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Randomized Phase III Trial of Pemetrexed Versus Docetaxel in Patients With Non–Small-Cell Lung Cancer Previously Treated With Chemotherapy

From Indiana University and the Hoosier Oncology Group; Eli Lilly and Company, Indianapolis, IN; The University of Texas M.D. Anderson Cancer Center, Houston, TX; University of Colorado Cancer Center, Denver, CO; Virginia Cancer Institute, Richmond, VA; Princess Margaret Hospital and the University of Toronto, Toronto, Ontario, Canada; Instituto Arnaldo Vieira de Carvalho, Sao Paolo, Brazil; San Camillo-Forlanini Hospitals, Rome, Italy; Chang Gung Memorial Hospital, Taoyuan, Taiwan; University Hospital Basel, Petersgraben Switzerland; Fachklinik München, Gauting; Hospital Grosshansdorf, Grosshansdorf; Krankenhaus Hofheim Am Taunus, Hofheim; Thoraxklinik-Heidelberg, Heidelberg, Germany; National University Hospital, Singapore; Semmelweis Medical University Diosarok, Budapest, Hungary; Centre Francois Baclesse, Caen, France; Mayo Hospital, Lahore, Pakistan.

Address reprint requests to Nasser Hanna, MD, Indiana University, 535 Barnhill Dr, Room 473, Indianapolis, IN 46202; e-mail: nhanna{at}iupui.edu

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
PURPOSE: To compare the efficacy and toxicity of pemetrexed versus docetaxel in patients with advanced non—small-cell lung cancer (NSCLC) previously treated with chemotherapy.

PATIENTS AND METHODS: Eligible patients had a performance status 0 to 2, previous treatment with one prior chemotherapy regimen for advanced NSCLC, and adequate organ function. Patients received pemetrexed 500 mg/m² intravenously (IV) day 1 with vitamin B₁₂, folic acid, and dexamethasone or docetaxel 75 mg/m² IV day 1 with dexamethasone every 21 days. The primary end point was overall survival.

RESULTS: Five hundred seventy-one patients were randomly assigned. Overall response rates were 9.1% and 8.8% (analysis of variance P = .105) for pemetrexed and docetaxel, respectively. Median progression-free survival was 2.9 months for each arm, and median survival time was 8.3 versus 7.9 months (P = not significant) for pemetrexed and docetaxel, respectively. The 1-year survival rate for each arm was 29.7%. Patients receiving docetaxel were more likely to have grade 3 or 4 neutropenia (40.2% v 5.3%; P < .001), febrile neutropenia (12.7% v 1.9%; P < .001), neutropenia with infections (3.3% v 0.0%; P = .004), hospitalizations for neutropenic fever (13.4% v 1.5%; P < .001), hospitalizations due to other drug related adverse events (10.5% v 6.4%; P = .092), use of granulocyte colony-stimulating factor support (19.2% v 2.6%, P < .001) and all grade alopecia (37.7% v 6.4%; P < .001) compared with patients receiving pemetrexed.

CONCLUSION: Treatment with pemetrexed resulted in clinically equivalent efficacy outcomes, but with significantly fewer side effects compared with docetaxel in the second-line treatment of patients with advanced NSCLC and should be considered a standard treatment option for second-line NSCLC when available.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
Lung cancer is the most common cancer in the world today (12.3% of all new cases), with an estimated 1.2 million new cases and 1.1 million deaths (17.8% of all cancer deaths) worldwide in 2000.¹ Non—small-cell lung cancer (NSCLC) accounts for approximately 80% of all cases of lung cancer. For chemotherapy-naïve patients with a good performance status (PS) and stage IIIb (with pleural effusion) or IV disease, platinum-based chemotherapy offers a modest survival advantage over best supportive care (BSC) alone.^2-4

Docetaxel (Taxotere; Aventis Pharmaceuticals, Bridgewater, NJ) is currently the only US Food and Drug Administration and European Agency for the Evaluation of Medical Products—approved chemotherapy agent for the second-line treatment of advanced NSCLC. The approval was based on phase III studies by Shepherd et al⁵ and Fossella et al.⁶ For patients with a good PS at the time of disease progression following first-line chemotherapy, docetaxel, despite a low response rate, is associated with a 10% to 20% prolongation of 1-year survival and an improved quality of life when compared with ifosfamide, vinorelbine, or BSC alone.^5,6 In view of these modest results, new agents with single-agent activity are greatly needed for this patient population.

