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Journal of Clinical Oncology, Vol 26, No 11 (April 10), 2008: pp. 1879-1885 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2007.12.2689 Phase III Trial Comparing Carboplatin, Paclitaxel, and Bexarotene With Carboplatin and Paclitaxel in Chemotherapy-Naïve Patients With Advanced or Metastatic Non–Small-Cell Lung Cancer: SPIRIT II
From Department of Thoracic/Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, TX; Clinical and Translational Research, Winship Cancer Institute at Emory University, Atlanta, GA; Ligand, San Diego, CA; US Oncology, Rocky Mountain Cancer Centers, Houston, TX; Zentralkrankenhaus Gauting, Abteilung Onkologie, Gauting bei Muenchen; Grosshansdorf Hospital, Grosshansdorf; Zentralkrankenhaus, Gauting, Germany; Department of Oncology, Sir Mortimer B. Davis - Jewish General Hospital, Montreal, Quebec, Canada; and Groupe Français de Pneumo Cancérologie, Aix en Provence, France Corresponding author: George R. Blumenschein Jr, MD, The University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd, Box 432, Houston, TX 77030; e-mail: gblumens{at}mdanderson.org
Purpose The purpose of this study was to determine whether addition of the synthetic rexinoid bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) to standard first-line carboplatin and paclitaxel therapy provides additional survival benefit in patients with advanced non–small-cell lung cancer (NSCLC). Patients and Methods Patients with stage IIIB disease with pleural effusion, or stage IV NSCLC and Eastern Cooperative Oncology Group performance status 0 to 1, were randomly assigned to bexarotene 400 mg/m2/d combined with carboplatin and paclitaxel, or assigned to carboplatin and paclitaxel alone. Bexarotene patients also received lipid-lowering agents on or before day 1. The primary efficacy end point was overall survival; secondary efficacy and supportive analyses were also conducted.
Results A total of 612 patients (306 per arm) were enrolled onto the study. In the intent-to-treat population, no significant difference in survival occurred between the two arms. However, a subpopulation (approximately 40%) of bexarotene-treated patients who experienced National Cancer Institute grade 3/4 hypertriglyceridemia had significantly longer median survival than control patients (12.4 v 9.2 months; log-rank, P = .014). Bexarotene-treated patients with grade 3/4 hypertriglyceridemia who received the most benefit included those who were male, were smokers, experienced 6-month prior weight loss Conclusion Although the addition of bexarotene to chemotherapy did not improve survival in the overall study population, occurrence of high-grade hypertriglyceridemia in bexarotene-treated patients strongly correlated with increased survival, suggesting that bexarotene may benefit a segment of first-line NSCLC patients.
Retinoid receptors, which play a critical role in cellular growth modulation, division, induction of differentiation, and activation of apoptosis, have been investigated as potential targets for novel cancer therapies for several years. The expression of many retinoid receptors, including retinoid-X receptor (RXR) β (RXRβ), is reduced in some non–small-cell lung cancer (NSCLC) biopsy specimens, and increased RXRβ expression has been associated with an increased survival in NSCLC patients.1 Bexarotene (Targretin; Eisai Inc, Woodcliff Lake, NJ) is a synthetic retinoid modulator of RXR used for the treatment of cutaneous T-cell lymphoma.2 It selectively binds and activates various RXR subtypes known to form heterodimers that transcriptionally regulate several gene networks.3 Bexarotene enhances the activity of several chemotherapeutic agents used in NSCLC, and has been shown to prevent or overcome paclitaxel resistance in NSCLC cell lines.4 In early trials, bexarotene demonstrated both satisfactory safety and promising efficacy.5,6 Impressive survival of 11.1 months was observed in phase I monotherapy trials in chemotherapy-refractory patients (Table 1). Additionally, in a first-line metastatic NSCLC phase I/II study, bexarotene combined with cisplatin and vinorelbine resulted in a median survival of 13.7 months (Table 1).7 Based on the promising survival results from multiple phase I/II studies, two phase III trials were initiated to compare the efficacy and safety of bexarotene combined with carboplatin and paclitaxel (Studies Providing Investigational Research in Targretin [SPIRIT] II study, described in this article), or cisplatin/vinorelbine (SPIRIT I study)7a in advanced NSCLC. The primary end point of the SPIRIT II study was to determine overall survival, with a secondary end point of 2-year survival. Descriptive analyses included progression-free survival (PFS), number of cycles, doses of chemotherapy administered, and tumor response (discussed in Assessments); subgroup evaluation of population pharmacokinetics, and biochemical and genetic biomarkers are presented elsewhere. Dose- and time-dependent hyperlipidemia—primarily hypertriglyceridemia—was observed in early bexarotene studies and was expected because of known effects of retinoids on lipid metabolism.13 This led to the administration of antilipid agents from baseline.
