SUPPLEMENT TO M A N A G E D. Care. Based on presentations at a roundtable meeting in Philadelphia on Nov. 8, 2004

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1 SUPPLEMENT TO Care M A N A G E D Managed Care Best Practices in The Treatment and Management Of Non-Small Cell Lung Cancer Based on presentations at a roundtable meeting in Philadelphia on Nov. 8, 2004 HIGHLIGHTS Non-Small Cell Lung Cancer An Overview Outlook for Non-Small Cell Lung Cancer Treatment Treatment Options a Medical Director s Perspective PANEL DISCUSSIONS Improving Survival and Quality of Life Benefit and Reimbursement Structures for Oncologics Fostering Appropriate Use of Oncologics Continuing education credit for physicians and pharmacists sponsored by The Chatham Institute Volume 14, No. 2 February 2005 This activity is supported by an educational grant from Genentech

2 WELCOME MESSAGE Care M A N A G E D JEFFREY L. LENOW, MD, JD Associate Professor of Medicine, Jefferson Medical College, Thomas Jefferson University; Chief Medical Officer, MediMedia USA Editor, MANAGED CARE JOHN A. MARCILLE Consulting Editor, MANAGED CARE Editor, Custom Publications MICHAEL D. DALZELL Managing Editor FRANK DIAMOND Senior Science Editor PAULA R. SIROIS Senior Contributing Editor PATRICK MULLEN Associate Editor TONY BERBERABE Contributing editors to this supplement WILLIAM EDELMAN SYLVIE KESTLER ANNE OSTROFF Design Director PHILIP DENLINGER Group Publisher TIMOTHY P. SEARCH, RPH Director, New Product Development TIMOTHY J. STEZZI Eastern Sales Manager SCOTT MACDONALD Midwest Sales Manager TERRY HICKS Director, Production Services WANETA PEART Circulation Manager JACQUELYN OTT It was the best of times, it was the worst of times. This sentiment, from Dickens A Tale of Two Cities, certainly applies to our tumultuous health care delivery environment. We seize on the promise of dynamic new biotechnologies offering targeted therapies for advanced oncologic diagnoses heretofore requisite of extremely toxic agents, an expectation that is supported in these pages. Yet, high costs, reimbursement constraints, and the deepening spectre of litigation challenge this point of view. We are part of a dynamic trend in health care in the Era of Accountability. Ever since the Institute of Medicine issued, in 1999, To Err Is Human, the time-honored edict among caregivers of First, do no harm has taken on even JEFFREY L. LENOW, MD, JD greater significance. The application of a more rigorous set of follow-up and clinical accountability now is in play. Our approaches to care are beginning to focus on the best evidence for quality outcomes, i.e., the discipline of evidence-based medicine (EBM). The news is largely positive. Government sanctioned and academic evidence-based research centers are dedicating serious resources to EBM. The confluence of refined research science and EBM is our great hope for future innovations. It also places a hallmark on the importance of multidisciplinary oversight for emerging technologies. On May 13, 2004, Richard Pazdur, MD, director of the Division of Oncology Drug Products at the Center for Drug Evaluation and Research addressed the Committee on Government Reform of the U.S. House of Representatives on scientific collaboration in oncologic research and practice. His words are exciting: Even for drugs intended for serious and fatal illnesses, there must be substantial evidence that the drug will have the effect it purports to have. I encourage review of Pazdur s comments, which underscore the importance of collaboration with major societies and advocacy groups to ensure optimal patient access and understanding of available best evidence-supported options, and among them the targeted therapies approach. There are no easy answers concerning the value of expensive options for people who may see but a few more months of existence. It is the best of times when a grandparent can live to see a grandchild s birth. It is the worst of times when cost and access constraints preclude such options. The literature contains no pharmacoeconomic models for hope. It s a question of How many angels can dance on the head of a pin? a question that is beyond the scope of this review. MANAGED CARE (ISSN ) is published monthly by MediMedia USA Inc., at 780 Township Line Road, Yardley, PA This is Vol. 14, No. 2. Periodicals postage paid at Morrisville, Pa., and at additional mailing offices. POSTMASTER: Send address changes to MANAGED CARE, 780 Township Line Road, Yardley, PA Price: $10 per copy, $93 per year in the United States; $120 per year elsewhere. editors_mail@managedcaremag.com. Phone: (267) ; fax (267) ; circulation inquiries (267) Copyright 2005 MediMedia USA Inc. PHOTOGRAPHS BY ROB CRANDALL

3 SUPPLEMENT TO Care M A N A G E D February 2005 Managed Care Best Practices in the Treatment and Management of Non-Small Cell Lung Cancer A CONTINUING EDUCATION ACTIVITY Based on the proceedings of a roundtable meeting in Philadelphia, November 8, 2004 Welcome Message Opposite JEFFREY L. LENOW,MD,JD,Associate Professor of Medicine, Jefferson Medical College, Thomas Jefferson University; Chief Medical Officer, MediMedia USA PRESENTATIONS Overview of Non-Small Cell Lung Cancer 4 WILLIAM A. FLOOD, MD, MS, Assistant Professor of Medicine Penn State Milton S. Hershey Medical Center, Pennsylvania State University Exploring the Future of Non-Small Cell Lung Cancer Treatment 9 SURESH RAMALINGAM,MD,Assistant Professor of Medicine University of Pittsburgh School of Medicine Roundtable Discussion 13 JEFFREY L. LENOW, MD, JD,moderator The Medical Director s Role in Oncologic Treatment Coverage 15 PHILIP L. BENDITT,MD,Medical Director for Quality Management, Health Partners; Clinical Assistant Professor, Drexel University College of Medicine Roundtable Discussion 20 JEFFREY L. LENOW, MD, JD,moderator Managing Pharmacotherapy in Cancer: A Case Study 22 JAMES T. KENNEY JR., RPH,MBA,Pharmacy Operations Manager, Harvard Pilgrim Health Care Roundtable Discussion 25 JEFFREY L. LENOW, MD, JD,moderator CONTINUING EDUCATION Continuing education objectives and accreditation statements 2 Post-test 27 Answer sheet/evaluation/certificate request 28 This supplement is supported by an educational grant from Genentech. The material in this supplement has been independently peer reviewed. The grantor played no role in reviewer selection. Opinions are those of the authors and do not necessarily reflect those of the institutions that employ the authors, Genentech, MediMedia USA, or the publisher, editor, or editorial board. Clinical judgment must guide each clinician in weighing the benefits of treatment against the risk of toxicity. Dosages, indications, and methods of use for products referred to in this supplement may reflect the clinical experience of the authors or may reflect the professional literature or other clinical sources and may not be the same as indicated on the approved package insert. Please consult the complete prescribing information on any products mentioned in this publication. MediMedia USA assumes no liability for the information published herein.

4 SELF-STUDY CONTINUING EDUCATION ACTIVITY Managed Care Best Practices in the Treatment and Management of Non-Small Cell Lung Cancer Continuing education credit is offered to physicians and pharmacists who read pages 4 through 26 of this publication, complete the post-test on page 27, and submit the evaluation form on page 28. Estimated time to complete this activity is 2 hours. Target audiences Managed health care professionals, including physicians, pharmacists, medical directors, chief medical officers, pharmacy directors, and other senior managers in managed care organizations. PURPOSE AND OVERVIEW These articles are derived from Managed Care Best Practices in the Treatment and Management of Non- Small Cell Lung Cancer, a roundtable meeting in Philadelphia on Nov. 8, Lung cancer is the most prevalent form of cancerrelated mortality in adults. Because the diagnosis of lung cancer at an advanced stage generally leads to a poor prognosis, it is important to diagnose lung cancer at an early and potentially curable stage or to expand the available treatment options. Non-small cell lung cancer (NSCLC) accounts for 80 percent of all cases of lung cancer and is most commonly treated through chemotherapy, radiation therapy, combined chemoradiotherapy, surgery, as well as biologic therapy and other experimental treatments. Due to the limitations of traditional therapies, researchers are focusing on biologic therapies and other experimental treatments for NSCLC, which includes molecular-targeted compounds. The most common abnormality found in NSCLC is an overexpression of the epidermal growth factor receptor (EGFR), which is associated with an increased resistance to therapy, greater metastatic potential, and poorer prognoses. Several molecular-targeted therapies have been developed or are in development to inhibit EGFR. Tyrosine kinase is a chemical that is triggered when the EGF attaches to the receptor, which sets off chemical processes inside cells that make them grow and divide. According to research, inhibiting this chemical process may prevent cancer cells from growing and spreading. Research that combines these agents with conventional treatments, such as chemotherapy, has shown them to be well tolerated with the potential for favorable outcomes. As scientific advances continue and the rates of NSCLC and other cancers rise, physicians as well as pharmacists will need to understand the widening treatment options that are becoming available. Educational objectives After reading this publication, participants should be able to: Describe the patterns that are characteristic of the progression of non-small cell lung cancer (NSCLC). Differentiate among the forms of treatment that are available for patients with resectable versus unresectable non-small cell lung cancer. Discuss the novel targeted agents now available or under development to treat patients with NSCLC. Explain how to maximize the benefits of these new therapeutic options to improve survival and quality of life, particularly in patients with advanced NSCLC. Focus on improving quality to control health plan costs, rather than raising premiums to balance the budget. Understand how to avoid abnormally high utilization and adverse selection while improving benefits for plan members. Provide an overview of benefit and reimbursement structures for oncologic drugs and the anomalies that currently exist within the system. Recognize utilization controls that are designed to foster appropriate use of oncologics within the cost-benefit system. CONTINUING EDUCATION This activity is sponsored by The Chatham Institute. Physicians The Chatham Institute is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The Chatham Institute designates this educational activity for a maximum of 2.0 category 1 credits toward the AMA Physician s Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity. Pharmacists The Chatham Institute is approved by the American Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This activity provides 2.0 contact hours (0.200 CEU) of continuing education for pharmacists. 2 SUPPLEMENT

5 ACPE Universal Program Number (UPN): H01 Release date: Feb. 15, 2005 Expiration date: Feb. 15, 2006 Medium: Journal supplement Planning committee members Timothy P. Search, RPh, group publisher, MANAGED CARE and BIOTECHNOLOGY HEALTHCARE; Michael D. Dalzell, editor, custom publications, MediMedia USA Managed Markets Publishing; Paula R. Sirois, senior science editor, MediMedia USA Managed Markets Publishing; Cyndi Grimes, managing director, The Chatham Institute. Conflict-of-interest policy and disclosures of significant relationships As an accredited provider, The Chatham Institute requires that its faculty comply with ACCME Standards for Commercial Support of Continuing Medical Education and disclose the existence of any significant financial interest or any other relationship a faculty member may have with the manufacturer(s) of any commercial product(s) or device(s). It also requires the faculty to disclose discussion of off-label uses in their presentations. Faculty disclosures Suresh Ramalingam, MD, acknowledges that he has received honoraria from Aventis, Genentech, and Eli Lilly. He also acknowledges that he discusses off-label usage for drugs mentioned in his article. William A. Flood, MD, MS, acknowledges that he has served on speaker s bureaus for Aventis, DesignWrite, and Genentech. Paul N. Urick, RPh, acknowledges that he has received honoraria from Genentech. Philip L. Benditt, MD, and James T. Kenney Jr., RPh, MBA, have declared that they have no financial interest, arrangement, or affiliation that would constitute a conflict of interest concerning this continuing education activity. SUPPLEMENT 3