Pemetrexed (Alimta, Eli Lilly and Company, Indianapolis, IN) is a novel, multitargeted antifolate chemotherapy agent that is active in multiple tumor types including NSCLC.^7-10 Its primary mechanism of action is to inhibit the enzyme thymidylate synthase, resulting in decreased thymidine necessary for pyrimidine synthesis. Pemetrexed also inhibits dihydrofolate reductase and glycinamide ribonucleotide formyl transferase, the latter of which is a folate-dependent enzyme involved in purine synthesis. Phase II studies of pemetrexed in previously untreated patients with NSCLC have demonstrated single agent response rates of 17% to 23%.^7,8 A phase II study of pemetrexed in patients with advanced NSCLC, who had progressed during or within 3 months of completing first-line chemotherapy, demonstrated a response rate of 8.9% and median survival time of 5.7 months.⁹

Folate and vitamin B₁₂ nutritional status affects the toxicity of pemetrexed, including rates of neutropenic fever. Treatment with pemetrexed without vitamin supplementation results in a significantly higher incidence of hematologic and nonhematologic toxicity.^10-12 Therefore, supplementation with folic acid at 350-1,000 µg orally daily and vitamin B₁₂ 1,000 µg IM every 9 weeks is essential to control the toxicity of pemetrexed. Bunn et al reported that in a multistudy single-agent database of 246 patients treated with pemetrexed, 5.0% versus 0% had drug-related deaths, 32.0% versus 2.6% had grade 4 neutropenia, and 37.0% versus 6.4% had any grade 4 hematologic or grade 3 or 4 nonhematologic toxicity, without and with vitamin supplementation, respectively.¹² Based on the similar efficacy observed between pemetrexed and docetaxel in separate trials and the expected lower toxicity rates with pemetrexed, a multinational phase III study comparing these two agents in the second-line treatment of NSCLC was undertaken.

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
Patients with histologic or cytologic confirmation of NSCLC with stage III or IV disease not amenable to curative therapy were assessed for eligibility. Eligible patients met the following criteria: treatment with only one prior chemotherapy regimen for advanced disease (one additional prior regimen was allowed for neoadjuvant, adjuvant, or neoadjuvant plus adjuvant therapy); measurable or evaluable disease; an Eastern Cooperative Oncology Group (ECOG) PS of 0 to 2; and adequate bone marrow, renal, and hepatic function. Patients with prior docetaxel or pemetrexed treatment, Common Toxicity Criteria (CTC) grade 3 peripheral neuropathy, an inability to interrupt nonsteroidal anti-inflammatory drugs, uncontrolled pleural effusions, symptomatic or uncontrolled brain metastases, or significant weight loss ( 10% body weight in the preceding 6 weeks) were ineligible. The protocol was approved through institutional ethics review boards, and all patients provided written informed consent before treatment.

Treatment Plan
Eligible patients were randomly assigned to receive either pemetrexed or docetaxel. Patient randomization was stratified for PS (0 or 1 v 2), prior platinum or paclitaxel use, number of prior chemotherapy regimens (1 or 2), time since last chemotherapy (< 3 v 3 months), best response to last chemotherapy (objective tumor response/stable disease versus progressive disease/unknown), stage (III v IV), baseline plasma homocysteine level (<12 µmol/L v 12 µmol/L), and center. Patients received either 500 mg/m² pemetrexed as a 10-minute intravenous infusion or 75 mg/m² docetaxel as a 1-hour intravenous infusion on day 1 of a 21-day cycle. Cycles were repeated until disease progression, unacceptable toxicity, or until the patient or the investigator requested therapy discontinuation. Patients on the pemetrexed arm were instructed to take folic acid 350-1,000 µg (or an equivalent) orally daily beginning approximately 1 to 2 weeks before the first dose of pemetrexed and continuing daily until 3 weeks after the last dose of pemetrexed. A 1,000 µg vitamin B₁₂ injection was administered intramuscularly approximately 1 to 2 weeks before the first dose of pemetrexed and was repeated approximately every 9 weeks until after discontinuation. Folic acid and vitamin B₁₂ were given because of their ability to reduce toxicities without affecting the efficacy of pemetrexed.¹¹ Patients on the pemetrexed arm were instructed to take dexamethasone (4 mg orally twice daily the day before, the day of, and the day after pemetrexed) as a prophylactic measure against skin rash. Patients on the docetaxel arm were instructed to take dexamethasone (8 mg orally twice daily the day before, the day of, and the day after docetaxel), but were not required to take vitamin supplementation. A maximum of two dose reductions were allowed based on nadir counts or clinically significant nonhematologic toxicities and dose delays up to 42 days from day 1 of the current cycle were permitted for recovery from adverse events. Granulocyte colony-stimulating factor support was allowed to treat a neutropenic event or as prophylaxis in a patient who had experienced a neutropenic event with a previous cycle.

