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Originally published as JCO Early Release 10.1200/JCO.2003.06.099 on July 1 2003 © 2003 American Society for Clinical Oncology Gemcitabine Plus Vinorelbine Compared With Cisplatin Plus Vinorelbine or Cisplatin Plus Gemcitabine for Advanced Non–Small-Cell Lung Cancer: A Phase III Trial of the Italian GEMVIN Investigators and the National Cancer Institute of Canada Clinical Trials Group
From the GEMVIN Investigators, Naples, Italy; and the National Cancer Institute of Canada Clinical Trials Group, Kingston, Canada. Address reprint requests to Cesare Gridelli, Clinical Trials Unit, National Cancer Institute, Via M Semmola; 80131 Naples, Italy; email: cgridelli{at}libero.it.
Purpose: Platinum-containing chemotherapy regimens are the standard treatment for patients with advanced non–small-cell lung cancer (NSCLC), although toxicity is common and may significantly affect the patient’s quality of life (QoL). This trial aimed to assess whether a combination of gemcitabine and vinorelbine had benefits in terms of QoL, without influencing negatively on survival, compared with cisplatin-containing regimens. Patients and Methods: Patients with stage IIIB (effusion and supraclavicular nodes) or IV documented NSCLC who were younger than 70 years of age were randomly assigned gemcitabine plus vinorelbine (GemVin) or either gemcitabine plus cisplatin or vinorelbine plus cisplatin (cisplatin-based). European Organization for Research and Treatment of Cancer scales were used for QoL analysis. Results: Five hundred one patients were randomly assigned to treatment. The median age was 62 years. There were no significant differences in global QoL scores between the two arms after 2 months of treatment. However, worsening scores for appetite, vomiting, and alopecia were significantly more common in the cisplatin-based arm. Median survival was 38 v 32 weeks and median progression-free survival was 23 v 17 weeks in the cisplatin-based versus GemVin arms, respectively. For the GemVin arm the hazard ratio for death was 1.15 (90% confidence interval [CI], 0.96 to 1.37) and the hazard ratio for progression was 1.29 (90% CI, 1.10 to 1.52). Grade 3 or 4 myelosuppression, vomiting, alopecia, and ototoxicity were significantly more frequent with cisplatin-based treatment. Conclusion: Global QoL is not improved with GemVin, although advantages in some components of QoL were apparent. GemVin is less toxic than standard cisplatin-based chemotherapy. There is a nonsignificant slight survival advantage with cisplatin-based chemotherapy. GemVin could be offered to advanced NSCLC patients who express concern about toxicity.
EPIDEMIOLOGIC ESTIMATES for the year 2000 showed that lung cancer was the most common cancer in the world, both in terms of incidence (with 1.2 million new cases corresponding to 12.3% of the world total) and mortality (with 1.2 million deaths corresponding to 17.8% of the total).1 Although incidence and death rates have stabilized and are slowly decreasing, especially among males, it is expected that lung cancer will continue to be a health issue of critical importance for decades to come. Older platinum-based (Pt-based) combination therapies prolong survival modestly compared with best supportive care in patients affected by advanced non–small-cell lung cancer (NSCLC).2 Recently, several new chemotherapeutic agents (paclitaxel, gemcitabine, docetaxel, vinorelbine, and irinotecan) have shown good single-agent activity. In randomized phase III trials, these agents in combination with a platinum compound have been associated with improved quality of life (QoL) and improved survival of 8 to 10 months.3 Recent randomized studies indicate that there are no significant differences in efficacy among several combinations of cisplatin with the new drugs, although they have shown varying profiles of toxicity.4,5 Cisplatin is associated with more toxicity than other drugs used to treat NSCLC. In addition to nausea and vomiting, which can be partially controlled with antiemetic therapy, cisplatin causes cumulative neuropathy as well as profound fatigue, ototoxicity, and