6 Overview of Non-Small Cell Lung Cancer WILLIAM A. FLOOD, MD, MS Assistant Professor, Division of Hematology/Medical Oncology Penn State Milton S. Hershey Medical Center, Pennsylvania State University, Hershey, Pa. Lung cancer is the primary cause of cancer-related mortality, with more patient deaths from nonsmall cell lung cancer (NSCLC) annually than from prostate, breast, and colon cancer combined. In 2003, lung cancer was associated with more than 150,000 deaths (Jemal 2003). Tobacco use and cigarette smoking are the predominant causes of lung cancer, accounting for 80 to 90 percent of U.S. cases. Other documented causes include exposure to radon, asbestos, and workplace chemicals. These factors contribute to the development of lung cancer due to their association with a progressive set of genetic changes that transform a normal cell into a malignant cell. We now understand the functional physiologic changes involved in this progression as well, making it possible to identify future therapeutic targets. Patterns of lung cancer progression Once cancer develops in the lung, the disease may progress in three distinct ways: The cancer may grow locally, compromising structures within the lung or chest depending on where it is located. The cancer can invade the chest wall or mediastinum. Malignant cells can drain through the lymphatics, generally from the periphery towards the central area. Tumors in the lymphatics tend to spread toward the mediastinum and subsequently toward the supraclavicular area. Lung cancer also can spread through the blood, metastisizing most often in the brain, bone, liver, adrenal glands, and the lungs (Ginsberg 1997). The four most common histologic types of lung cancer, in order of prevalence, are adenocarcinomas (40 percent), squamous cell carcinomas (30 percent), small cell carcinomas (18 percent), and non-small cell carcinomas (15 percent). Importantly, there has been a significant shift in the histology of lung cancer within the United States. Squamous cell and small cell carcinomas have become less common, accompanied by an increased frequency of adenocarcinomas. This shift in tumor types WILLIAM A. FLOOD, MD, MS may be explained by changes in cigarettes. As filters have become tighter, the particulates that carry carcinogens into the lungs have become smaller and are lodged in the peripheral, relatively glandular area of the lungs, away from the central airways with squamous cell and neuroendocrine cell populations (Ginsberg 1997). Also, the lower yield of nicotine in more modern cigarettes may lead to more frequent and deep inhalation, again depositing tobacco-related carcinogens more peripherally (Stellman 1997). Treating patients with stage IV disease First-line therapy: platinum-based therapy with newer drugs. While the official American Joint Committee on Cancer (AJCC) staging system is fairly complex, patients with NSCLC usually fall into three general categories: wet IIIB or metastatic disease; localized, unresectable disease; and localized, potentially resectable disease. As patients with wet IIIB or stage IV disease* have either a malignant pleural effusion or systemic metastasis beyond the lung, these patients cannot be treated surgically or with targeted radiation therapy. Chemotherapy is the optimal treatment in patients whose disease has spread beyond the localized area. This setting also provides the opportunity to identify active systemic therapies that can then be considered an option for treatment of patients in earlier stage disease to improve outcome. Historically, there are four generations of chemotherapy used in the treatment of patients with NSCLC: 1) alkylating agents; 2) the vinca alkaloids and etoposide; 3) platinum compounds; and 4) the newer drugs, including taxanes, such as paclitaxel and docetaxel; gemcitabine, and vinorelbine. A meta-analysis was conducted to evaluate the effect of the first three on survival in patients with NSCLC in all stages. Data from 52 randomized clinical trials showed that regimens containing cisplatin improved survival compared with best supportive care. There was a 10 percent improvement in survival at 1 year and an overall hazard ratio for death of 0.73 (P<.0001) * For a guide to the staging of lung cancer, refer to the following Web site: « CRI_2_4_3X_How_is_lung_cancer_staged_26.asp?sitearea». 4 SUPPLEMENT

7 (NSCLC Collaborative Group 1995). Conversely, therapy with alkylating agents tended to show a detrimental effect of chemotherapy, with a 6 percent decrease in survival. Furthermore, the 4 percent survival benefit associated with use of vinca alkaloids and/or etoposide did not reach statistical significance (P=.40). Consequently, platinum-based therapy emerged as the standard chemotherapy in NSCLC. The role of newer drugs in combination with cisplatin was subsequently explored in a number of randomized trials. For example, the Eastern Cooperative Oncology Group conducted a randomized trial in chemotherapynaive patients with stage IIIB or IV NSCLC, comparing cisplatin plus paclitaxel with the then-standard chemotherapy of cisplatin plus etoposide (ECOG5592). The study s objective was to determine whether addition of the new agent, paclitaxel, would further improve survival compared with cisplatin plus etoposide (Figure 1). The two paclitaxel-containing arms showed improved survival compared with cisplatin plus etoposide (Bonomi 2000). These findings were consistent with studies conducted by the Southwest Oncology Group (Wozniak 1998) and the Hoosier Oncology Group (Sandler 2000), which showed that the addition of vinorelbine and gemcitabine, respectively, to cisplatin in chemotherapy-naive patients with advanced NSCLC proved superior to cisplatin alone in response rate and overall survival. To investigate whether the new drugs alone provided the benefit in these patients, the Cancer and Leukemia Group B (CALGB) conducted a study in which patients with stage IIIB and IV disease were randomized to paclitaxel alone or paclitaxel plus carboplatin. There was a clear benefit for the combination compared with single-agent therapy with paclitaxel, with 1-year survival rates of 37 percent and 33, respectively (Lilenbaum 2002). Three randomized trials evaluated various platinum/new drug combinations: ECOG1594, SWOG9509, and TAX326. Overall, these studies failed to demonstrate the superiority of any one combination. Nevertheless, in the TAX326 trial, improvement in patients treated with docetaxel plus cisplatin was statistically significant in median and overall survival compared with vinorelbine plus cisplatin, the control arm of that study. Based on these data, the current standard chemotherapy for patients with wet IIIB or stage IV disease is a platinum agent (cisplatin or carboplatin) with one of the newer drugs (paclitaxel, docetaxel, gemcitabine, or vinorelbine). FIGURE 1 Median survival (months) EC: 7.6 P (135 mg/m 2 ) C: 9.5 P (250 mg/m 2 ) CG: 10.1 PC/PCG: year survival (%) EC: 31.8 P (135 mg/m 2 ) C: 37.4 P (250 mg/m 2 ) CG: 40.3 PC/PCG: 38.9 ADAPTED FROM BONOMI 2000 Beyond first-line therapy with conventional chemotherapy. As chemotherapy is not curative, active therapy beyond initial treatment is needed. To date, two conventional chemotherapy drugs are approved for second-line or greater therapy for NSCLC. Docetaxel was the first drug approved in this setting based on the results of two multicenter trials. Patients whose tumor had recurred after initial platinum-based therapy were randomized across three treatment arms: docetaxel, 75 mg/m 2, docetaxel, 100 mg/m 2,or vinorelbine or ifosfamide (Figure 2, page 6). Patients randomized to the lower dose of docetaxel achieved a 6.7 percent response rate and those at the higher dose achieved a 10.8 percent response rate, both of which were significantly higher than the 0.8 percent response achieved with vinorelbine or ifosfamide (P=.002). In addition,1-year survival was improved in the two docetaxel arms compared to the vinorelbine or ifosfamide arm (32 percent vs. 10 percent, P=.002), when adjusted for later taxane use. These findings were consistent with those reported by Shepherd and colleagues. Patients who were previously treated were randomized to either docetaxel or best supportive care alone. There was a clear benefit in median and overall survival for patients who received docetaxel. Time to progression was significantly longer with docetaxel (10.6 weeks vs. 6.7 weeks, P<.001). Similarly, median survival was longer (7.0 vs. 4.6 months, P=.010). Shepherd and colleagues also collected data on the use of supportive medications, particularly analgesic medications, and the use of radiation to palliate symptoms. There were strong trends favoring docetaxel compared with best supportive care ECOG5592: Effect of new agent on survival C=cisplatin, E=etoposide, PC=lowdose paclitaxel/cisplatin, PCG=high-dose paclitaxel/cisplatin w/granulocyte-colony stimulating factor support. *P-value pertains to the comparison of both paclitaxel-containing arms vs. the etoposide/cisplatin control arm. Percent surviving EC P=.048 PC/PCG Months SUPPLEMENT 5