Eligibility Criteria The main eligibility criteria for this study included histologically or cytologically confirmed NSCLC (stage IIIB disease with pleural effusion, or stage IV disease), no prior platinum-based chemotherapy for any indication, and at least one measurable or assessable NSCLC lesion that had not been previously irradiated unless radiation therapy occurred more than 3 weeks before study entry and the lesion had progressed after the radiation therapy. Additional criteria included Eastern Cooperative Oncology Group performance status of 0 or 1, anticipation of completion of at least four cycles of carboplatin/paclitaxel chemotherapy in approximately 3 months, no known brain metastasis, and acceptable organ function. Patients were required to have normal or normalized triglyceride levels before the study initiation. Informed consent was obtained from eligible patients before prestudy assessments. The study protocol was approved by the institutional review board or the ethics committee of each participating center in agreement with local regulatory requirements (Fig 1).
Trial Design This was a multicenter, multinational, randomized, open-label, comparative phase III study. Before the patients were randomly assigned, they were stratified according to sex and disease stage (TNM stage IIIB disease with pleural effusion v stage IV disease). Eligible patients were randomly enrolled in one of two treatment arms (Fig 2). All patients received paclitaxel 200 mg/m2 infused intravenously over 3 hours, followed by carboplatin-administered intravenously, dose-adjusted to achieve area under the time-concentration curve (AUC) 6 according to the Calvert formula once every 3 weeks. All patients were scheduled to have at least four cycles of chemotherapy, consisting of one cycle every 3 weeks. Bexarotene (75-mg capsules) 400 mg/m2/d was administered orally once a day, and the total once-daily dose was rounded to the nearest 37.5 mg. If the initial dosage was not well tolerated, it was reduced by increments of 100 mg/m2/d, or suspended if required. Patients enrolled in this arm also received an antilipid agent beginning on or before day 1. The suggested antilipid agents were atorvastatin and fenofibrate, with dose adjustments performed as necessary.
Statistical Analysis The statistical design of this study aimed to detect a  30% survival benefit in the bexarotene arm, with 80% power at a two-sided, 5%  level using the log-rank test. A 600-patient accrual (300 in each arm) was planned to achieve the target of 456 death events; 612 patients (306 patients in the bexarotene arm, and 306 patients in the control arm) were actually enrolled onto the study and considered to be the intent-to-treat (ITT) population. The median follow-up period was 21.8 months (range, 18.3 to 32.5 months). The primary efficacy analysis was a log-rank test for overall survival between the two arms in ITT patients, stratifying for TNM stage and sex; the secondary efficacy end point was a 2-year survival rate. Other end points included median survival, 1-year survival, median PFS, and safety evaluations. The Cox regression method was used in additional survival analyses. Safety evaluation was based on all patients who were exposed to at least one dose of any study medication. The unplanned and retrospective analyses were conducted on a hypertriglyceridemia subgroup in the bexarotene arm to evaluate further the effects of bexarotene on this unique segment of NSCLC patients.
Assessments Levels of lipids, thyroid-stimulating hormone, and thyroid marker thyroxine were evaluated regularly in bexarotene-treated patients only. At the beginning of the study, patients enrolled in the bexarotene arm underwent more frequent CBC monitoring, which may have initially altered observed neutropenia incidence in the bexarotene arm. Subsequently, the protocol was amended to include CBC monitoring every 3 weeks in both treatment arms. Approximately 49% of the patients enrolled onto the study after this protocol amendment.
Patients This multicenter study was primarily conducted in the United States (67%), but the study also enrolled patients from Canada (5%), Germany (18%), France (7%), Spain (3%), and Austria (1%). Patient demographics are listed in Table 2. The patient populations in the two treatment arms were well balanced, with no significant differences between the two groups. In total, 612 patients were enrolled onto the study, with 588 patients (96%) receiving at least one dose of any of the study drugs. Of these, 293 patients (96%) were in the bexarotene arm and 295 patients (96%) were in the control arm. Patients in the bexarotene arm received a mean of 3.7 cycles of carboplatin/paclitaxel, whereas those in the control arm received a mean of 4.3 cycles (P = .0002). The average dose of carboplatin was 5.8 AUC (total dose, 21.1 AUC), and 5.9 AUC (total dose, 25.4 AUC) in the bexarotene and control arms, respectively; the average dose of paclitaxel was 194.2 mg/m2 (total dose, 708.1 mg/m2), and 195.5 mg/m2 (total dose, 844.8 mg/m2) in the bexarotene and control arms, respectively (P < .0001).