The baseline assessment included a history and physical examination, complete blood count, comprehensive blood chemistries, calculated creatinine clearance, vitamin metabolite panel, chest x-ray and computed tomorgraphy scan of the chest and the upper abdomen. Bone scans and brain imaging were performed only if clinically indicated. The Lung Cancer Symptom Scale (LCSS) was administered at baseline and weekly during the study. The observer LCSS was administered at baseline and at the end of each cycle.¹³ Toxicity evaluations were based on the National Cancer Institute CTC, version 2. Hematologic laboratory values and folic acid compliance (pemetrexed arm only) were evaluated weekly. Chemistry laboratory values were evaluated following days one and eight of each cycle. Tumor measurements were assessed after every two cycles.

Statistical Analysis
The primary objective of the study was to compare overall survival between the two treatment groups on an intent-to-treat basis. Secondary objectives were to compare toxicities (including use of concomitant supportive measures), objective response rates (RR), progression-free survival (PFS), time to progressive disease (TPD), time to treatment failure (TTF), time to response, duration of response, and quality-of-life measurements (using the LCSS) between the treatment groups.

Unless otherwise noted, all tests of hypotheses were conducted at the = 0.05 level, with a 95% CI. Cox proportional hazard models were used to compare the overall survival time and other time-to-event end points between the treatment arms; Kaplan-Meier estimates were used to assess the median time-to-event parameters, except for time-to-response using analysis of variance. The study was designed to have an 81% chance of demonstrating noninferiority for survival time (defined as pemetrexed arm 10% worse than docetaxel arm) for pemetrexed when compared to docetaxel using the true hazard ratio (HR) to be 0.83. This translated to an upper bound of the 95% CI less than 1.11 for the HR of pemetrexed over docetaxel. In addition, the hypothesis that pemetrexed retained 50% of the survival benefit of docetaxel over BSC using data from the randomized comparative trial of docetaxel versus BSC by Shepherd et al⁵ was prospectively planned (percent retention method).¹⁴ In the trial reported by Shepherd et al, the HR of docetaxel over BSC was estimated to be 0.56 (95% CI, 0.35 to 0.88). Setting the percentage of historical benefit at 50% and maintaining an approximate one-sided 2.5% type I error, an upper 95% CI bound of less than 1.21 for the HR of pemetrexed over docetaxel was required to establish the noninferiority of pemetrexed.

Tumor response was compared using the Fisher's exact test with 95% CI calculated using the method of Leemis and Trivedi.¹⁵ A Cox proportional multiple regression (CMR) model was developed with an interactive stepwise regression to identify the potential factors as predictors of survival independent of therapy. A final model was fitted on the survival, including therapy in the model to estimate the treatment effect adjusting for these factors. The incidence of CTC toxicities, adverse events, concomitant medications used, and hospitalizations were analyzed using Fisher's exact test. Distribution of changes from baseline in the average symptom burden index (ASBI) of the patient LCSS, and individual symptoms of the observer LCSS, were compared with the Mental-Haenszel ² test.¹⁶

The overall survival time was defined as the time from the date of randomization to date of death due to any cause. Patients who were alive on the date of last follow-up were censored on that date. PFS was the time from randomization until documented progression or death from any cause and was censored at the date of the last follow-up visit for patients who were still alive and who had not progressed. TPD was defined as the time from the date of randomization to the first date of documented disease progression and was censored at the date of death for patients who died without documented disease progression or the date of the last follow-up visit for patients who were still alive and who had not progressed. TTF was defined as the time from randomization to the date of progression of disease, discontinuation of treatment, or death due to any cause and was censored at the date of the last follow-up visit for patients who did not discontinue, who were still alive, and who did not have disease progression. Tumor response was assessed using the Southwest Oncology Group criteria¹⁷ and required confirmation at least 4 weeks after initial response (Complete response [CR] defined as complete disappearance of all measurable and evaluable disease; partial response [PR] defined as 50% decrease in the sum of products of perpendicular diameters of all measurable lesions; progressive disease [PD] defined as 50% increase in the sum of products of all measurable lesions, or worsening of evaluable disease, or appearance of any new lesions; and stable disease [SD] defined as not qualifying for CR, PR, or PD). Duration of tumor response was defined as the time from the date of the first objective status assessment of CR or PR until the first date of documented disease progression or death due to any cause and was censored at the date of the last follow-up visit for tumor responders who were still alive and who had not progressed. Duration of clinical benefit (CR/PR/SD) was defined as the time from the date of randomization to the first date of documented disease progression or death due to any cause for patients who had a best overall tumor response better than progressive disease and was censored at the date of the last follow-up visit for those patients who were still alive and had not progressed.