renal toxicity. Some patients are unable to tolerate the drug and thus tend to terminate treatment early. The combination of GemVin showed additive effects when it was tested in experimental models.6 This nonplatinum regimen, when tested in several phase II clinical trials,7–16 showed good tolerability and sufficient clinical activity to justify phase III testing. In a randomized phase II study testing three different dose levels of the combination, the schedule with gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2, administered on days 1 and 8 every 3 weeks, resulted in similar activity and better tolerability than two schedules with higher doses of either gemcitabine (1,200 mg/m2) or vinorelbine (30 mg/m2). Furthermore, the schedule with both drugs at the higher dose levels proved to be unfeasible because of neutropenia.7 Overall, in 126 advanced NSCLC patients younger than 70 years of age, the combination produced a response rate of 26% and a median survival of 33 weeks.7 The goals of antineoplastic chemotherapy in patients with advanced NSCLC are palliation of symptoms, improvement in QoL, and prolongation of survival. Because treatment is not curative, the toxicity and QoL associated with different chemotherapy regimens should be critical for decision making for both physicians and patients. However, most studies thus far have reported survival as the primary end point, and QoL, when reported at all, has been a secondary end point even though it may serve as an important indicator both of the palliative benefit of a chemotherapeutic regimen and of the impact of different toxicity profiles. We designed this study to examine differences in the global QoL between a platinum- and a non–platinum-containing combination regimen as the primary end point. Our hypothesis was that patients receiving the noncisplatin regimen would experience similar efficacy (survival) with improved toxicity and QoL scores. The nonplatinum regimen (GemVin) and doses of drugs were selected on the basis of the results of the above-reported randomized phase II study.7 For the control arm, two combinations were selected (cisplatin plus vinorelbine [PV] and cisplatin plus gemcitabine [PG]) because these were the most frequently adopted combinations in clinical practice in Italy at the time the study was planned. Doses were consistent with clinical practice, and the dose-intensity of each drug was approximately equal to that in the regimens in common use in both Italy and Canada. In addition, the cycle length (3 weeks) with chemotherapy administration scheduled on days 1 and 8 was the same as in the experimental arm, which avoids possible biases in comparison. Random assignment of patients to one of the two treatments in the control arm produced a balanced rate of patients receiving vinorelbine or gemcitabine in that arm, thus reducing biases that might have arisen if there had been a difference in efficacy between gemcitabine and vinorelbine. We did not expect a difference, however, because phase II data indicated that these two combinations were likely to be equivalent even though direct comparisons between PG versus PV did not exist at the time.4,5
Patients were eligible if they had histologic or cytologic proof of NSCLC and were younger than 70 years of age. Patients had to have stage IV disease or stage IIIB disease with malignant pleural effusion or supraclavicular nodes. They could not have received any prior chemotherapy, but could have received prior radiation. Patients had to have an Eastern Cooperative Oncology Group performance status of 0, 1, or 2; adequate hematology (absolute neutrophil count  2000/µL, platelets 100,000/µL, and hemoglobin 10 g/dL) and biochemistry (serum creatinine  1.25 x upper normal limit, AST and ALT and bilirubin 1.25 x upper normal limit, unless as a result of liver metastases); and be willing and able to complete QoL questionnaires. Patients were ineligible if they had brain metastases or a history of prior invasive malignancy. The study was approved by ethical committees at participating institutions and all patients provided written informed consent.
