurse, pharmacist, or physician should be conscious of waste, salvage what can be salvaged, and be prudent with all resources at their disposal. But as reimbursement is put under the microscope, it will soon be beyond the prudent nurse or pharmacist to make an impact, as saving a few dollars will no longer be enough. A time is coming where there is no more manipulation or cost cut-

ting, and a decision will have to be made whether to abandon certain patient payer types or close the doors altogether. In my own region of Southern California, this is beginning to occur. I work near a private, not-for-profit hospital that has a foundation endowment in excess of $150 million and frequently has donations from a very affluent community to assist with building and other programs. Late last year, this hospital announced that it would no longer be accepting Medicaid patients. This raises the question that if it cannot absorb the lowered

A time is coming where there is no more manipulation or cost cutting, and a decision will have to be made whether to abandon certain patient payer types or close the doors altogether. reimbursement rate of state-funded Medicaid, who can? I see their decision as a harbinger of similar future events, one that CMS will need to pay attention to as Medicare beneficiaries’ access to care will be affected. If the environment that the physician oncology practice and hospital outpatient cancer clinic find themselves in does not improve, there are certain to be serious deliberations about which patients can continue to be accepted and even whether the current business model makes sense and will remain viable. The laws that were passed in 1997 and 2003 have begun to have impacts, and they are for the most part at odds with the current model most of us use to treat patients with cancer. The time is fast approaching when we will need to give clear guidance to our representatives in Washington as to what is happening with the treatment of cancer patients and the tough decisions we are being forced to consider. Let us hope that the oncology care we are so proud of does not become so expensive that we cannot afford to continue to offer it. We are engaged in a war—the war on cancer that stands at 38 years and counting. We are fighting to win. Let us hope that we will be allowed to see a day in the near future when reimbursement is not the biggest thing that healthcare providers have to worry about. n

Multidisciplinary Cancer Care

Register to receive your subscription at NO CHARGE today! Written by and for oncology nurses offering you the following: • Concise reviews of hot topics in the peer-reviewed literature by clinical specialists with key point ‘takeaways’ • Coverage of key research studies and on-the-scene reports from oncology medical meetings • Continuing education articles at no charge and post-tests, offering you a convenient way to obtain contact hours • Interviews with renowned thought leaders in the oncology nursing community • A “Policy Watch” column covering legislation and policy changes that affect cancer care in your areas of practice • Articles of special interest to student nurses, your future colleagues

To begin receiving issues of The Oncology Nurse, register online at www.theoncologynurse.com

GH Green Hill Healthcare Communications

,LLC LLC ™

™

Your Innovative Partners in Medical Media

Medications Used for the Treatment of Lung Cancer

ung cancer forms in tissues of the lung, usually in the cells lining the air passages. The two main types are small-cell lung cancer and non– small-cell lung cancer. This section will assist healthcare professionals and payers by providing appropriate coding, billing, and reimbursement information associated with the management of lung cancer.

The section includes: • Associated ICD-9-CM codes used for the classification of lung cancer • Drugs that have been FDA-approved in the treatment of lung cancer • Drugs included in the NCCN (National Comprehensive Cancer Network) Drugs and Biologics Compendium for off-label use in lung cancer. NCCN is recognized by the Centers for Medicare and Medicaid Services (CMS) as a referencing source • Corresponding HCPCS/CPT codes and code descriptions • Current code price (AWP-based pricing) • Most recent ASP + 6% (Medicare allowable) • Possible CPT administration codes for each medication

Associated ICD-9-CM Codes Used for Lung Cancer 162

Malignant neoplasm of trachea, bronchus, and lung 162.0 Trachea Cartilage of trachea Mucosa of trachea 162.2 Main bronchus Carina Hilus of lung 162.3 Upper lobe, bronchus or lung 162.4 Middle lobe, bronchus or lung 162.5 Lower lobe, bronchus or lung 162.8 Other parts of bronchus or lung Malignant neoplasm of contiguous or overlapping sites of bronchus or lung whose point of origin cannot be determined 162.9 Bronchus and lung, unspecified

Multidisciplinary Cancer Care

Generic (brand) name

HCPCS code: code description

bevacizumab (Avastin)

J9035: injection, bevacizumab, 10 mg

carboplatin (Paraplatin)

J9045: injection, carboplatin, 50 mg

cetuximab (Erbitux)

FDAapproved for lung cancer

NCCN Drugs and Biologics Compendiumâ&#x20AC;&#x201C; approved for lung cancer

Current code price (AWPbased pricing)

Medicare allowable (ASP + 6%), effective 1/1/09-3/31/09

CPT administration codes 96413, 96415

$68.75

$57.38

$85.10

$5.75

J9055: injection, cetuximab, 10 mg

$60.00

$49.75

cisplatin (Platinol-AQ)

J9060: cisplatin, powder or solution, per 10 mg

$4.51

$2.23

96409, 96413, 96415

cisplatin (Platinol-AQ)

J9062: cisplatin, 50 mg

$22.56

$11.14

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J8530: cyclophosphamide, oral, 25 mg

$2.09

$0.92

cyclophosphamide (Cytoxan)

J9090: cyclophosphamide, 500 mg

$31.60

$14.50

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J9091: cyclophosphamide, 1g

$56.90

$29.00

96409, 96413, 96415

cyclophosphamide (Cytoxan)

J9092: cyclophosphamide, 2g

$52.50

$58.00

96409, 96413, 96415

docetaxel (Taxotere)