The overall bexarotene mean daily dose was 315 mg/m2, with 60% of patients receiving doses above the mean and 40% of patients receiving doses below the mean. Patients in the bexarotene arm were given the following antilipid agents starting on or before day 1: atorvastatin (72%), other statins (14%), fenofibrate (18%), ciprofibrate (< 1%), or other antilipid agents (2%). Some patients received more than one of these antilipid agents. The poststudy anticancer therapies received by the two treatment arms were similar (Appendix Table A1, online only).
Efficacy To rule out the possibility that the type of antilipid agent administered might have affected survival, survival in the bexarotene arm was also analyzed with respect to various antilipid agents. Median survival was 9.0 months among 232 patients treated with statins, and 7.7 months for 37 patients treated with fibrates (not significant). Tumor response did not differ significantly between the two treatment arms. Patients enrolled in the bexarotene arm had an overall tumor response rate of 19.3%, compared to an overall tumor response rate of 23.5% for patients enrolled in the control arm (P = .24). Disease stabilization was achieved in 40.2% and 37.6% of patients in the bexarotene and control arms, respectively.
Hypertriglyceridemia Subgroup Analysis
As expected, hypertriglyceridemia was noted in the majority of patients in the bexarotene arm. To determine whether bexarotene may have been under-administered in an effort to minimize hypertriglyceridemia, bexarotene-dose reduction was examined with respect to survival and to elevated triglycerides. Two distinct groups were identified: patients who were highly sensitive to bexarotene-induced triglyceride elevations and those who were not (Fig 3). Approximately 40% of patients in the bexarotene arm experienced rapid National Cancer Institute, grade 3/4, serum-triglyceride elevations (
Analyses of absolute triglyceride levels were conducted to validate these findings. When patients were divided into three subgroups correlating to the upper third (> 67%), middle third (> 33% to 67%), and lower third (  33%) of absolute triglyceride levels following bexarotene administration, median survival was 12.4 months, 9.1 months, and 5.4 months, respectively; all subgroups were significantly different from each other (P < .05; Fig 4). Survival in the upper-third subgroup was similar to that of the bexarotene, grade 3/4, hypertriglyceridemia subgroup, and was better than that of the control group (P = .0093). The primary difference between the initial hypertriglyceridemia subgroup analysis and this analysis was that survival in the middle-third subgroup was similar to that of the control group (P = .71). Survival in the lower-third subgroup was similar to that of the bexarotene, grade 0 to 2, hypertriglyceridemia subgroup, and was shorter than that of the control group (P < .0001).
A survival hazard ratio analysis demonstrated that bexarotene-treated patients who experienced grade 3/4 hypertriglyceridemia had a better prognosis when evaluated along several parameters than patients in the control arm (Appendix Fig A2, online only). In particular, patients within this subgroup who were male, had stage IV disease, had demonstrated a prior 6-month weight loss 5%, or were smokers had significantly longer survival times than patients in the control arm, thereby demonstrating a survival benefit for NSCLC patients who typically have an unfavorable prognosis. A univariate Cox regression analysis in the ITT population demonstrated that survival differences by baseline prognostic factors were not significant among the treatment groups. A time-dependent multivariate analysis revealed that—regardless of subgroup criteria—bexarotene-treated patients who experienced high-grade triglyceride elevation experienced a survival advantage and a more favorable overall response to treatment. Bexarotene-treated patients with grade 3/4 hypertriglyceridemia also had higher rates of skin rash and hypothyroidism compared with bexarotene-treated patients who did not experience high-grade hypertriglyceridemia. This suggests that other body systems, not just those involved in lipid metabolism, were sensitive to the effects of bexarotene.
Safety and Tolerability
More patients withdrew from the bexarotene arm than from the control arm with each subsequent cycle of therapy (cycle 3, n = 178 and n = 215; cycle 4, n = 148 and n = 184 in the bexarotene and control arms, respectively). The most common reason for early withdrawal was disease progression, which occurred in 79 patients in the bexarotene arm, and 77 patients in the control arm. Overall, 18.8% of patients in the bexarotene arm withdrew due to bexarotene toxicity, the most frequent toxicity being hypertriglyceridemia (10.6%). Hypertriglyceridemia was also the most common cause for dose suspension and dose reduction in bexarotene-treated patients.