8 FIGURE 2 Overall patient survival with docetaxel monotherapy vs. vinorelbine or ifosfamide Treatment groups (intent to treat) D100 mg/m 2 D75 mg/m 2 V/I (N=125) (N=125) (N=123) Censored observations* Number of patients % Median survival, months year survival, % % confidence interval, % P, χ 2 test D vs. V/I D ( ) vs. V/I <.001 NOTE: Patients censored for subsequent chemotherapy on removal from study (in addition to lost to contact or alive at cutoff date). *Patients lost to contact or alive at cutoff date or received subsequent chemotherapy. D=docetaxel, V/I=vinorelbine or ifosfamide. ADAPTED FROM FOSSELLA 2000 (Shepherd 2000). In both studies, docetaxel was better tolerated at the 75 mg/m 2 dose. The second chemotherapy drug approved for secondline or greater therapy is pemetrexed. When studied in patients who had failed at least one prior chemotherapy regimen, pemetrexed was associated with equivalent response and survival outcomes to docetaxel, but with significantly fewer side effects (Hanna 2004). Targeted therapies: gefitinib and erlotinib. The efficacy of gefitinib (Iressa), an epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI), was evaluated in patients with advanced NSCLC. They received gefitinib as either second-line therapy or as third-line or greater therapy, in two randomized multicenter global and U.S.-based clinical trials: Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL]-1 and IDEAL-2, respectively. In IDEAL-1, once-daily oral treatment with gefitinib at 250 mg or 500 mg achieved a tumor response rate of 18 percent and 19 percent, respectively, and there was a rapid improvement in symptoms. In the U.S. trial, IDEAL-2, symptom improvement rates with 250 mg/day or 500 mg/day were 43 percent and 35 percent, respectively. Therefore, it was concluded that gefitinib may offer an option as salvage treatment in patients with advanced solid tumors who have received or progressed after prior chemotherapy regimens, of which at least one contained a platinum agent (Herbst 2003). Erlotinib, another EGFR inhibitor, was approved in November by the U.S. Food and Drug Administration for treatment of NSCLC after failure of at least one prior chemotherapy regimen, and it has demonstrated a clear benefit in progression-free and overall survival compared with placebo (Shepherd 2004). Suresh Ramalingam, MD, discusses the use of erlotinib in his article in this supplement entitled Exploring the Future of Non-Small Cell Lung Cancer, which begins on page 9. Treating patients with unresectable disease Locally advanced NSCLC usually is considered to be unresectable when it involves local structures that cannot be removed (such as a tumor in the lung extending into the vertebrae, trachea, or mediastinal tissues) or with bilateral mediastinal lymph node involvement. Over the last 20 years, treatment of patients with unresectable NSCLC has improved steadily, shifting from radiation alone to the sequential or concurrent use of active chemotherapy and radiation. The apparent synergy between appropriate chemotherapy and radiation has produced this improvement in overall survival. One challenge has been determining the proper way to introduce the new drugs into combined modality therapy, as they are much more potent radiation sensitizers than platinum alone. Generally, there have been three different strategies: the first involves the use of lower doses of chemotherapy during radiation, followed by full-dose therapy for several cycles. This approach was used in the Locally Advanced Multimodality Protocol (LAMP), which was a randomized phase 2 study of three regimens employing paclitaxel, carboplatin, and thoracic radiation therapy (Figure 3). Patients were treated with radiation combined with low doses of paclitaxel and carboplatin weekly, followed by two cycles of conventional doses of paclitaxel/carboplatin that had the best outcome, with a median survival of 16.1 months (Choy 2002). A second strategy is to use the newer drug at full doses after initial chemotherapy and radiation are completed. This approach was evaluated in a phase 2 study by SWOG (S9504). Patients with unresectable stage IIIB NSCLC were first treated with cisplatin and etoposide administered concurrently with radiation therapy, followed by 3 cycles of docetaxel at 75 mg/m 2 beginning4 to 6 weeks after the initial chemoradiotherapy was completed. Patients treated with consolidation docetaxel had a median survival of 26 months, median progression-free survival of 16 months, and a survival rate of 37 percent at 3 years. Although there have been no randomized trials yet reported comparing these different strategies, these results are the best to date in this patient population (Gandara 2003). 6 SUPPLEMENT

9 FIGURE 3 Locally Advanced Multimodality Protocol (LAMP) Arm First treatment Second treatment I P 200 / C AUC 6 ( 2) RT II P 200 / C AUC 6 ( 2) P 45 / C AUC 2 / RT III P 45 / C AUC 2 / RT P 200 / C AUC 6 ( 2) AUC=area under the curve, P=paclitaxel, C=carboplatin, RT=63 Gy Median survival Months I II III Treatment arm ADAPTED FROM CHOY 2002 A third approach is the use of the new chemotherapy in a fairly straightforward fashion as induction therapy, followed by a novel schedule of radiation therapy. ECOG explored this approach in E2597. After 2 cycles of paclitaxel/carboplatin chemotherapy, patients were randomized to one of two radiation therapy regimens: a standard arm of 64 Gy given in daily fractions of 2 Gy; or hyperfractionated accelerated radiation therapy (HART), in which radiation was given in 1.5 Gy fractions 3 times daily to a total of 57.6 Gy. Median survival of patients in the HART arm was 20.3 months, compared with 13.7 months in the standard radiation therapy arm (Belani 2003). Although this difference did not reach statistical significance due to insufficient patient accrual, these are impressive results for this patient population. ECOG will be studying this approach in future trials. Treating patients with resectable disease Patients with resectable NSCLC generally fall into two groups: those with or those without lymph node involvement in the ipsilateral mediastinum (referred to as N2 disease). This difference is crucial, as current standard approaches for these two populations are quite different. Patients with resectable N2 disease who are undergoing surgery usually are treated preoperatively with chemotherapy or chemotherapy and radiation. This approach is based on two randomized trials in which patients with N2 disease were randomized between surgery alone or preoperative platinum-based chemotherapy, followed by surgery. In both trials, patients who received chemotherapy had an improved median survival compared with those who had surgery alone: 22 vs. 10 months and 21 vs. 14 months, respectively (Rosell 1999, Roth ). While these trials have been criticized, the concept of preoperative treatment in this population has become a standard of care. SWOG elected to study the combination of chemotherapy and radiation as preoperative therapy in this population. In this phase 2 trial, cisplatin and etoposide were given during radiation therapy to 45 Gy, and additional chemotherapy/radiation was administered in patients who were unresectable or who 16.1 had positive margins or residual lymph node involvement at surgery (Albain 1995). Of the treated patients, 85 percent were resectable and the 3-year survival was 27 percent. Complete sterilization of the mediastinal lymph nodes by the preoperative treatment was the strongest predictor of survival, as those with the absence of tumor in the N2 nodes had a 3-year survival of 44 percent compared with 18 percent in those with residual disease (P=.0005). Based on these results, SWOG conducted a follow-up study (North American Intergroup Trial 0139) to determine if there is a need for surgery in patients receiving appropriate chemotherapy plus radiation. Patients who had N2 disease received preoperative chemotherapy plus radiation and were then randomized to undergo surgical resection or additional chemotherapy and radiation. Interestingly, there did not appear to be a significant difference between the two approaches although follow-up continues (Albain 2003). These data have not changed practice but have reinforced prior practice. Thoracic oncologists who believe surgery is important in these patients continue to perform surgery with preoperative and postoperative therapy, while those who believe that surgery does not add to nonoperative treatment use definitive chemotherapy and radiation in unresectable patients. For those patients without N2 involvement, surgery remains the cornerstone of treatment. Although surgery alone was the standard approach, three recently reported trials have shown benefits from adjuvant platinum-based chemotherapy. In the International Adjuvant Lung Cancer Trial (IALT), patients with T2-3 tumors and/or nodal involvement who received chemotherapy had a significantly higher survival rate (44.5 percent vs percent) and higher disease-free survival rate (39.4 percent vs percent) at 5 years than those followed by observation alone (Arriagada 2004). These findings were further supported by those of the CALGB (Strauss 2004) and the National Cancer Institute of Canada (Winton 2004) in which patients with stage IB disease or stage IB SUPPLEMENT 7

10 through IIB disease had a 15 percent increase in longterm survival after adjuvant chemotherapy compared to surgery alone. In conclusion, it is apparent that treatment of patients with NSCLC is dependent on a number of variables, with the most critical being the stage of disease. The introduction of new drugs, such as the taxanes, gemcitabine, and vinorelbine, offers new options for improved survival in these patients in all stages of the disease. References Albain KS, Rusch VW, Crowley JJ, et al. Concurrent cisplatin/etoposide plus chest radiotherapy followed by surgery for stages IIIA (N2) and IIIB non-small cell lung cancer: mature results of Southwest Oncology Group phase II study J Clin Oncol. 1995;13: Albain KS, Scott CB, Rusch VR, et al. Phase III comparison of concurrent chemotherapy plus radiotherapy (CT/RT) and CT/RT followed by surgical resection for stage IIIA(pN2) non-small cell lung cancer (NSCLC): initial results from intergroup trial 0139 (RTOG 93-09). Proc Am Soc Clin Oncol. 2003;22:621 (abstr 2497). Arriagada R, Bergman B, Dunant A, et al, for the International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with complete resected non-small cell lung cancer. N Engl J Med. 2004;350: C. P. Belani, W. Wang, D. H. Johnson, et al. Induction chemotherapy followed by standard thoracic radiotherapy (Std.TRT) vs. hyperfractionated accelerated radiotherapy (HART) for patients with unresectable stage III A & B nonsmall cell lung cancer (NSCLC): phase III study of the Eastern Cooperative Oncology Group (ECOG 2597). Proc Am Soc Clin Oncol. 2003;22:622 (abstr 2500). Bonomi P, Kim K, Fairclough D, et al. Comparison of survival and quality of life in advanced non-small cell lung cancer patients treated with two dose levels of paclitaxel combined with cisplatin versus etoposide with cisplatin: results of an Eastern Cooperative Oncology Group trial. J Clin Oncol. 2000;18: Choy H. Preliminary report of locally advanced multimodality protocol (LAMP): ACR 427: a randomized phase II study of three chemo-radiation regimens with paclitaxel, carboplatin, and thoracic radiation (TRT) for patients with locally advanced non small cell lung cancer (LA-NSCLC). Proc Am Soc Clin Oncol. 2002;21:A1160. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group. J Clin Oncol. 2000;18: Gandara DR, Chansky K, Albain KS, et al. Consolidation docetaxel after concurrent chemoradiotherapy in stage IIIB non-small cell lung cancer: phase II Southwest Oncology Group Study S9504. J Clin Oncol. 2003;21: Ginsberg RJ, Vokes EE, Raben A. Non-small cell lung cancer. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology, 5th ed. 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Br Med J. 1995;311: Rosell R, Gomez-Codina J, Camps C, et al. Preresectional chemotherapy in stage IIIA non-small cell lung cancer: a 7- year assessment of a randomized controlled trial. Lung Cancer. 1999;47:7 14. Roth JA, Atkinson EN, Fossella F, et al. Long-term follow-up of patients enrolled in a randomized controlled trial comparing perioperative chemotherapy and surgery with surgery alone in patients with stage IIIA non-small cell lung cancer. Lung Cancer. 1999;47:1 6. Sandler AB, Nemunaitis J, Denham C, et al. Phase III trial of gemcitabine plus cisplatin versus cisplatin alone in patients with locally advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2000;18: Shepherd FA, Dancey J, Ramlau R, et al. Prospective randomized trial of docetaxel versus best supportive care in patients with non-small cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol. 2000;18: Shepherd FA, Pereira J, Ciuleanu TE. A randomized placebocontrolled trial of erlotinib in patients with advanced nonsmall cell lung cancer (NSCLC) following failure of 1st line or 2nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. J Clin Oncol ASCO Annual Meeting Proceedings (Post- Meeting Edition) (July 15 suppl);22:7022. Strauss G, Herndon J, Maddaus MA, et al. Randomized clinical trial of adjuvant chemotherapy with paclitaxel and carboplatin following resection in Stage IB non-small cell lung cancer (NSCLC): Report of Cancer and Leukemia Group B (CALGB) Protocol Proc Am Soc Clin Oncol. 2004; 23:A7019. Stellman SD, Muscat JE, Hoffmann D, Wynder EL. Impact of filter cigarette smoking on lung cancer histology. Prev Med. 1997;26: Winton TL, Livingston R, Johnson D, et al. A prospective randomised trial of adjuvant vinorelbine (VIN) and cisplatin (CIS) in completely resected stage IB and II non small cell lung cancer (NSCLC) Intergroup JBR.10. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) (July 15 suppl);22:7018. Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized trial comparing cisplatin with cisplatin plus vinorelbine in the treatment of advanced non-small cell lung cancer: a Southwest Oncology Group study. J Clin Oncol. 1998;16: SUPPLEMENT