For each patient, LCSS scores were rated as improved, stable, or worsened based on comparison with baseline. The average symptom burden index (ASBI) was the average of the six symptom-specific questions regarding anorexia, fatigue, cough, dyspnea, hemoptysis, and pain.¹³ Meaningful change for the ASBI was defined as at least half of the SD of the baseline ASBI for all patients that was maintained for at least 4 consecutive weeks.¹⁸ Meaningful change for observer LCSS scales was defined as at least a one-point change on the five-point scale that was maintained for at least two cycles. Changes in LCSS scores that could not be confirmed were classified as unknown.

	RESULTS

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From March 2001 through February 2002, 571 patients were randomly assigned to receive either pemetrexed or docetaxel. Two hundred sixty-five of 283 patients randomly assigned to pemetrexed received at least one cycle of therapy (18 patients received no treatment due to: failure to meet inclusion criteria [n = 7], death from disease [n = 5], other adverse events [n = 3], personal conflict [n = 2], or protocol violation [n = 1]). Two hundred seventy-six of 288 patients randomly assigned to docetaxel received at least one cycle of therapy (12 patients received no treatment due to failure to meet inclusion criteria [n = 2], death from disease or other cause [n = 2], personal conflict [n = 5], loss to follow-up [n = 3].) At the time of analysis, 409 (71.6%) of 571 patients had died. The median follow-up for all patients was 7.5 months, and the clinical data were collected up to January 30, 2003. The baseline patient and disease characteristics are listed in Table 1.

Treatment Administered
The median number of cycles of chemotherapy administered was four in each group, with a range of one to 20 and one to14 for patients receiving pemetrexed and docetaxel, respectively. Patients received 96.6% and 94.4% of the planned dose-intensity of pemetrexed and docetaxel, respectively (P = not significant).

Efficacy
There was no significant difference in overall RR (9.1% v 8.8%) or SD rates (45.8% v 46.4%) between the pemetrexed and docetaxel arms, respectively. The RR to second-line treatment in patients with a CR or PR, SD, and PD to first-line therapy was 11.1%, 10.2%, and 4.6%, respectively, and the SD rate to second-line treatment in patients with a CR or PR, SD, and PD to first-line therapy was 47.0%, 50.0%, and 40.3% respectively.

Paclitaxel sensitivity and resistance in first-line treatment did not predict for a difference in response between pemetrexed and docetaxel in second-line treatment (P = not significant). Patients who achieved a CR or PR with first-line paclitaxel (n = 54) had a 7.1% versus 3.9% RR to pemetrexed and docetaxel, respectively (SD rates were 32.1% v 30.8%). Patients with SD following first-line paclitaxel (n = 55) had an RR of 3.8% versus 6.9% for pemetrexed and docetaxel, respectively (SD rates were 50.0% v 51.7%) and patients with PD (or unknown response) with first-line paclitaxel (n = 44) had an RR of 5.3% versus 4.0% for pemetrexed and docetaxel, respectively (SD rates 42.1% v 48.0%).

There were no significant differences in PFS (Fig 1, Table 2), TPD and TTF (Table 2). There was also no significant difference in median time to response, median duration of response, and median duration of clinical benefit (Table 2). On an intent-to-treat basis, the median survival time for pemetrexed was 8.3 months versus 7.9 for docetaxel (HR, 0.99; 95% CI, 0.82 to 1.2; noninferiority P = .226; Fig 2). Using the percent retention method, the estimate of the percentage of survival benefit (of docetaxel over BSC) retained by pemetrexed was 102% with the lower 95% CI bound of 52% and was statistically significant (P = .047). The 1-year overall survival rate for each arm was 29.7%.

View larger version (14K): [in this window] [in a new window]   Fig 1. Median progression-free survival (MPFS). Pts, patients. Mo, months.