This study, unfortunately, joins a long list of recent clinical trials in which the addition of a third experimental agent to standard chemotherapy doublets has not demonstrated a survival benefit (Appendix Table A2, online only). However, this was not due to the study design, the drug dose, or any known heterogeneity in the study population. Notably, retrospective analysis demonstrated a significantly prolonged survival in a large subpopulation that experienced bexarotene-induced, grade 3/4 hypertriglyceridemia. This represents well over one third (  40%) of the bexarotene study population. Overall survival in these patients exceeded 12 months, which has only been observed in one other phase III clinical trial in advanced NSCLC.14 Furthermore, these results support the concept that sensitivity to bexarotene—determined by the degree of induced hypertriglyceridemia—may define the subpopulations of NSCLC patients who are likely to have distinct survival benefit. A similar correlation between bexarotene-induced hypertriglyceridemia and survival has been noted in several other studies, including the SPIRIT I study.7a Retrospective analyses of the two first-line phase I/II studies7,9 that led to the design and enabled the conduct of the SPIRIT studies also revealed either significant or numeric correlations between bexarotene-induced hypertriglyceridemia and improved survival (A. Negro-Vilar, unpublished data, 2006). Recently, a significant correlation between bexarotene-induced hypertriglyceridemia and survival was reported in a phase II bexarotene monotherapy trial in chemotherapy-refractory advanced NSCLC patients.11
This phase III study demonstrates that bexarotene treatment is associated with survival benefit in patients who develop rapid and high-grade hypertriglyceridemia and who are male, have stage IV disease, are smokers, and who have experienced Although the hypertriglyceridemia observed in this study was anticipated,15 the association between triglyceride elevation and prolonged survival in bexarotene-treated patients was not expected. Equally surprising was the observation that bexarotene-treated patients with low-grade triglyceride elevation had a shorter mean survival than patients who did not receive bexarotene; these results warrant further investigation. Several possible explanations could account for these observations. Thus far, a separate analysis to be published elsewhere has not found any pharmacokinetic explanations. Pharmacogenomic effects, as well as any impact of lipid signaling and metabolism pathways on tumor progression, may provide some insight and will be presented in a separate report. In the interim, these results suggest that grade 3/4 hypertriglyceridemia may serve as a biochemical marker for survival advantage of bexarotene treatment in NSCLC, whereas grade 0 to 2 hypertriglyceridemia is indicative of a lack of response or possibly poor prognosis. In control patients in whom triglyceride levels were slightly increased during the study compared with baseline (data not shown), hazard-ratio analysis showed a trend but no statistically significant correlation between increased triglyceride levels and survival in control patients. Whether hypertriglyceridemia is a prognostic factor that identifies patients with a higher probability of survival regardless of bexarotene treatment, or a predictive factor that identifies an important subgroup of patients who should benefit from bexarotene treatment, and whether development of hypertriglyceridemia can be used for patient selection in first-line NSCLC studies remain to be determined. In conclusion, bexarotene did not improve overall survival when added to carboplatin and paclitaxel in first-line treatment of NSCLC in the ITT population. However, a subset analysis indicated that a bexarotene-treated subpopulation of patients with high-grade triglyceride elevation had improved survival. Notably, this subpopulation included patients with typically unfavorable characteristics (stage IV disease, male, smoker, and substantial prior weight loss). Whether hypertriglyceridemia is a predictive biomarker of bexarotene sensitivity leading to potential survival benefit in this population of patients, or just a prognostic factor, warrants further study specifically designed to address this question. Ongoing biomarker analyses from the SPIRIT trials may help identify likely responders and possibly determinants of survival to better select patients for future studies.