11 Exploring the Future Of Non-Small Cell Lung Cancer Treatment SURESH RAMALINGAM, MD Assistant Professor of Medicine, Department of Medicine, Division of Medical Oncology University of Pittsburgh School of Medicine, Pittsburgh The treatment of advanced non-small cell lung cancer (NSCLC) has evolved rapidly in recent years. The development of several novel chemotherapeutic agents has led to modest improvements in both survival and quality of life for patients with advanced NSCLC. It appears, however, that a chemotherapy efficacy plateau has been reached in first-line and second-line therapy of patients with advanced NSCLC (Schiller 2002). Further, combination chemotherapy may be suboptimal for some patient subgroups, such as those with a poor performance status. Therefore, it is necessary to develop novel treatment options for NSCLC that will not only improve survival, but also have minimal toxicities. Inhibition of the epidermal growth factor receptor (EGFR) is a novel strategy that recently has been proven successful for the treatment of NSCLC. Epidermal growth factor receptor pathway Activation of the EGFR pathway results in cell proliferation, inhibition of apoptosis, angiogenesis, and tumor metastasis. It is therefore a rational target for the treatment of cancer. There are four known receptors in the EGFR family: human epidermal growth factor receptor 1 (HER1), HER2, HER3, and HER4. The ligands to the EGFR include epidermal growth factor, transforming growth factor alpha and beta cellulin, among others. Binding of the ligand to the external domain of the receptor results in either homodimerization (when two of the same receptor types of the EGFR family bind together), or heterodimerization (when two different receptors bind together). Either process initiates a cascade of postreceptor mechanisms that lead to increased angiogenesis, reduction in apoptosis, and increased cell proliferation (Figure 1, page 10) (Huang 1999). Either a monoclonal antibody against the receptor or a small molecule tyrosine kinase inhibitor (TKI) that acts at the internal domain of the receptor can block the EGFR. Reports reveal that 40 to 80 percent of NSCLC overexpress the EGFR. An advantage to such a targeted approach is the relatively small effect on normal cells, as the treatment is specifically directed against the EGFR. SURESH RAMALINGAM, MD EGFR-TKIs Efficacy. Gefitinib (Iressa) is a small molecule EGFR- TKI that was tested in two randomized trials: Iressa Dose Evaluation in Advanced Lung Cancer [IDEAL]-1 and IDEAL-2. In IDEAL-1, patients with advanced NSCLC who had received prior platinum-based chemotherapy were randomized to receive gefitinib at 250 mg or 500 mg. Partial responses were noted in 19 percent of patients at both doses. An additional 30 percent of patients had stable disease. Notably, there was no difference in efficacy between the 250 mg and 500 mg doses (Fukuoka 2003). Grade 3 skin rash and diarrhea were more frequent with 500 mg of gefitinib. In contrast to IDEAL-1, the IDEAL-2 study enrolled patients who had progressed following platinum-based chemotherapy and second-line therapy with docetaxel. The results were comparable with those of IDEAL-1. The study also noted important improvements in several lung-cancer-related symptoms for patients treated with gefitinib. Further, symptom improvement correlated well with objective tumor response. Median survival in both studies approached 6 to 8 months (Giaccone 2004a). Based on these studies, the U.S. Food and Drug Administration approved gefitinib as third-line therapy for patients with NSCLC who progressed following firstline chemotherapy including a platinum-based regimen and salvage chemotherapy using a docetaxel regimen. Yet, in December 2004,* the manufacturer of gefitinib, AstraZeneca, announced that a statistically significant survival benefit was not seen in the Iressa Survival Evaluation in Lung Cancer trial (ISEL; study 709). ISEL enrolled 1,692 patients with advanced NSCLC who had progressed or no longer could tolerate chemotherapy. Among patients receiving gefitinib 250 mg daily as monotherapy, median survival was prolonged by 5.6 months, compared with 5.1 months among patients receiving placebo (P=.11). These findings led AstraZeneca to withdraw its application to market gefitinib in Europe. * This information became available after the meeting on Nov. 8, SUPPLEMENT 9

12 FIGURE 1 HER1/EGFR tumorigenic functions HER1/EGFR Invasion Metastasis P P Adaptor proteins PLC Grb2 Signaling cascades Nucleus Gene activation DNA repair Cell cycle progression Myc Fos M G 2 G 1 S Jun Adhesion Apoptosis Survival Proliferation Angiogenesis EGFR=epidermal growth factor receptor, Grb2=growth factor receptor-bound protein 2, HER=human epidermal growth factor receptor, PLC=phospholipase C. SOURCE: HUANG 1999 Erlotinib (Tarceva), another small molecule inhibitor of the EGFR tyrosine kinase, was compared with placebo in a randomized phase 3 trial (JBR.21) by the National Cancer Institute of Canada. Patients with NSCLC (N=730) who had progressed following either 1 or 2 prior chemotherapy regimens were enrolled in the study. The primary endpoint was determination of overall survival. The study was designed to detect a 33 percent improvement in overall survival with erlotinib compared with placebo. Erlotinib was administered at 150 mg orally daily. Median survival and time to progression improved with erlotinib. Median survival was 6.7 months in the erlotinib group versus 4.6 months with placebo (HR, 0.73; P<.001). The response rate was 9 percent for patients treated with erlotinib, and stable disease was noted in an additional 35 percent (Shepherd 2004). The time to deterioration of several lung cancer-related symptoms was longer for patients treated with erlotinib compared with placebo. This is the first study to demonstrate a survival advantage with an EGFR-TKI for NSCLC. On the basis of this trial, in November 2004 the FDA approved erlotinib for treatment of patients with locally advanced or metastatic NSCLC after the failure of chemotherapy. Erlotinib is the only drug in its class to demonstrate a survival benefit in a phase 3 trial enrolling patients with advanced NSCLC. Tolerability. Skin rash and diarrhea are the most prevalent toxicities associated with EGFR-TKIs (Table 1) (Kris 2003, Fukuoka 2003). The typical skin rash is an acneform or a maculopapular rash involving the face, upper chest, and back. The rash tends to be mild and usually improves within 3 or 4 weeks of therapy initiation. Interstitial pneumonitis was reported, primarily in Japan, with the use of gefitinib for advanced NSCLC. In Japan, the incidence of interstitial pneumonitis is approximately 3 percent (N=1,976) (Seto 2004) to 7 percent (N=325) (Hotta 2004). In North America, however, the risk of interstitial pneumonitis occurs in less than 1 percent of patients treated with erlotinib or gefitinib. Combination therapy: EGFR-TKI plus chemotherapy Though EGFR-TKIs are active as single agents for the treatment of advanced NSCLC, there appears to be no TABLE 1 Erlotinib: toxicity Skin rash 76% Grade 3 skin rash 9% Diarrhea 55% Grade 3/4 diarrhea 6% Ocular toxicity 28% Pneumonitis 3% Grade 3 pneumonitis <1% Treatment discontinuation from toxicity 5% SOURCE: SHEPHERD SUPPLEMENT

13 benefit to combining an EGFR-TKI with chemotherapy. In large randomized trials comparing chemotherapy with or without an EGFR- TKI (gefitinib or erlotinib) for first-line therapy of advanced NSCLC, no improvement in efficacy was noted using the chemotherapy/ EGFR-TKI combination over chemotherapy alone (INTACT I, INTACT II, TALENT, TRIB- UTE) (Giaccone 2004b, Herbst 2004). An interesting observation emerged from these trials, in that it was found that some patient subsets may still benefit from the combination of chemotherapy with an EGFR-TKI. Never-smokers who were treated in the TRIBUTE trial had a median survival period of 23 months with erlotinib plus chemotherapy, compared with 10 months with chemotherapy alone. Also, changing the sequence in which the EGFR-TKI is given with chemotherapy may be important to maximize the therapeutic potential of these agents. For example, for patients with breast cancer, sequential administration of tamoxifen and chemotherapy is superior to concurrent administration (Albain 2002). Clinical trials are underway to determine the appropriate sequence of combining an EGFR-TKI with chemotherapy. Monoclonal antibodies Cetuximab (Erbitux) is a chimeric monoclonal antibody that targets HER1, and it has been approved for treatment of advanced colorectal cancer. Preliminary results of a phase 2 clinical trial with cetuximab for patients with advanced NSCLC reported a response rate of 6 percent. Cetuximab also can be safely combined with chemotherapy. In a randomized phase 2 trial, chemotherapy-naïve patients with advanced NSCLC (N=43) were treated with chemotherapy (cisplatin plus vinorelbine) with or without cetuximab. There was a modest improvement in median survival for the combination versus chemotherapy alone. Based on these promising results, a phase 3 trial is being conducted to evaluate the combination of cetuximab with chemotherapy (Rosell 2004). Panitumumab (ABX-EGF) is a fully human IgG 2 monoclonal antibody that targets the EGFR. A phase 1 trial in chemotherapy-naïve patients (N=19) with advanced NSCLC evaluated panitumumab (1, 2, and 2.5 mg/kg) in combination with carboplatin and paclitaxel. The regimen was well tolerated and associated with a provocative median survival of 17 months (Crawford 2004). Subsequently, a randomized phase 2 trial was conducted in patients with advanced NSCLC to compare the efficacy of panitumumab with chemotherapy; the results are eagerly awaited. Several other monoclonal antibodies against the EGFR are also in various developmental stages. Compared with EGFR-TKIs, monoclonal TABLE 2 Patients with mutations are more sensitive to EGFR TKIs No. of EGFR mutations Reference TKI patients (%) Paez 2004 Gefitinib Lynch 2004 Gefitinib 9 89 Pao 2004 Gefitinib Pao 2004 Erlotinib % of 31 patients who responded to HER1/EGFR-targeted TKIs carried HER1/EGFR mutations No HER1/EGFR mutations were found in patients (n=29) who did not respond to HER1/EGFR TKIs EGFR=epidermal growth factor receptor, HER=human epidermal growth factor receptor, TKI=tyrosine kinase inhibitor. antibodies are associated with a higher incidence of skin rash, but a less common incidence of diarrhea. Activating mutations in the EGFR Recent studies have identified activating mutations in the adenosine triphosphate binding site of the EGFR tyrosine kinase in the tumors of patients who experienced robust responses to treatment with an EGFR-TKI. The presence of these somatic mutations results in enhanced susceptibility to treatment with an EGFR-TKI. Such a gain in function mutations is present in approximately 10 percent of patients with NSCLC. Mutations appear to be more common in females, those with adenocarcinoma histology, never-smokers, and Japanese individuals (Table 2) (Lynch 2004, Paez 2004, Pao 2004). Although patients with such mutations are particularly sensitive to these targeted agents, patients without the mutation also appear to benefit from EGFR-TKIs, although the extent of benefit may be less. In a small study conducted by Janni et al (unpublished data) five patients who experienced stable disease with EGFR-TKIs did not harbor the mutation. Therefore, until further data become available, screening for EGFR mutations prior to the initiation of therapy with a TKI cannot be recommended outside of a clinical trial. Antiangiogenic therapy For tumors to grow beyond the size of 3 to 4 mm, formation of new blood vessels (neoangiogenesis) is essential. Neovascularization is mediated by varying factors produced by the tumor microenvironment. The vascular endothelial growth factor (VEGF), secreted by the tumors, is an important mediator of angiogenesis. VEGF binds to specific receptors in the vascular endothelium and activates downstream signals that stimulate the growth of new blood vessels. Therefore, it has become an important target for cancer treatment. Bevacizumab, a SUPPLEMENT 11