Assessments
Treatment
QoL
Statistical Considerations Design. The primary end point of the study was QoL. Global health status scale (items 29 and 30) of EORTC QLQ-C30 at the end of the second cycle was used to estimate the planned sample size. Secondary end points included survival, progression-free survival, toxicity, and objective response. The study was targeted to have a power of 90% to recognize an effect of 35% (ie, a difference between mean scores of global health status equal to 35% of the standard deviation) at the end of the second cycle of chemotherapy; this difference, although quite small, is consistent with a conservative approach considering that effect sizes of 50% or more have been correlated with conditions of "moderate" or "very much" positive changes in a subjective satisfaction questionnaire.19 With a two-sided significance level of .05, we needed a total of 350 patients to be available for QoL evaluation (nQuery Advisor 4.0, Statistical Solutions Ltd, Cork, Ireland). Assuming a 20% drop-out rate, 420 patients were planned to be randomly assigned to treatment; in fact, because of a higher missing data rate, about 500 patients were eventually needed. An interim analysis for survival was planned when 50% of the planned study accrual had occurred and these patients had been observed for 4 months. According to the Pocock sequential group design,20 the study would have been closed if the difference in survival had been significant at the one-sided .029 level. Accordingly, the second (and final) survival analysis had a similar one-sided .029 significance level. With the planned sample size and 336 deaths, the study had 80% power to recognize a 9-week shortening of median survival for GemVin compared with Pt-based regimens (expected median survival of 36 weeks), using an overall one-sided .05 significance level and the Pocock’s group sequential design (East Software 2.0, 1992; Cytel Software Corp, Cambridge, MA). Analysis. QoL data were analyzed according to the Guidelines of the Quality of Life Committee of National Cancer Institute of Canada Cancer Treatment Group.21 The pattern of missing data was analyzed under different frames: rate of patients completing baseline assessments and the assessments at designated time points over the total number of patients eligible and entered onto the trial, rate of patients completing assessments at designated time points while enrolled onto the study over the total number completing assessment at baseline, and rate of patients completing assessments at designated time points over the number of patients still enrolled onto the study that were expected to complete questionnaires at each of those time points.
Comparison of scores of global health status at the end of the second cycle of chemotherapy was the primary end point of the study; scores were compared by Wilcoxon rank sum test. Change scores (ie, differences from baseline) were calculated at each time point for each domain or symptom and within each arm. The best response from baseline was calculated for each domain or symptom as follows. A change score of at least 10 points from baseline was defined as clinically relevant.19 For each domain patients were considered improved if they reported a score Overall survival was defined as the interval from date of random assignment to treatment and date of death or last follow-up information for living patients. Time to progression was defined as the interval from date of random assignment to treatment and date of progression or death, whichever occurred first, or last follow-up information for living patients and patients whose disease did not progress. Time-to-event curves were estimated by the Kaplan-Meier product limit method24 and compared by the Mantel-Haenszel test.25 The Cox proportional hazards model26 was used to assess the effect of treatment after adjustment by other prognostic variables. World Health Organization criteria27 were used to classify response and toxicity.
Objective responses were evaluated at the end of the third and sixth cycles of treatment by repeating staging procedures. The best response was recorded for each patient. For clinically evident or suspected progression of the disease, response evaluation was anticipated. Confirmation of response after 1 month was not performed. Patients who died before completion of restaging procedures were defined as having progressed on the date of death. Patients who stopped treatment because of toxicity or refusal before restaging were defined as nonresponders in the calculation of response rate. The objective response rate was defined as the proportion of complete and partial responses compared with the total number of patients. The difference of objective responses between arms was assessed by The worst degree of toxicity experienced throughout the treatment was computed for each patient. Two tests were performed for each type of toxicity: patterns of toxicity (five levels) between the two study arms were compared by an exact linear rank test and rates of severe toxicity (grades 3 to 4 v grades 0 to 2) were compared by Fisher’s exact test (StatXact Turbo).