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors. Employment or Leadership Position: Show-Li Sun, Ligand (C); Jinkun K. Zhang, Ligand (C); Zofia E. Dziewanowska, Ligand (C); Andres Negro-Vilar, Ligand (C) Consultant or Advisory Role: George R. Blumenschein Jr, Ligand (C); Fadlo R. Khuri, Ligand (C); Ulrich Gatzemeier, Eli Lilly & Co (C), AstraZeneca (C), Roche (C); Andres Negro-Vilar, Ligand (C) Stock Ownership: Show-Li Sun, Ligand; Jinkun K. Zhang, Ligand; Andres Negro-Vilar, Ligand Honoraria: Ulrich Gatzemeier, Biogenerix, GlaxoSmithKline, Pierre Fabre Research Funding: George R. Blumenschein Jr, Ligand; Ulrich Gatzemeier, Roche, Alpha Cell Expert Testimony: None Other Remuneration: None
Conception and design: Fadlo R. Khuri, Wilson H. Miller Jr, Zofia E. Dziewanowska, Andres Negro-Vilar Financial support: Zofia E. Dziewanowska Administrative support: Zofia E. Dziewanowska, Andres Negro-Vilar Provision of study materials or patients: George R. Blumenschein Jr, Ulrich Gatzemeier, Wilson H. Miller Jr, Robert M. Jotte, Zofia E. Dziewanowska Collection and assembly of data: Joachim von Pawel, Ulrich Gatzemeier, Jacques Le Treut, Zofia E. Dziewanowska Data analysis and interpretation: George R. Blumenschein Jr, Fadlo R. Khuri, Joachim von Pawel, Ulrich Gatzemeier, Wilson H. Miller Jr, Jinkun K. Zhang, Zofia E. Dziewanowska, Andres Negro-Vilar Manuscript writing: George R. Blumenschein Jr, Zofia E. Dziewanowska, Andres Negro-Vilar Final approval of manuscript: George R. Blumenschein Jr, Ulrich Gatzemeier, Wilson H. Miller Jr, Jacques Le Treut, Show-Li Sun, Zofia E. Dziewanowska, Andres Negro-Vilar
We thank the following principal investigators for participating in this study: David Adkins, Sutter Gould Medical Foundation; Vicente Alberola, Hospital Arnau de Villanova; Rafat Ansari, Michiana Hematology-Oncology; Francis Arena, Arena Oncology Associates; James Arseneau, US Oncology; Sanjay Awasthi, US Oncology; Charles Beall, Morgantown Internal Medicine Group Inc; Henri Berard, Hopital d'Instruction des Armee Saint-Anne; Zale Bernstein, Erie County Medical Center; William Berry, US Oncology; Alberto Bessudo, Medical Group of North County Inc, San Diego Cancer Center; Birbal Bhaskar, Medical Oncology Care Associates; Jacob Bitran, Oncology Specialists, SC, Lutheran General Cancer Care Center, Division of Hematology/Oncology; David Bodkin, Sharp Health Care; Timothy Brotherton, Danville Hematology & Oncology Inc; Jean-Michel Chavaillon, Centre Hospitalier d'Antibes-Juan-Les-Pins; Sant P. Chawla, Ligand; Christos Chouaid, Hopital Saint Antoine; Naveed Chowhan, Cancer Care Center; Billy Clowney, Santee Hematology & Oncology; Paul Conkling, Virginia Oncology Associates; John Costanzi, Lone Star Oncology Consultants PA; Stephane Culine, Centre Regional de Lutte contre le Cancer (CRLC), Val d'Aurelle-Paul Lamarque; Stephen Davidson, Montgomery Cancer Center LLC; Eknath Deo, Coast Hematology-Oncology Associates; Christopher Desch, Virginia Cancer Institute; Christian Dittrich, Kaiser-Franz-Josef-Spital; Anibal Drelichman, Providence Cancer Institute; Josef Eckmayr, Allgemeines offentliches Krankenhaus der barmherzigen Schwestern vom Heiligen Kreuz Pneumologie; Peter Eisenberg, California Cancer Care Inc; Lionel Falchero, Centre Hospitalieri; John Feigert, Arlington Fairfax Hematology Oncology C.; Robert Figlin, University of California, Los Angeles Medical Center; Patrick Flynn, US Oncology; Pierre Fournel, CHU - Hopital Nord; Nashat Gabrail, Ligand; Antonio Galann Brotons, Hospital de Sagunto; Lawrence Garbo, US Oncology; George Geils, Charleston Hematology Oncology PA; Russell Gollard, Cancer & Blood Specialists of Nevada; M. Gonzalez, Liberty Hematology/Oncology; Gary Gordon, Northwest Oncology & Hematology, SC; Richard Grapski, Thompson Cancer Survival Center; Volker