14 monoclonal antibody against VEGF (rhu-monoclonal antibody [Avastin]), has been approved by the FDA for the treatment of patients with metastatic colorectal cancer in combination with 5-fluorouracil-based chemotherapy. It is being investigated in combination with chemotherapy for the treatment of advanced NSCLC. A randomized phase 2 trial demonstrated a superior response rate for bevacizumab in combination with chemotherapy (31.5 percent for the combination compared with 19 percent with chemotherapy alone) for previously untreated patients with advanced NSCLC (Johnson 2004). Nevertheless, there were six cases of life-threatening hemoptysis among 66 patients receiving chemotherapy plus bevacizumab, with four fatalities. This adverse event was noted primarily in patients with centrally located tumors and those with squamous cell histology (Johnson 2004). Therefore, the confirmatory phase 3 trial excluded patients with centrally located tumors and those with squamous cell histology. In this trial, conducted by the Eastern Cooperative Oncology Group (ECOG 4599), patients with previously untreated advanced NSCLC received the combination of carboplatin and paclitaxel with or without bevacizumab. The study has enrolled more than 850 patients and the results are eagerly awaited. Clinical trials also are underway to evaluate the utility of various small molecule inhibitors that target the VEGF receptor and agents that cause regression of existing tumor vasculature (vascular targeting agents). Combination of targeted agents NSCLC exhibits wide heterogeneity and a variety of molecular abnormalities within the same tumor. Therefore, targeting multiple molecular pathways with a combination of agents appears to be a novel strategy for the treatment of NSCLC. In a phase 1/2 trial (N=40), patients with advanced NSCLC who received 1 or more prior chemotherapy regimen(s) were treated with the combination of erlotinib and bevacizumab (Sandler 2004). The combination was safe and associated with a provocative response rate of 23 percent. Disease stabilization was achieved in an additional 65 percent of patients. These promising results are being followed up with a larger randomized clinical trial. Proteasome inhibition Bortezomib (PS-341, Velcade) is a proteasome inhibitor that has been approved for the treatment of multiple myeloma. It acts by inhibition of the 26S proteasome, a large protein complex that degrades ubiquitinated proteins (Adams 1999). Preliminary results from clinical trials of bortezomib for the treatment of advanced NSCLC have demonstrated promising results. A randomized phase 2 trial compared bortezomib alone with bortezomib plus docetaxel for patients with advanced NSCLC who progressed following platinumbased chemotherapy (Fanucchi 2004). Recently presented preliminary data revealed a response rate of 10 percent with bortezomib alone (N=29). For patients treated with the combination of bortezomib with docetaxel, the response rate was 16 percent (N=31). A phase 1 study combined bortezomib with the regimen of carboplatin-gemcitabine for first-line therapy of advanced NSCLC. In addition to establishing the safety of the combination, the study demonstrated a promising response rate of 33 percent (Davies 2004). This has led to a larger phase 2 study of a carboplatin-gemcitabinebortezomib combination for advanced NSCLC by the Southwest Oncology Group. EGFR signaling pathways EGFR signaling occurs through one of two known pathways PI3-kinase pathway and the Ras-Raf-MEK signaling pathway. Therefore, downstream signals of the EGFR pathway can be inhibited by targeting one or more of these proteins. Agents that target and inhibit the Raf pathway are under development. Sorafenib (BAY ) is an orally administered agent that inhibits both B-Raf and the VEGF receptor. It has demonstrated antitumor activity in earlyphase trials in various solid tumor types. Based on these observations, ECOG is conducting a phase 2 trial to evaluate the efficacy of sorafenib as third-line treatment for patients with advanced NSCLC who failed previous chemotherapy. Conclusion Molecularly targeted agents are under rigorous investigation in various stages of advanced NSCLC. The JBR.21 trial is the first randomized clinical trial to establish a survival advantage with an EGFR-TKI for patients with advanced NSCLC with erlotinib, which recently received FDA approval. Clinical trials are underway to evaluate EGFR-TKIs in the treatment of earlier stages of NSCLC. Ongoing clinical trials will study the utility of combining agents that target different cellular pathways or multiple steps of the same downstream pathways. Appropriate selection methods are necessary to identify patients likely to benefit from specific targeted interventions, based on baseline tumor biology. Proteomic and genomic techniques are being evaluated as selection methods for targeted therapy. Certain baseline clinical characteristics of the patient also may provide helpful clues to prediction of response to therapy. If proven to be optimal, these techniques will likely be incorporated into routine patient care leading to optimal use of the targeted agents in subgroups of patients likely to benefit, thereby allowing for efficient utilization of resources. Incorporation of targeted agents into current treatment paradigms represents the next major challenge and advance for patients with NSCLC. 12 SUPPLEMENT

15 References Adams J, Palombella VJ, Sausville EA, et al. Proteasome inhibitors: a novel class of potent and effective antitumor agents. Can Res. 1999;59: Albain KS, Green SJ, Ravdin PM, et al. Adjuvant chemohormonal therapy for primary breast cancer should be sequential instead of concurrent: initial results from intergroup trial 0100 (SWOG-8814) ASCO Annual Meeting Proceedings. 2002:Abstract 143. Crawford J, Sandler AB, Hammond LA, et al. ABX-EGF in combination with paclitaxel and carboplatin for advanced nonsmall cell lung cancer (NSCLC). J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2004;22 (July 15 suppl): Davies AM, Lara PN, Lau DH, et al. The proteasome inhibitor, bortezomib, in combination with gemcitabine (Gem) and carboplatin (Carbo) in advanced non-small cell lung cancer (NSCLC): final results of a phase I California Cancer Consortium study. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition). 2004;22 (July 15 suppl):7106. Fanucchi MP, Belt RJ, Fossella FV, et al. Phase (ph) 2 study of bortezomib ± docetaxel in previously treated patients (pts) with advanced non-small cell lung cancer (NSCLC): Preliminary results. J Clin Oncol ASCO Annual Meeting Proceedings (July 15 suppl);22:7107. Fukuoka M, Yano S, Giaccone G, et al. Multi-institutional randomized phase 2 trial of gefitinib for previously treated patients with advanced non-small cell lung cancer. J Clin Oncol. 2003;21: Epub 2003 May 14. Giaccone G. The role of gefitinib in lung cancer treatment. Clin Cancer Res. 2004a;10(12 pt 2):4233s 4237s. Giaccone G, Herbst RS, Manegold C, et al. Gefitinib in combination with gemcitabine and cisplatin in advanced non-small cell lung cancer: a phase III trial INTACT 1. J Clin Oncol. 2004b;22: Herbst RS, Giaccone G, Schiller JH, et al. Gefitinib in combination with paclitaxel and carboplatin in advanced non-small cell lung cancer: a phase III trial INTACT 2. J Clin Oncol. 2004;22: Hotta K, Harita S, Bessho A, et al. Interstitial lung disease (ILD) during gefitinib treatment in Japanese patients with nonsmall cell lung cancer (NSCLC): Okayama Lung Cancer Study Group. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) (July 15 suppl); 22:7063. Huang SM, Harari PM. Epidermal growth factor receptor inhibition in cancer therapy: biology, rationale and preliminary clinical results. Invest New Drugs. 1999;17: Johnson DH, Fehrenberger L, Novotny WF, et al. Randomized phase 2 trial comparing bevacizumab plus carboplatin and paclitaxel with carboplatin and paclitaxel alone in previously untreated locally advanced or metastatic non-small cell lung cancer. J Clin Oncol. 2004;22: Kris MG, Natale RB, Herbst RS, et al. Efficacy of gefitinib, an inhibitor of the epidermal growth factor receptor tyrosine kinase, in symptomatic patients with non-small cell lung cancer: a randomized trial. JAMA. 2003;290: Lynch TJ, Bell DW, Sordella R, et al. Activating mutations in the epidermal growth factor receptor underlying responsiveness of non small cell lung cancer to gefitinib. N Engl J Med. 2004;350: Paez JG, Janne PA, Lee JC, et al. EGFR mutations in lung cancer: correlation with clinical response to gefitinib therapy. Science. 2004;304: Epub 2004 April 29. Pao W, Miller V, Zakowski M, et al. EGF receptor gene mutations are common in lung cancers from never smokers and are associated with sensitivity of tumors to gefitinib and erlotinib. Proc Natl Acad Sci USA. 2004;101: Rosell R, Daniel C, Ramlau R, et al. Randomized phase II study of cetuximab in combination with cisplatin and vinorelbine (V) vs. CV alone in the first-line treatment of patients (pts) with epidermal growth factor receptor (EGFR)-expressing advanced non-small cell lung cancer (NSCLC). J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) (July 15 suppl);22:7012. Sandler AB, Blumenschein GR, Henderson T, et al. Phase I/II trial evaluating the anti-vegf MAb bevacizumab in combination with erlotinib, a HER1/EGFR-TK inhibitor, for patients with recurrent non-small cell lung cancer. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) (July 15 suppl);22:2000. Schiller JH, Harrington D, Belani CP, et al, Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small cell lung cancer. N Engl J Med. 2002;346: Seto T, Yamamoto N. Interstitial lung diseases (ILD) induced by gefitinib in patients with advanced non-small cell lung cancer (NSCLC): results of a West Japan Thoracic Oncology Group (WJTOG) epidemiological survey. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) (July 15 suppl);22:7064. Shepherd FA, Pereira J, Ciuleanu TE, et al. A randomized placebocontrolled trial of erlotinib in patients with advanced nonsmall cell lung cancer (NSCLC) following failure of 1 st line or 2 nd line chemotherapy. A National Cancer Institute of Canada Clinical Trials Group (NCIC CTG) trial. J Clin Oncol ASCO Annual Meeting Proceedings (Post-Meeting Edition) (July 15 suppl);22:7022. DISCUSSION JEFFREY L. LENOW, MD, JD: Where do you begin a discussion with your patients about the novel targeted therapies? How do you include them in the decisionmaking process regarding their treatment? WILLIAM A. FLOOD, MD, MS: When talking to patients about first-line therapy, we usually consider standard platinum-based options as well as available trials. As there is no clear difference in efficacy, differences in treatment schedules and toxicity are important issues for our patients. Furthermore, there are different toxicity profiles to consider. Any taxane-based regimen may have a slightly higher risk for paresthesias, with a greater need for steroid premedications. These medications are problematic for patients with diabetes, those with neurologic issues, and the like. Gemcitabine [Gemzar] may have some increased risk for decreases in blood counts but has fewer issues regarding hair loss. We then ask patients which regimen would best suit their lifestyle. When it comes to the epidermal growth factor re- SUPPLEMENT 13