Patient Characteristics A study flow diagram is reported in Figure 1  . The study opened in Italian centers in October 1998, and in Canadian centers in May 1999. Of 526 registered patients, 503 patients were randomly assigned to treatment in the study between October 1998 and March 2001. Accrual from Canadian centers accounted for 18% of accrual. Two patients participating in other studies were randomly assigned in error to this trial, had not consented to it, and did not receive trial therapy. These two patients were not included in the analyses because of the absence of consent. A total of 18 patients were considered ineligible because of wrong disease stage (n = 5), prior chemotherapy (n = 4), age greater than 70 years (n = 2), histology other than NSCLC (n = 2), brain metastases (n = 2), comorbidity (n = 1), prior malignancy (n = 1), and withdrawal of consent (n = 1). The baseline characteristics for the 501 patients are shown in Table 1 and were well balanced between arms. The median age was 62 years, 80% of patients were male, Eastern Cooperative Oncology Group performance status was 0 to 1 in 87% of patients, and 80% of patients had stage IV disease. In the Pt-based group, 125 patients were assigned to receive PG and 125 patients were assigned to receive PV.
Chemotherapy Among patients assigned Pt-based chemotherapy, eight did not receive the assigned treatment (four were lost to follow-up immediately, three refused any chemotherapy after random assignment to treatment, and one had clinical progression of brain metastases before starting chemotherapy). Among patients assigned GemVin, six did not receive the assigned treatment (one received PG, four were lost to follow-up immediately, and one refused any chemotherapy after random assignment to treatment). A mean number of 3.8 and 3.9 cycles were administered in the Pt-based and the GemVin arms, respectively. In the two arms, 36% and 37.5%, respectively, of patients received all of the planned six cycles. Median time of treatment in the two arms was 85 and 83 days, respectively. Chemotherapy was omitted on day 8 in 118 of 953 (12.4%) cycles with Pt-based chemotherapy and in 97 of 991 (9.8%) cycles with GemVin. Reasons for stopping treatment were different between the two arms (P = .0001); treatment was stopped before the sixth cycle because of disease-related causes (progression or death) in 31.6% and 43.8% of the patients, and because of toxicity or refusal in 30.8% and 15.5% of the patients in the Pt-based and the GemVin arms, respectively. Second-line chemotherapy was given to 118 patients (23.6%) with no apparent difference between the two arms (22.8% and 24.3% in the Pt-based and the GemVin arms, respectively). In the Pt-based arm, gemcitabine or vinorelbine was given as second-line therapy in 22 patients, docetaxel was given in 18 patients, paclitaxel was given in five patients, carboplatin was given in five patients, and other drugs were given in eight patients. In the GemVin arm, cisplatin (alone or in combination with other drugs) was given in 16 patients, carboplatin was given in 15 patients, docetaxel was given in 18 patients, paclitaxel was given in one patient, gemcitabine or vinorelbine was given again in seven patients, and other drugs were given in four patients.
QoL There were no differences in any of the compliance parameters between the two study arms. The rate of completed questionnaires, out of those expected (ie, on-treatment patients), declined slightly to 84% (172 of 205), 75% (148 of 197), 85% (140 of 165), and 80% (111 of 139) in the Pt-based arm and to 82% (163 of 199), 81% (157 of 194), 74% (129 of 174), and 74% (110 of 149) in the GemVin arm at assessments made at weeks 1, 3, 6, and 9, respectively.
Baseline mean scores were comparable between the two arms for all of the QoL items (Table 2
Marginal changes from baseline of QoL domains over time are depicted in Figures 2 through 4. As shown in Figure 2, role and emotional functioning had higher (better) scores with GemVin; at week 1 (corresponding to day 8 of cycle 1), mean changes were always worse in the Pt-based arm. Among symptoms evaluated by the QLQ-C30 and QLQ-LC-13 (Fig 3 and 4; positive changes indicate worsening), loss of appetite, fatigue, vomiting, and hair loss—all of which were anticipated side effects of chemotherapy—were worse in the Pt-based arm, across all of the periods, particularly at week 1 for the former three symptoms. In contrast, slight advantages in cough, shoulder pain, and analgesic consumption were seen among patients receiving Pt-based treatment.