J9170: injection, docetaxel, 20 mg

$459.33

$336.94

96413

doxorubicin HCl (Adriamycin)

J9000: injection, doxorubicin hydrochloride, 10 mg

$13.75

$3.79

96409

erlotinib (Tarceva)

J8999*: prescription drug, oral, chemotherapeutic, not otherwise specified

NDC level pricing

N/A

etoposide (Vepesid)

J8560: etoposide, oral, 50 mg

$47.64

$29.57

N/A

etoposide (Toposar)

J9181: injection, etoposide, 10 mg

$0.55

$0.48

96413, 96415

gefitinib (Iressa)

J8565: gefitinib, oral, 250 mg

$70.91

N/A

gemcitabine (Gemzar)

J9201: injection, gemcitabine hydrochloride, 200 mg

$172.41

$138.19

ifosfamide (Ifex)

J9208: injection, ifosfamide, 1 g

$58.75

$33.50

96413, 96415

irinotecan (Camptosar)

J9206: injection, irinotecan, 20 mg

$32.81

$21.72

96413, 96415

mechlorethamine HCl (Mustargen)

J9230: injection, mechlorethamine hydrochloride, (nitrogen mustard), 10 mg

$177.29

$147.18

$19.50

$5.83

96365, 96374

$3.56

$0.16

N/A

mesna (Mesnex)

J9209: injection, mesna, 200 mg

methotrexate

J8610: methotrexate, oral, 2.5 mg

March/April 2009

3 3 3

96409, 96413, 96415 96413, 96415

N/A

96413

96409

Generic (brand) name

HCPCS code: code description

methotrexate sodium

J9250: methotrexate sodium, 5 mg

methotrexate sodium

J9260: methotrexate sodium, 50 mg

FDAapproved for lung cancer 3

NCCN Drugs and Biologics Compendium– approved for lung cancer

Current code price (AWPbased pricing)

Medicare allowable (ASP + 6%), effective 1/1/09-3/31/09

CPT administration codes

$0.24

$0.21

96372, 96374, 96401, 96409, 96450

$2.38

$2.30

96372, 96374, 96401, 96409, 96450

mitomycin (Mutamycin)

J9280: mitomycin, 5 mg

$70.00

$15.30

96409

mitomycin (Mutamycin)

J9290: mitomycin, 20 mg

$227.50

$61.18

96409

mitomycin (Mutamycin)

J9291: mitomycin, 40 mg

$312.50

$122.37

96409

paclitaxel (Taxol)

J9265: injection, paclitaxel, 30 mg

$21.38

$7.56

96413, 96415

$11.29

$9.07

96413

paclitaxel protein-bound J9264: injection, paclitaxel particles (Abraxane) protein-bound particles, 1 mg

pemetrexed (Alimta)

J9305: injection, pemetrexed, 10 mg

$60.21

$48.22

96409

porfimer sodium (Photofrin)

J9600: injection, porfimer sodium, 75 mg

$3,276.45

$2,595.68

96409

topotecan (Hycamtin)

J8705: topotecan, oral, 0.25 mg

$84.43

$69.89

topotecan (Hycamtin)

J9350: injection topotecan, 4 mg

$1,229.00

$939.34

96413

vinBLAStine (Velban)

J9360: injection, vinblastine sulfate, 1 mg

$3.31

$0.79

96409

vinCRIStine (Vincasar)

J9370: vincristine sulfate, 1 mg

$10.00

$6.42

96409

vinCRIStine (Vincasar)

J9375: vincristine sulfate, 2 mg

$20.00

$12.83

96409

vinCRIStine (Vincasar)

J9380: vincristine sulfate, 5 mg

$50.00

$32.08

96409

vinorelbine tartrate (Navelbine)

J9390: injection, vinorelbine tartrate, per 10 mg

$44.38

$15.70

96409

N/A

*When billing a nonclassified medication using a CMS 1500 claim form, you must include both the HCPCS code (ie, J8999 for Tarceva) in column 24D and the drug name, strength, and NDC in box 19 to ensure appropriate reimbursement. References • HCPCS Level II Expert; 2009 • CPT 2009; 2008 • ICD-9-CM for Professionals, Volumes 1 & 2; 2009 • The Drug Reimbursement Coding and Pricing Guide, Vol 6, No 1; R•J Health Systems International LLC; 1st Quarter 2009 • FDA-approved indication (from products' prescribing information) • NCCN • www.ReimbursementCodes.com powered by R•J Health Systems International, LLC, Wethersfield, Connecticut • CMS-Medicare allowable 1st Quarter 2009 (effective dates 1/1/09-3/31/09). Prices listed herein are effective as of March 3, 2009. ASP indicates average sales price; AWP, average wholesale price; CMS, Centers for Medicare and Medicaid Services; CPT, Current Procedural Terminology; FDA, US Food and Drug Administration; HCPCS, Healthcare Common Procedure Coding System; NCCN, National Comprehensive Cancer Network; NDC, National Drug Code.

Multidisciplinary Cancer Care

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 upto-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) • Radiopharmaceuticals

Does your revenue stream run as productively as possible? Contact R•J Health Systems, and mention Journal of Multidisciplinary Cancer Care. PO BOX 290616, Wethersfield, CT 06109 • T: (860) 563-1223 • F: (860) 563-1650 • www.RJHealthSystems.com

March/April 2009

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

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 alone 5

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 largeB-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.

PROVE N. POWE R FU L.