16 ceptor [EGFR] inhibitors, I consider patient characteristics that can be measured, such as gender; tumor pathology; and, more importantly, smoking. I tend to use docetaxel [Taxotere] or pemetrexed [Alimta] as salvage therapies before an EGFR inhibitor. Conversely, for our nonsmoking patients, an EGFR inhibitor is a more relevant option earlier in treatment. SURESH RAMALINGAM, MD: When talking to patients, my first responsibility is to fill in the information gap that they are experiencing, which has come about as a result of the different perspectives on treatment they ve gathered from various sources. In addition to standard therapeutic options, we also discuss participation in clinical trials. LENOW: How do you respond to the skeptical patient who believes your decision is founded on the need to recruit patients for clinical trials? RAMALINGAM: When we discuss clinical trials with patients, we never tell them that the trial is a preferable option to receiving standard therapy. Rather, we present it as an option along with other therapeutic choices. We also explain to the patients that all trials include the standard treatment when one exists, and other trials are designed for patients who have run out of options. In our experience, a thorough discussion about the clinical trials process leads to greater likelihood of acceptance by the patient. LENOW: What do you tell your patients to expect from use of these drugs in terms of survival? FLOOD: Results of key trials have distinguished patients who are particularly sensitive to these agents from those who are not. With this information, we can help patients better understand their potential to respond to these targeted drugs and guide their expectations. LENOW: Are you concerned that the insurance industry may one day make coverage determinations and treatment decisions based on genetic predispositions? For example, we have seen that certain subset populations seem to respond better to certain targeted therapies than others. RAMALINGAM: There is not yet enough knowledge to negatively select patients for EGFR inhibitor therapy. Identification of predictive markers that will guide patient selection is an active area of research. It is likely that tumor-specific and patient-specific characteristics will guide targeted therapy in the years to come. LENOW: You said early in your presentation that standard chemotherapy has basically reached a plateau, regardless of the combinations used. So is there an excitement about the new, targeted therapies as options to chemotherapy? RAMALINGAM: Absolutely. When the results of the IDEAL trials became available, the follow-up randomized clinical trials (INTACT I and II) accrued patients at an unprecedented pace more than 1,000 PANELISTS William A. Flood, MD, MS Assistant Professor Division of Hematology/Medical Oncology Penn State Milton S. Hershey Medical Center Pennsylvania State University Hershey, Pa. Jeffrey L. Lenow, MD, JD Associate Professor of Medicine Department of Family Medicine Jefferson Medical College Thomas Jefferson University Philadelphia Chief Medical Officer, MediMedia USA Yardley, Pa. Suresh Ramalingam, MD Assistant Professor of Medicine Department of Medicine Division of Medical Oncology University of Pittsburgh School of Medicine Pittsburgh, Pa. patients each within a year. There is a great deal of enthusiasm among oncologists and patients about EGFR inhibitors and other targeted agents. LENOW: These targeted therapies may have the advantage, at the least, of being much less toxic than conventional therapy. Also, the delivery method is much simpler. How does that fit in with your review of treatment options in the second and third levels of care? RAMALINGAM: The level of monitoring (both clinical and laboratory parameters) is distinctly different and convenient for the targeted agents. The frequency of follow up for my patients who are receiving gefitinib or erlotinib [Tarceva] is reduced compared to those on chemotherapy. It also allows for earlier intervention in the event of toxicity, which is not an option with chemotherapy (where the drug has already been administered). The favorable toxicity profiles of the EGFR inhibitors and the convenience of administration are much appreciated by the patients. There are no good patient selection methods to choose between a targeted agent versus chemotherapy for advanced NSCLC, especially in the second-line setting. Both choices should be discussed with the patient, whose input will be an important factor in the choice of therapy. How I would select patients for chemotherapy versus targeted therapies in the secondline setting is a challenging question. Currently, there is no reliable system for selecting patients for these new therapies. For now, either is a viable option. 14 SUPPLEMENT

17 The Medical Director s Role In Oncologic Treatment Coverage PHILIP L. BENDITT, MD Medical Director for Quality Management, Health Partners, Philadelphia; Clinical Assistant Professor, Drexel University College of Medicine, Philadelphia For many observers, medical director may be an imposing title; for many others, it also may evoke a trace of fear and loathing, especially when combined with such terms as quality management or health plan. But what is the real role of the medical director when it comes to quality management of a health plan? Trying to tap dance through a mine field? Attempting to please all the people all the time? Making every effort, while avoiding the alligators, to remember that your original purpose was to drain the swamp? All those images are at least somewhat appropriate, but, of course, limited. Evolving role As the managed care industry embraces the practice of evidence-based medicine in decision-support management, it fosters a genuinely fair balance between patient advocacy and a responsible fiscal approach. In a managed care environment, the medical director s role has evolved beyond traditional utilization oversight and provider-network problem solving. Typically, the medical director has become pivotal in the incorporation of data relating to quality of life (QOL) issues into the decision-making process. Calculating QOL is particularly vital in the management of complex health disorders, many of which are in the gray zone of approval. Often in the treatment of oncology and similarly grave conditions, health plans must weigh therapies on the scale of practical benefit for all stakeholders in the medical process patient, family members, caregivers, physicians, employer, health plan, and others. Comparing standard-of-care therapies against nonstandard therapies of promising potential is increasingly common. To complicate matters, the typical experimental and investigational language seen in many insurance-benefits manuals may lead to the inference that the plan will reject, out of hand, all therapies not formally approved as standard of care. In a managed care setting, the medical team s casemanagement prerogative typically allows for special-case PHILIP L. BENDITT, MD considerations in such matters. Successful exercise of this option depends on technology assessment that is more thorough than it was during the industry s formative years. Health-related QOL data have facilitated clinical care studies, clinical trials, and cost-effectiveness studies; in cancer treatment, they have influenced treatment decisions and care (Schwartz 2002). Therefore, the real objective of a health plan s medical director who is in charge of quality management is to ensure that plan members receive the best possible care, while maintaining fiscal responsibility often in an environment that is inherently challenging. At the same time, the medical director must incorporate QOL data and issues into the process of finding the protocols and regimens that will yield the best results for all stakeholders. This occasionally means pushing the standard-of-care envelope. Facing challenges Health Partners primarily provides managed Medicaid coverage to about 140,000 members and managed Medicare coverage to another 14,000 to 15,000 members in Philadelphia and the surrounding counties. As medical director of a health plan that primarily deals with government-mandated coverage, one major challenge that I face is to establish and maintain a good provider network. Establishing coverage parameters for oncologic medicine necessitates specific considerations, yet those therapies usually must pass through the same process as everything else before the plan makes coverage decisions. Health plans differ in in a host of ways. Nevertheless, there are some constants as well as some challenges that those in the practitioner community do not always appreciate fully. One general constant among health plans which tends to vary substantially from one plan to another in terms of how it is managed is cost control. Health care is not the only industry in which there are major cost con- SUPPLEMENT 15

18 straints. To cite an example, budget problems are forcing the airlines to cut back services in some cases, drastically. Managing the health plan budget In health care, costs always enter into the equation. All managed care plans work on a budget. While airlines can cut back on routes, meals, even the amount of air in the cabin, most health plans would be hard pressed to cut back on the services that are provided. The alternative is to increase premiums. For years, Americans have had to cope with major increases in insurance premiums. Although costs did plateau in the late 90s, both costs and premiums recently began to rise again, and they have continued to increase at about the same rate throughout the first years of the new millennium. Increasing premiums, however, is one luxury that Health Partners, as a government-funded health plan, simply does not have. The state of Pennsylvania sets the rates at which the Medicaid managed care organizations are paid, and the MCOs contracts with the state stipulate that those premiums must be actuarially sound. In that context, Health Partners waits each year to find out if its premiums will be increased, and, if so, what the amount of that increase will be, and finally, what the state has determined actuarial soundness to be. Focusing on quality For Health Partners, the yearly premium situation has become just another black box, effectively removing from the equation the option of developing any plans that are based on premium-increase revenues. Making the budget work means controlling costs by working in the margins of the budget, primarily to eliminate waste. Controlling waste usually means taking a cautious approach Preemptive coverage How ThinPrep Gained Health Plan Approval When it was first approved by the U.S. Food and Drug Administration in the spring of 1996, the word spread, by way of the nonmedical press, that ThinPrep was perhaps the most astounding advancement in screening for cervical cancer since George N. Papanicolaou and Herbert F. Traut published a paper, Diagnosis of Uterine Cancer by the Vaginal Smear, in 1943 (ASCP 2003). At that time, the American College of Obstetricians and Gynecologists (ACOG) cautioned that ThinPrep was too new to demonstrate a proven advantage to the traditional Pap smear. In the first edition of its women s newsletter, Women s Health Issues & You, in the fall of 2002, the Pennsylvania Section of ACOG dealt with the issue, citing extensive magazine and television advertising (Honebrink 2002). Analyzing the situation, author Ann Honebrink, MD, wrote that this was...a wonderful example of many of the issues we face in today s medical decision making where optimal patient care, control of health care costs and the business interests of the company promoting a new technology make sorting out what is the right thing to do a very complicated process. She wrote that while useful, Pap screening is not perfect, and the new technology...may address some of these imperfections. There is a 5 percent to 10 percent false negative rate in traditional PAP smear screening. ThinPrep... has the potential to decrease this false negative rate by picking up more potentially precancerous changes. Honebrink also noted, because ThinPrep involves the suspension of cells in a liquid solution and then placing them on a slide after a filtration process, clearer readings are often possible. After discussing the positive aspects of the therapy, the author addressed the downside of the new test: Preparation of slides for screening by this technique is more labor intensive than traditional PAP smears, she wrote. Reading the slides requires retraining of the technicians and pathologists since this preparation technique causes cells to look somewhat different. Finally, the cost/test is $15 $25 higher for Thin- Prep than for traditional PAP smears. That cost adds up when you consider that this is a test that most women should have once a year. Even though ACOG is an advocacy group for physicians and their patients and maintains the necessity of working to ensure that health plan members receive the best possible care, the College also instructed newsletter readers on the finer points of fiscal responsibility. Keep in mind that our (national) health care budget is not... unlimited... and that cost is an unfortunately necessary factor in decision making, especially with new technologies that have yet to be proven to have an actual impact on death or suffering from the disease they are designed to detect, Honebrink cautioned. Remember that while there is a lower false negative rate in detection of precancerous change with ThinPrep technique, it remains to be seen whether or not this will translate into reduction of continued on page SUPPLEMENT