View larger version (15K): [in this window] [in a new window]   Fig 2. Median survival time (MST). Mo, months; yr, year; Pts, patients.

Multiple Regression Analysis
CMR analysis was performed on 532 patients to identify additional factors that affected survival and to estimate the treatment effect adjusting for these factors. The CMR analysis showed that pemetrexed and docetaxel achieved similar survival after adjusting for all baseline factors. The factors significantly associated with increased survival were: PS 0 or 1 (HR, 0.25; 95% CI, 0.19 to 0.34; P < .001), stage III disease (HR, 0.77; 95% CI, 0.60 to 0.97; P = .026), and longer time since last chemotherapy (HR, 0.74; 95% CI, 0.60-0.97; P = .004). Similar survival was seen between treatment groups after adjusting for each of these factors (HR, 0.93; 95% CI, 0.76-1.13; noninferiority P = .051; Table 3).

	DISCUSSION

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The patients receiving docetaxel in the current study performed as well as (or in some categories better than) the patients receiving docetaxel on the phase III studies reported by Shepherd et al⁵ and Fossella et al.⁶ The RR to docetaxel at 75 mg/m² on all three studies was 6.7% to 8.8% and the SD rate was 36% to 46%. The median survival time for docetaxel was 5.7 months in the Fossella et al study, 7.5 months in the Shepherd et al study, and 7.9 months in this study.

The design and patient characteristics of this trial have similarities, but also important distinctions from the trials previously reported by Shepherd et al and Fossella et al. Each study evaluated patients who had previously received chemotherapy for advanced NSCLC, required an ECOG PS 0 to 2, and excluded patients with symptomatic brain metastases. However, only the current study limited patients to one prior chemotherapy regimen for advanced disease (25% to 35% of patients on the other trials had received > one prior regimen for metastatic disease), did not require prior platinum (although 95% of patients had received platinum) and excluded patients with uncontrolled pleural effusions and significant weight loss. The study by Shepherd et al did not allow prior paclitaxel, while 42% of patients (on the 75 mg/m² arm of docetaxel) had received paclitaxel on the Fossella et al study as did 25% in this study. Prior treatment with paclitaxel did not seem to reduce efficacy to any of the agents under study in either of the trials. PS 2 patients made up approximately 24% and 18% of those treated with docetaxel in the Shepherd et al and Fossella et al studies. Approximately 12% on each arm in this study had a PS of 2. Otherwise, the patient characteristics were similar on all three studies (sex, age, stage, % with PD to first-line therapy). Patients on this study and the Fossella et al study did not routinely receive G-CSF as prophylaxis, unless the patient had already experienced a neutropenic event with a previous cycle, but rather only as treatment for toxicity. Therefore, the high rates of use of G-CSF on the docetaxel arm of the current study cannot be attributed to the routine use of G-CSF for prophylaxis.

Although there was clinically equivalent efficacy demonstrated between the two agents in this study, there were several clinically and statistically significant differences in their toxicity profiles. There were higher rates of neutropenia (with and without complications) and more frequent use of G-CSF for patients on the docetaxel arm when compared to the pemetrexed arm. The rate of grade 3 or 4 neutropenia due to docetaxel in our study was 40.2%, which is significantly lower than the rates of neutropenia reported with the 75 mg/m² docetaxel arms of the studies by Shepherd et al (67.3%) and Fossella et al (> 54%). The rate of neutropenic fever due to docetaxel in our study was 12.7%, which is also comparable to that observed in the combined docetaxel arms in the Shepherd et al (11.5%) and Fossella et al studies (10%). When considering only the 75 mg/m² arms of those studies, however, the rate of neutropenic fever was lower in the Shepherd et al study (1.8%) and Fossella et al study (8%) when compared with our study, despite a significantly higher percentage of patients at risk. Pemetrexed treated patients experienced significantly fewer hospitalizations for neutropenic fever. Rates of infection with docetaxel were also comparable between the three studies (approximately 3% in the combined docetaxel arms). The higher rate of neutropenic complications with docetaxel in this study is not related to the duration of treatment given (median 3 to 4 cycles on each study), patient characteristics—the Shepherd et al study had more PS 2 patients, and they were more heavily pretreated with chemotherapy in that 25% were receiving docetaxel as third-line or greater—or use of prophylactic G-CSF without a preceding neutropenic event. In addition, the rates of other hematologic toxicities (anemia and thrombocytopenia) were comparable among the three studies.