Gressler, Hope Oncology; Manuel Guerra, Oncology and Radiology Associates, PA; Manish Gupta, US Oncology; Jayne Gurtler, Ligand; Troy Guthrie Jr, University of Florida/Jacksonville; Stephane Hominal, Centre Hospitalier General de la Region Annecienne; Jack Hong, Chesapeake Oncology Hematology Associates; William Hrushesky, WJB Dorn VA Medical Center, Research Service; Rudolf Huber, Ludwig-Maximillian-Universitat; John Hunter, US Oncology; Amelia Insa Molla, Hospital Clinico Universitario de Valencia; Thierry Jahan, UCSF Mount Zion Comprehensive Cancer Center; Haresh Jhangiani, Compassionate Cancer Care Medical Group Inc; Glen Justice, Pacific Coast Hematology/Oncology Medical Group Inc; Gregory Kalemkerian, University of Michigan Medical Center; Nirmala Kania, Orange Medical Group; Dinesh Kapur, Eastern Connecticut Hematology & Oncology Associates; Basil Kasimis, VA New Jersey Health Care System; Peter Kennedy, Metropolitan Hematology/Oncology Medical Group Inc; Roger Keresztes, New York Presbyterian Hospital, Weill Medical College of Cornell University; Pankaj Khandelwal, US Oncology; Ron Kirschling, St Luke's Hosptial, Oncology/Hematology Specialty Clinic; Jean Kleisbauer, CHU Hopital St Marguerite; J. Kuebler, Columbus Community Clinical Oncology Program; John Kugler, Oncology Hematology Associates of Central Illinois PC; David Loesch, US Oncology; Shakun Malik, Lombardi Cancer Center, Georgetown University Medical Center; Thomas Marsland, Integrated Community Oncology Network; Yves Martinet, Service de Pneumology, Hopital Adulte de Brabois; Ostap Melnyk, Bay Area Cancer Research Group LLC; Luis Meza, Southwest Oncology Associates; Manuel Modiano, ACRC/Arizona Clinical Research Center Inc; Isabelle Monnet, DOP International; Joaquim Montalar Salcedo, Hospital Universitario La Fe; Joseph Muscato, US Oncology; M. Nagy, Nevada Cancer Center; James Neidhart, San Juan Oncology Associates; Marcus Neubauer, US Oncology; Ira Oliff/Peterson, Midwest Cancer Research Group Inc; Mark Olsen, US Oncology; Richard Orlowski, Northwestern Carolina Oncology and Hematology PA; David Perry, Washington Hospital Center, Washington Cancer Institute; Jonathan Polikoff, Southern California Permanente Medical Group; Haralambos Raftopoulos, Columbia Presbyterian Medical Center, The Herbert Irving Pavilion; Vijay Raghavan, Carroll, Sheth, and Robert Raju, US Oncology; Nithya Ramnath, Roswell Park Cancer Institute; Mark Rarick, Oncology/Hematology, Kaiser Permanente, Northwest; Joseph Readling, Broom City Oncology; Donald Richards, US Oncology; James Rigas, Dartmouth-Hitchcock Medical Center; Gerald Robbins, Florida Cancer Institute; Robert Ruxer, US Oncology; Michael Savin, US Oncology; Fred Schreiber, Watson Clinic LLP; Paul Schwarzenberger, Clinical Oncology Research Associates LLC; Stephen Shlaer, Medical Oncology Associates of Augusta; George Sotos, Associates in Oncology/Hematology PC; Armin Steinmetz, Department of Internal Medicine, St. Nikolaus-Stiftshospital Andernach, Teaching Hospital University of Bonn; Muhammad Tai, US Oncology; John Thachil, US Oncology; Pascal Thomas, Centre Hospitalier General; Alain Vergnenegre, Hopital du Cluzeau; Norbert Vetter, Sozialmedizinisches Zentrum Baumgartner Hohe; William Von Stubbe, Internal Medicine Associates of Yakima Inc; P.L. Walde, Algoma Regional Cancer Program, Sault Area Hospital; Theodore Walters, St. Luke's/Mountain State Tumor Institute; David Watkins, US Oncology; Jonathan Wilson, Humber River Regional Hospital; Christian Witt, Charite Universitatsklinikum der Humboldt-Universitat zu Berlin, Campus Charite Mitte, Medizinische Kliniken; Israel Wiznitzer, Comprehensive Cancer Care Specialists of Boca Raton; Albert Wood, Cancer Specialists of South Texas; Hen-Vai Wu, Somerset Hematology-Oncology Associates; Furhan Yunus, University of Tennessee Cancer Institute; Harvey Zimbler, Berkshire Hematology Oncology.
Presented in part at the 41st Annual Meeting of the American Society of Clinical Oncology, May 13-17, 2005, Orlando, FL; and the 11th World Conference on Lung Cancer, July 3-6, 2005, Barcelona, Spain. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