19 to providing coverage for new therapies and ensuring that these therapies are used appropriately. The plan has no choice but to turn its attention to quality, which means analyzing patient outcomes. Health plan administrators need to know if truly improved outcomes are going to result from any new therapies, not only those in the oncology venue. Other factors also relate to coverage decisions U.S. Food and Drug Administration approval, off-label use, coverage-exclusion (certain drugs and treatments are excluded from Medicaid coverage), coverage decisions made by other plans but all other factors simply influence the main body of evidence derived from assessing patient outcomes. Industry focus on data No coverage decision at least, one that is responsible to both the plan and its members can be made in an informational void. Decision makers need data. Realizing that good data typically generate more questions than they answer and that, as a smaller plan, conducting extensive information-gathering efforts is not always feasible. Health Partners relies on several external sources and services to monitor the state of the health care industry, base its coverage decisions on evidence-based medicine, follow a practical standard of care, and review the literature and gather reliable data. (See Informational Sources for Decision-making Data, page 19.) Seeking added value Health Partners attempts to establish which therapies are investigational, as opposed to state-of-the-art. The medical and pharmacy directors want to know what therapies are on the cutting edge. They need to know, for example, Is this just another new statin, or is this the new statin that s going to clean out everybody s arteries and do away with cardiovascular disease as we know it? continued from page 16 death and suffering from cervical cancer. As business interests become more and more intertwined with the provision of medical care, be sure that you and your doctor use objective information and not advertising hype to help in your decision making. While increased consumer awareness of both new screening technologies and treatment options is a good thing...issues are often too complex to distill into a sound byte. In this situation, press coverage strongly influenced health plan coverage. ThinPrep was at the nexus of an extensive media blitz, and at least one large national health plan expected plan members to demand it regardless of whether scientific evidence justified its higher cost. To avoid the probable member- and practitioner-generated flak and the potential adverse news coverage, the plan simply provided coverage. According to the manufacturer, currently, the ThinPrep Pap Test is the most widely used method for cervical cancer screening in the United States... [it] is the only liquid-based cytology method approved by the U.S. FDA as significantly more effective than the conventional Pap smear for detection of cervical abnormalities. Most importantly, since FDA approval, more than 100 studies have been published, in peerreviewed medical journals, demonstrating a wide range of clinical benefits of the ThinPrep Pap Test, including increased disease detection, reduction of equivocal diagnoses, improved specimen adequacy, cost effectiveness and the ability to perform additional tests out of the same vial, such as HPV [human papilloma virus] and chlamydia/gonorrhea (Cytyc 2004). Because most health plans do provide ThinPrep coverage now, the plan appears to have made a wise decision, as this technology has been proven. Nevertheless, when the plan chose to provide coverage, years earlier, this was not the case. All things considered, the plan may have made the right decision for the wrong reason. Perhaps some health plans can afford to make such risky decisions based on expectations of product success and member pressure. Perhaps this decision was a no-brainer from the beginning; after all, as the saying goes, nothing succeeds like success. On the other hand, for many other health plan medical directors, rolling the coverage dice is neither a financial nor a clinical option. References ASCP (American Society for Clinical Pathology), October George Papanicolaou, MD. Chicago: American Society for Clinical Pathology. Available online at: « papanicolaou.asp». Accessed Jan. 26, CAQH. About CAQH Available at: « org/about.html». Accessed Jan. 2, Cytyc. Cervical Cancer Screening: Overview. Cytyc Corp., Available at: « women_cervical_cancer.shtml». Accessed Dec. 9, ECRI. Should I Enter a Clinical Trial? Available at: « Patient_Information/ Patient_Information.aspx». Accessed Jan.5, Honebrink A. New Technology Alert What s a ThinPrep and Do I Need It? Women s Health Issues & You, Fall 2002, Pennsylvania Section, American College of Obstetricians and Gynecologists. Available at: « 00Fall_WN.html». Accessed Dec. 9, Schwartz CE, Sprangers MAG. An Introduction to Quality-of- Life Assessment in Oncology: The Value of Measuring Patient-Reported Outcomes. Am J Manag Care. 2002; 8;S550 S559. SUPPLEMENT 17

20 When that issue is established, the question becomes, Does the new agent add value? In its simplest form, value equals, more or less, quality divided by cost. For a commercial plan, covering incremental cost means increasing premiums. Walking the quality tightrope Occasionally, focusing on increasing quality and improving patient outcomes can pose its own problems. On one hand, plan directors want to make sure that their patients are getting the best treatment; on the other hand, providing outstanding benefits can attract members who are likely to be high utilizers. Case study in infertility. Apart from the limited coverage that a few states mandate, a limited number of plans offer carte blanche coverage for infertility. Several years ago the head of the women s health program at a large national health plan devised an excellent benefit for infertility. The benefit worked well, bringing new members into the plan, but two problems arose: adverse selection and success. Again and again, women who were having fertility problems joined the plan, got pregnant, and then left the plan. Eventually, this coverage became a rider: if a member complained that the plan did not offer infertility coverage, they were told that the option was available but had not been chosen by their employer. Case study in HIV. In Southeastern Pennsylvania, where Philadelphia is located, and in the western part of the commonwealth, where Pittsburgh is situated, Medicaid managed care is mandatory. In one health plan in the greater Philadelphia area, the medical director took to heart the message that disease management (DM) makes for better outcomes and helps to control costs. So he set up an excellent DM program for HIV. Enrollment of HIV patients increased significantly in this plan, because word of it spread through the HIV community. The plan suffered from adverse selection. Every health plan must walk its own tightrope and make the best possible coverage decisions. Planning damage control for when the unexpected happens is tricky but necessary. Control Although health plans influence the benefits provided to enrollees, the final word about what is and is not covered, and to what extent, often lies elsewhere. As sponsors, employers are the penultimate payers in commercial plans. (We, the general public, are the ultimate payers as the increased cost of health care benefits makes its way into the costs of goods and services we purchase.) What employers do and do not want to cover is important, and they can make certain choices as far as what is covered. Occasionally, a health plan will decide to provide coverage based on motivations other than science or on flawed science. Two examples are as follows: Several years ago many health plans decided to cover high-dose chemotherapy and autologous-bone-marrow transplantation as treatment for advanced breast cancer. These decisions were initially based upon pressure from advocacy groups who felt that this was the best treatment for these patients and this was initially supported by a few published studies. These studies were later proven to be flawed. Several months after it was approved, a large national health plan, made the decision to cover ThinPrep (Cytyc Corp., Marlborough, Mass.), a relatively new Pap smear technology, before it was widely accepted by the medical community and before the American College of Obstetricians and Gynecologists (ACOG) supported its use. This decision was based on nonmedical administrators fears that this would result in a backlash against the organization. (See the sidebar, How ThinPrep Gained Health Plan Approval, on page 16.) Specific oncology considerations When investigating an oncologic agent, Health Partners focuses on survival rates and QOL issues. The first question to ask about a new agent for cancer therapy is whether it prolongs patient survival; the second is: How much survival advantage does the agent offer? The rest of the deliberation centers on QOL issues. Does the new agent provide better symptom control? Among cancer victims who are still employed, does it get them back to work? Does it help them return to work more quickly? Case study in QOL. A man who was vacationing returned home because he was vomiting blood. In investigating the patient s hematemesis, he was found to have pancreatic cancer. According to the patient s wife, his internist had advised the patient against receiving chemotherapy, because the treatments would only make him sicker and would not greatly prolong his life. When the husband and wife sat down with the oncologist, however, they were advised that the patient had one chance in four of responding to chemotherapy. They were not informed what respond meant. After a few months treatment the man succumbed to his disease. It is difficult to know whether the days or weeks of additional life were worth the side effects of the chemotherapy treatments. Conclusion Generally, making coverage decisions about oncologic agents is comparable to making the same types of decisions about other coverage issues. But when a plan makes decisions about oncologic agents, specific elements apply. Risk/benefit analysis takes on a different tone and tenor. continued on page SUPPLEMENT

21 Informational Sources for Decision-making Data In this Age of Information, many health plans, particularly smaller ones, may need to turn to external sources when deliberating plan coverage. When the budget simply cannot accommodate the generation of necessary data and invaluable perspective, outsourcing information becomes a must. The health care industry has recognized that collaboration on quality improvement initiatives makes sense to enhance overall patient QOL in a variety of health conditions. Toward this end, many of the largest health insurance entities including Anthem, Independence Blue Cross, Aetna, and WellPoint, to name a few are participating in an effort called the Council for Affordable Quality Healthcare (CAQH). The CAQH is an unprecedented collaboration of the nation s leading health plans, networks, and industry trade associations, working together to help improve the health care experience for consumers and health care providers. CAQH builds on the collective commitment of its members to develop and implement programs that reduce administrative burdens for physicians and patients, and improve quality of care. Examples of their efforts include uniform credentialing strategies, new prescribing standards, and cardiac improvement programming. In another critical industry effort, a leading trade association for managed care, the American Association of Health Plans (AAHP, now America s HealthInsurance Plans, or AHIP), joined ECRI, a not-for-profit health care research organization based in Plymouth Meeting, Pa.) to co-promote ECRI s consumer-driven guide to cancer-trial participation. ECRI is one of a small number of evidence-based practice centers that are government-sanctioned through the Agency for Healthcare Research and Quality. Dedicated to the nonprofit study of evidencebased solutions for health-outcome improvement, the ECRI guide is the first comprehensive reference designed for patients and their physicians to use to answer patient questions about the risks, benefits, and implications of entering a clinical trial. It provides a detailed road map for patients to navigate the decision-making process (ECRI 2005). The guide helps patients to also sort through the ethical challenges that can arise from new product use and trials associated with the use of approved agents but in different applications. This is an excellent way for the medical director in a managed care organization to help balance what can be very challenging issues for all parties involved. The guide is available online, free of charge, at both « and « Many such sources exist, and several are accessible on the Internet. The following are a few examples: ECRI « (formerly the Emergency Care Research Institute) is an independent, not-for-profit health-services research agency that disseminates information about health care safety, quality, and cost-effectiveness. The organization focuses on health care technology, risk assessment and management, quality issues, and health care environmental management. Agency for Healthcare Research and Quality « (formerly the Agency for Health Care Policy and Research), of the National Health Information Center of the U.S. Department of Health and Human Services, provides publications that cover such topics as medical treatment effectiveness, health care costs and utilization, health care expenditures, health information systems, health technology assessment, clinical practice guidelines, and funding opportunities for grants and contracts. Rx2000 Institute « is a nonprofit organization focusing on HIPAA education, outreach and research services. This group conducts HIPAA workshops and conferences and operates the HIPAA Security Consortium. National Guideline Clearinghouse « is an AHRQ initiative and a comprehensive database of evidencebased clinical practice guidelines and related documents, offering summaries, full-text guidelines, head-to-head guideline comparisons, and other electronic and print documents. Major for-profit health plans, from Aetna to Well- Point, also maintain web sites on the Internet, and provide both free and paid information, as do health care consultation and other firms. To mention only one of these, the Blue Cross/Blue Shield Association supports a Technology Evaluation Center « which reviews the literature, primarily focusing on devices, but often reviewing treatments, including the newest chemotherapy and other cancer therapies. For more information about private insurers and the services they offer, visit America s Health Insurance Plans « which maintains links to insurance company web sites that may offer information and guidance. SUPPLEMENT 19