In this study, patients treated with pemetrexed had a significantly lower rate of alopecia (P < .001) and a trend toward lower rates of grade 3 or 4 diarrhea (P = .069) compared with patients receiving docetaxel. An increase in ALT was the only toxicity that was higher in the pemetrexed arm (P = .028). Overall, the rates of improvement or stabilization of baseline symptoms were similar between the two arms (P = .145).

In conclusion, treatment with pemetrexed demonstrated clinically equivalent efficacy with a significantly improved safety profile compared with those receiving docetaxel in the second-line setting for advanced NSCLC in this study. Based on these results, treatment with pemetrexed should be considered a standard treatment option for second-line NSCLC.

	APPENDIX

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
The following persons and institutions participated in this study: Argentina: Claudia Bagnes, Hospital Dr Tornu, Buenos Aries; Federica Coppola, Hospital Aleman, Buenos Aries; Silvia Jovtis, Complejo Medico Churruca Visca, Buenos Aires; Moises Rosenberg, Hospital Ferrer, Buenos Aries; Austria: Kurt Aigner, A. ö. Krankenhaus der Elisabethinen, Linz; Gerhard Baumgartner, Krankenhaus der Stadt Wien Lainz, Vienna; Josef Eckmayr, A. ö. Krankenhaus Wels, Wels; Robert Pirker, Universitätsklinik für Innere Medizin I, Vienna; Belgium: Lionel Bosquée, CHR de la Citadelle, Liège; Jean-François Rosier, Hôpital de Jolimont, Haine-St-Paul; Johan Vansteenkiste, UZ Gasthuisberg, Leuven; Brazil: Carlos Barrios, Hospital Sao Lucas PUC, Porto Alegre; Sebastião Cabral, CEONG; Cid Gusmão, Hospital 9 de Julho; Arthur Malzyner, Hospital Albert Einstein; Jose R. Pereira, Instituto Arnaldo Vieira de Carvalho, Sao Paulo; Alessandro Vasconcelos, Núcleo de Oncologia da Bahia; Canada: Vira Hirsh, Royal Victoria Hospital, Montreal; Martin C. Palmer, Charles Butts, Cross Cancer Institute, Edmonton; Francis A. Shepherd, Princess Margaret Hospital, Toronto; David Stewart, Scott Laurie, Ottawa Regional Cancer Center, Ottawa; Czech Republic: Jaromir Roubec, Fakultni Nemocnice S Poliklinkou, Ostrava-Poruba; France: Alain Depierre, Centre Hospitalier Universitaire, Besancon; Radj Gervais, Centre Francois Baclesse, Caen; Jean-Jacques Lafitte, Hopital Calmette, Lille; Maurice Perol, Hopital De La Croix Rousse, Lyon; Jean-Louis Pujol, Hopital Arnaud De Villeneuve, Montpellier; Gilles Robinet, Hopital Morvan-Brest; Dominique Spaeth, Centre Alexis Vautrin, Vandoeuvre-les-Nancy; Thierry Urban, Centre Hospitalier Universitaire, Angers; Germany: Ulrich Gatzemeier, Krankenhaus Grosshansdorf; Eckart Laack Universitaetsklinikum Hamburg Eppendorf; Rudolf Huber, Klinikum Innenstadt München; Gabriele Koschel, Allgem. Krankenhaus Hamburg/Harburg; Cornelius Kortsik, St. Hildegardis Krankenhaus, Mainz; Christian Manegold, Thorax-Klinik Heidelberg-Rohrbach; Joerg Mezger, St. Vincentius Krankenhaus, Karlsruhe; Thomas Mueller, Kliniken des Main-Taunus-Kreises, Hofheim; Dirk Hartwigsen, Malteser Krankenhaus, St Franziskus Hospital, Flensburg; Nicolas Dickgreber Otto von Guericke Universitat, Magdeburg; Joachim von Pawel, Asklepios Fachklinik, Gauting; Hungary: Gabor Kovacs, Gyula Ostoros, Orszagos Koranyi TBC es Pulmonologiai Intezet; Budapest; P. Magyar, Klara Szondy, Pulmonary Clinic of Semmelweis Medical University, Budapest; India: Pramod Kumar Julka, All India Institute of Medical Sciences, New Delhi; Radheshyam Nayak, Curie Centre of Oncology, Bangalore; Jagdev Singh Sekhon, Dayanand Medical College and Hospital, Ludhiana; Subhashini John, Christian Medical College, Vellore; Dinesh Chandra Doval, Rajiv Gandhi Cancer Institute & Research Centre, Delhi; Atul Sharma, All India Institute of Medical Sciences, New Delhi; Israel: Maya Gottfried, Meir Hospital, Kfar Saba; Italy: V. Adamo, Universita Di Messina/Policlinico, Messina; Lucio Crino, zospedale Bellaira, Bologna; Fillipo DeMarinis, Camillo Forlanini, Rome; Massimo Rinaldi, Istituti Fisioterapici Ospedalieri, Rome; Korea: Yung-Jue Bang, Seoul National University Hospital, Seoul; Joo-Hang Kim, Yonsei Cancer Center, Seoul; Keunchil Park, Samsung Medical Center, Seoul; Netherlands: Harry J. Groen, University Hospital, Groningen; Franz M. Schramel, St Antonius Hospital, Nieuwegein; Jan Van Meerbeeck, University Hospital Rotterdam, Rotterdam; Pakistan: Tariq N. Ansari, Combine Military Hospital, Rawalpindi; Prof. Shaharyar, Mayo Hospital, Lahore; Tariq Siddiqui, Aga Khan University & Hospital, Karachi; M. Zaidi, Baquai Institute of Oncology, Karachi; Poland: Prof. Jacek Jassem, Katedra i Klinika Onkologii i Radioterapii AM w Gdansku; Portugal: Fernando Barata, Centro Hospitalar de Coimbra, Coimbra; Manuela Bernardo, Hospital dos Capuchos, Lisboa; Jose Duro Costa, Instituto Português de Oncologia de Lisboa, Lisboa; Maria José Melo, Hospital de Pulido Valente, Lisboa; Bárbara Parente, Centro Hospitalar de Vila Nova de Gaia, Vila Nova de Gaia; Mário Passos, Centro Hospitalar do Funchal, Funchal; Henrique Queiroga, Hospital de São João, Porto; Evaristo Sanches, Instituto Portugues de Oncologia do Porto, Porto; Encarnação Teixeira, Hospital de Santa Maria, Lisboa; Russia: Avgust M. Garin, Russian Cancer Research Center, Moscow; Professor Vera A. Gorbunova, Russian Cancer Research Center, Moscow; Professor Mikhail R. Lichinitser, Russian Cancer Research Center, Moscow; Singapore: Swan-Swan Leong, Eng-Huat Tan, Soo-Thye Lim, National Cancer Centre; Hong-Liang Lim, Boon-Cher Goh, Ross-Lai-Kit Soo, Seng-Weng Wong, National University Hospital; South Africa: Raymond P. Abratt, Groote Schuur Hospital, Cape Town; Sean Brennam, East Cape Oncology Cenre- St. George's Hospital, Port Elizabeth; Paul Ruff, Johannesburg General Hospital, Parktown; Spain: Emilio Esteban, Hospital General de Asturias, Oviedo; José R. Barceló, Hospital de Cruces, Barakaldo; Enriqueta Felip, Hospital Vall d'Hebrón, Barcelona; Pilar Garrido, Hospital Ramón y Cajal, Madrid; Rafael Rosell, Hospital Germans Trias i Pujol, Badalona; Switzerland: Miklos Pless, Marc Salzberg, Kantonsspital, Basel; Rolf Stahel, Universitaetshospital, Zurich; Taiwan: Gee-Chen Chang, Taichung Veterans General Hospital, Taichung; Te-Chun Hsia, China Medical College Hospital, Taichung; Hon-Ki Hsu, Kaohsiung Veterans General Hospital, Kaohsiung; Wu-Chou Su, National Cheng Kung University Hospital, Tainan; Chun-Ming Tsai, Veterans General Hospital Taipei, Taipei; Thomas Chang-Yao Tsao, Chang Gung Memorial Hospital - Linkou-Taiwan, Tao-Yuan; Ming-Fang Wu, Chung Shan Medical & Dental College Hospital, Taichung; Chih-Hsin Yang, National Taiwan University Hospital, Taipei; United States: Kathy S. Albain, Loyola University Medical Center, Maywood, IL; Rafat H. Ansari, Michiana Hematology Oncology, South Bend, IN; Susanne M. Arnold, University of Kentucky, Lexington, KY; James D. Bearden, Palmento Hematology Oncology Associates PC, Spartanburg, SC; Joseph M. Beck, Little Rock, AR; Sumeet Bhatia, Community Cancer Care Inc, Indianapolis, IN; Neal Paul Christiansen, South Carolina Oncology Associates PA, Columbia, SC; Christopher E. Desch, Hematology Oncology Associates, Richmond, VA; Elliot Dickman, Meridia Hillcrest Hospital Cancer Center, Mayfield Heights, OH; Tracy William Dobbs, Baptist Medical Tower, Knoxville, TN; Arkadiusz