22 Can you prolong the patient s life? For how long? At what cost? What does your patient gain by having an extra month to live? What will the quality of that extra month of living be? When facing health care coverage issues, we ask about the return on investment. Yet, the question is difficult to answer, because how do you value a human life? Making some decisions becomes extremely difficult, almost to the point of sometimes necessitating an ethics committee to make a decision about what a health plan is going to cover, not just in oncologic treatment, but in many other areas as well. DISCUSSION SURESH RAMALINGAM, MD: When a cancer drug is approved, does a plan really have the option of not covering it, or does it simply have to figure out how to deal with coverage? PAUL N. URICK, RPH: Health plans strive to be there when you need them, so they focus on organizing the best care available for its members. As such, plans work hard to allocate dollars toward its members in need. Naturally, there is substantial debate when considering therapies or procedures approved for discretionary or desire-satisfying uses only. In stark contrast, discussions about cancer therapies are generally on care coordination, rather than being a debate for coverage. Deciding on the use of a new drug for cancer is most often a matter driven by the oncologist s assessment of each patient. WILLIAM A. FLOOD, MD, MS: At present, there is very little head-to-head competition among cancer therapies. For example, there are only two taxanes, one gemcitabine, and one 5FU; there has been little need or incentive to choose the optimal and most cost-effective drug in a class. PHILIP L. BENDITT, MD: If you ve seen one managed care plan, you ve seen one managed care plan. Coverage may depend on whether the medication is oral or injectable. Generally, oral cancer therapies are managed because they are covered as pharmacy benefits, and they are more tightly managed than intravenous therapies, which are medical benefits. JAMES T. KENNEY JR., RPH, MBA: We really do not know the cost of cancer treatments well enough to compare them, because the medical claims data are not accurate enough for that. FLOOD: What measure is used to determine return on investment [ROI]? JEFFREY L. LENOW, MD, JD: The managed care industry is a business, with shareholders and financial accountabilities for the viability of the organization. Even not-for-profit HMOs measure ROI. No margin, no mission. BENDITT: We manage our budget to a slim margin, between 0 percent and 1 percent, even though we need not show a profit to provide the best health care that PANELISTS Philip L. Benditt, MD Medical Director for Quality Management Health Partners Clinical Assistant Professor Drexel University College of Medicine Philadelphia, Pa. William A. Flood, MD, MS Assistant Professor Division of Hematology/Medical Oncology Penn State Milton S. Hershey Medical Center Pennsylvania State University Hershey, Pa. James T. Kenney Jr., RPh, MBA Pharmacy Operations Manager Harvard Pilgrim Health Care Wellesley, Mass. Jeffrey L. Lenow, MD, JD Associate Professor of Medicine Department of Family Medicine Jefferson Medical College Thomas Jefferson University Philadelphia, Pa. Chief Medical Officer, MediMedia USA Yardley, Pa. Suresh Ramalingam, MD Assistant Professor of Medicine Department of Medicine Division of Medical Oncology University of Pittsburgh School of Medicine Pittsburgh, Pa. Paul N. Urick, RPh Vice President, Pharmacy Services Independence Blue Cross Philadelphia, Pa. 20 SUPPLEMENT

23 we can realizing that our resources are not unlimited. [Editor s note: Benditt works for a Medicaid-based HMO in Pennsylvania.] URICK: ROI is tough to come by in this market, and health plans earn it through a reputation for being there for its members in a time of need. Today, members have more choice than ever when shopping for insurance, so you need something convincing and reliable to compete. Plans gauge their success not only on traditional financial metrics, but also on quality. Quality of health plan networks, products, and feedback from the members they serve are good ways for successful plans to gauge ROI in today s hypercompetitive market. RAMALINGAM: Even small increments in patient survival that are associated with an improved quality of life provide a meaningful endpoint for the treatment of non-small cell lung cancer. From a patient s standpoint, even an improvement in survival of 1 month can mean a lot. URICK: To the patient, that month can mean everything in the world. LENOW: My sense is that all would agree that a qualityof-life improvement for a month or two, with minimal side effects, is worthwhile. FLOOD: There are two patient-expectation issues in managed care. One is extremely intimate working with the practicing oncologist to achieve potential benefits and deal with any side effects of a therapy. The other is very broad the realization that some treatments may exist but that they are out of reach, because the plan does not provide that particular coverage. We talk about taking a rational approach to health care. What the purchaser can actually assess personally, balancing risk and cost against benefit, is rational. Managed care removes the patient from this equation, so this process cannot be rational for the patient. LENOW: Do patient advocates in managed care ever feel that they have an advocacy role for the overall health care delivery system? RAMALINGAM: We are all cognizant of cost and the load that new drug costs put on the system. URICK: How do you view current literature regarding advances in cancer treatment and new drugs in development that may prolong survival? [Editor s note: In remarks to Congress in 2001, Richard Pazdur, MD, director of the Division of Oncology Drug Products, Center for Drug Evaluation and Research, U.S. Food and Drug Administration, announced the FDA s intention to accelerate the development of new cancer therapies. Medicare now supports nine clinical trials at an estimated cost of $300 million investigating off-label uses for oncology drugs. Further, ECRI, a not-for-profit research agency, has published Should I Enter a Clinical Trial?: A Patient Reference Guide for Adults with a Serious or Life- Threatening Illness. Commissioned by the American Association of Health Plans, the report is available online at: « Patient_Reference_Guide/summary.pdf».] FLOOD: Clinical trials are run by someone for some goal. A pharmaceutical company s goal is usually expanding indications for a drug, and if the National Cancer Institute sponsors a trial, its goal is usually to move the treatment forward, but in neither case do the trials provide the data that managed care plans need. BENDITT: We need head-to-head studies, which many drug companies are not willing to do. We also need a good working definition of value. KENNEY: We want to get the best value and the best outcome at the lowest cost. That is the challenge, and we cannot determine that from the data that we re getting and make the necessary kinds of decisions. LENOW: It is difficult, at best, to try to define improved outcomes, let alone determine what true cost is. The pharmacoeconomic equation is daunting, and the managed care industry tends to be isolated in these kinds of discussions. SUPPLEMENT 21

24 Managing Pharmacotherapy in Cancer: A Case Study JAMES T. KENNEY JR., RPH, MBA Pharmacy Operations Manager, Harvard Pilgrim Health Care, Wellesley, Mass. The oral oncologic agents are not managed differently than other oral therapies. The obvious benefits of oral over parenteral products are that there are no administration costs, some products tend to be less costly, they produce improved satisfaction, and their ease of use and controlled distribution are both superior. Do oncologists know what they spend and the total cost of care for these patients? Those data are not readily accessible. Yet pharmacy data include exactly what was dispensed to a certain patient population. In the oral oncology market, with the limited number of cancers being treated, these data represent about 5 percent to 10 percent of the total. Statistically, however, they will probably be about 25 percent over the next decade. Thus, the pharmacy and therapeutics (P&T) committees must study many oral products, and oncologists will need to determine the role of these drugs in therapy. Coverage of oral oncologic drugs From a managed care perspective, therapy is most valuable when targeted to specific patients. The wish is to avoid the inappropriate use of a therapy that will not necessarily help the patient, even though it will not hurt. Oral oncologic drugs are covered under the pharmacy benefit (Table 1), a determination that is based on the route of administration. Any new oral oncologic drug is managed by the P&T committee and the formulary committee of the individual health plans. There are some anomalies in the system. With Medicare Part B, oral therapies are covered if an injectable is available; otherwise, they are not covered. A therapy that is oral, less toxic, and less costly may be better for a patient, but because of the current benefit and reimbursement structure, it may not be available to that patient. Barriers to those therapies must be avoided. When new therapies enter the market, the benefit language is the driver (Table 2). Self-administered medications whether oral, topical, or subcutaneous are usually covered under the pharmacy benefit; office-administered medications are covered under the medical benefit. Thus, the costs of a drug that is normally man- aged through the medical claims system could be charged back to the medical system, even though the claims processing is managed under the pharmacy benefit, so that budget finances remain in the appropriate categories. Online claim submission through the pharmacy benefit manager, the National Drug Code (NDC) level of detail, the three-tier copayment, and financial reporting are most important. When claims for high-cost biologic and injectable agents are dispensed by a specialty pharmacy and processed via the pharmacy benefit, reporting is much more accurate, and the ability to manage the product utilization is improved. Specialty pharmacies also help in providing case management services with nurses and pharmacists. Patients may actually call the physician office less often to manage side JAMES T. KENNEY JR., effects, because the specialty pharmacy can RPH, MBA help them through that experience. In a typical 30-day cycle, compliance programs inform the patient on day 21 that it is time for a refill; the caller then can ask how the patient is feeling and inquire about any side effects or adverse events. This provides an opportunity to engage the physician, if appropriate, or to help the patient with those issues and enhance compliance with therapy. The P&T committee annually reviews new products by therapeutic class, allowing drugs to be scheduled as they come to market. Oncology drugs, however, are reviewed on an ad hoc basis. The committee relies heavily TABLE 1 Coverage issues Oral drugs covered under managed care pharmacy benefit Medicare Part B Oral cancer therapies covered if injectable form is also available Drugs available only in oral form are not covered Medicare Modernization Act Section 641 demonstration Part D coverage begins Jan. 1, SUPPLEMENT