Dudek, University of Minnesota, Minneapolis, MN; John R. Eckardt, St John's Mercy Medical Center; Saint Louis, MO; Peter D. Eisenberg, Marin Oncology Associates, Greenbrae, CA; John E. Feldmann, Mobile Infirmary Medical Center, Mobile, AL; Jose A. Figueroa, Joe Arrington's Cancer Center; Lubbock, TX; William B. Fisher, Medical Consultants, Muncie, IN; Frank V. Fossella, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Stephen L. Graziano, SUNY Upstate Medical University, Syracuse, NY; Nasser H. Hanna, Indiana University, Indianapolis, IN; Ronald D. Hart, Milwaukee, WI; Abdul-Rahman Jazieh, Barrett Cancer Center, Cincinnati, OH; Glenn R. Justice, University of Southern California, Fountain Valley, CA; Peter Kennedy, Metropolitan Oncology, Los Angeles, CA; Philip Kuebler, Columbia Oncology Associates, Columbus, OH; Tim Larson, Hubert Humphrey Cancer Center, Robbinsdale, MN; James E. Liebmann, New Mexico Oncology Hematology Consultants, Albuquerque, NM; Alan P. Lyss, Missouri Baptist Cancer Center, Saint Louis, MO; Alex Makalinao, California Hematology Oncology Medical Group, Los Angeles, CA; Jerry Malefatto, Oncology Associates of Bridgeport, Trumbull, CT; Bernard A. Mason, Pennsylvania Oncology Hematology Associates, Philadelphia, PA; Sreenivasa R. Nattam, Fort Wayne Medical Oncology Hematology, Fort Wayne, IN; Nadim F. Nimeh, Lawton, OK; David Peereboom, Cleveland Clinic Foundation, Cleveland, OH; Michael C. Perry, Ellis Fischel Cancer Center, Columbia, MO; Victor M. Priego, Center for Cancer & Blood Disorders, Bethesda, MD; David Arthur Rinaldi, Louisiana Oncology Associates, Lafayette, LA; Lee Schwartzberg, Memphis, TN; Miho Tao Scott, Hematology Oncology Associates, Fort Collins, CO; Todd David Shuster, Labey Clinic Medical Center, Burlington, MA; Haluk Tezcan, Coeur D'Alene, ID; Manuel Valdivieso, Dallas, TX; R. Timothy Webb, Genesis Cancer Center, Hot Springs, AR.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION APPENDIX Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Owns stock (not including shares held through a public mutual fund): Paolo Paoletti, Eli Lilly; Frances A. Shepherd, Eli Lilly. Acted as a consultant within the last 2 years: Nasser Hanna, Eli Lilly, Aventis; Ulrich Gatzemeier, Eli Lilly; Paul A. Bunn Jr., Eli Lilly; Miklos Pless, Eli Lilly; Christian Manegold, Eli Lilly; Frank V. Fossella, Eli Lilly, Aventis; Frances A. Sheperd, Eli Lilly, Aventis. Performed contract work within the last 2 years: Paul A. Bunn Jr., Eli Lilly; Frances A. Sheperd, Eli Lilly. Received more than $2,000 a year from a company for either of the last 2 years: Nasser Hanna, Eli Lilly, Aventis; Ulrich Gatzemeier, Eli Lilly; Paul A. Bunn Jr., Eli Lilly; Christian Manegold, Eli Lilly; Frank V. Fossella, Eli Lilly, Aventis; Frances A. Sheperd, Eli Lilly, Aventis.

	Acknowledgment

 
We acknowledge the contributions of Alexandria E. Barile, Michael Bierman, Louis Kayitalire, Patrick McAndrews, Donna L. Miller, Patricia Moore, and Sesha Reddigari for their assistance in either the conduct of this study or the preparation of this manuscript.

	NOTES

 
Supported by Eli Lilly and Company, Indianapolis, IN.

Presented in part at the 39th annual meeting of the American Society of Clinical Oncology, Chicago, IL, June 2003, and the 10th World Conference on Lung Cancer meeting of the International Association for the Study of Lung Cancer, Vancouver, Canada, August 2003.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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Submitted August 26, 2003; accepted February 20, 2004.

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