Details of the best response for the different QoL items in the two arms are presented in Table 2  . Overall, in both arms, almost 40% of patients exhibited an improved global QoL and one fourth of patients remained stable. After adjustment for possible confounding variables, significant differences were seen only for appetite, vomiting, and hair loss (all symptoms were worse in the Pt-based arm). Some differences, which were not significant, were observed for dyspnea and cough (higher rates of worsening patients with GemVin).
Survival, Progression-Free Survival, and Tumor Response
Toxicity All patients who received at least one dose of chemotherapy were included in the safety analyses (n = 487). Toxicity is summarized in Table 4 . Patients who received Pt-based therapy had more myelosuppression (anemia, neutropenia, and thrombocytopenia), vomiting, renal toxicity, hair loss, ototoxicity, and fatigue, whereas patients treated with GemVin had more hepatic toxicity. For severe (grade 3 or 4) toxicity, leukopenia, neutropenia, vomiting, hair loss, and ototoxicity were significantly more frequent in the Pt-based arm. There were 18 grade 3 or 4 events while patients received treatment without evidence of progression; 11 events occurred in the Pt-based arm and seven events occurred in the GemVin arm (P = .31). Causes of death with Pt-based treatment were cardiac (five patients), stroke, diabetic coma, acute renal failure, infection, bleeding, and disseminated intravascular coagulation (one patient each); with GemVin treatment, causes were cardiac (four patients), pneumonitis, colitis, and stroke (one patient each). RBC transfusions were given to 27 (11%) and 19 (8%) patients in the Pt-based and GemVin arms, respectively (P = .19); platelet transfusions were required in four patients (2%) and one (< 1%) patient, respectively (P = .17).
Treatment with palliative chemotherapy for patients with advanced NSCLC has become standard practice internationally on the basis of the evidence of a small prolongation of survival as compared with supportive care2 and, more recently, on the evidence of positive effects on patients’ QoL and symptoms.28,29 Furthermore, economic evaluations have shown that the cost of chemotherapy falls within an acceptable range for year of life gained.30 Although at least three generations of chemotherapy regimens can be defined, cisplatin is still considered a key drug and no major differences can be identified among different combinations of platinum with other new drugs.4,5 Two trials have shown that three or four cycles of treatment are not less effective than longer treatments with six or eight cycles.31,32 However, the impact of chemotherapy on survival compared with supportive care is limited, and is less than 2 months.2,33 Such modest improvements in survival were considered inadequate by the majority of a group of patients who had received chemotherapy with cisplatin for NSCLC, and who were interviewed about their attitudes about chemotherapy.34 The median threshold in survival gain over supportive care for accepting chemotherapy was 9 months with highly toxic chemotherapy, and 4.5 months with less toxic regimens; these values seem higher than reasonable expectations with currently available chemotherapy regimens. On these grounds, protection of QoL, through reduction of toxicity, becomes an important goal of clinical research in advanced NSCLC, until newer and more innovative therapeutic or diagnostic strategies improve the unfavorable prognosis of this disease. In this study with advanced NSCLC patients, we show that a non–cisplatin-containing regimen, GemVin, compared with commonly used cisplatin combinations (PV and PG) does not improve global QoL, but does produce advantages in some of its components. The non–cisplatin-containing treatment is significantly less toxic as compared with standard cisplatin-based chemotherapy, according to both physicians’ evaluation of toxicity and patients’ assessments of QoL items that explore toxicity-related domains. This finding should be interpreted with the knowledge that physicians were not blinded and that analysis of QoL could be affected by multiple comparisons problems. In contrast, however, the cisplatin-containing regimens produce longer time to progression (6 weeks advantage at median and 4% absolute improvement at 1 year). In addition, there is a statistically not significant survival advantage for patients receiving cisplatin, measurable as a prolongation of 6 weeks in median survival and an absolute improvement of 6% at 1 year. Although the extent of this advantage is below the threshold that was considered as clinically relevant when the study was planned (ie, 9 weeks in median survival), it should be noted that survival differences of this magnitude, or even less, have been statistically significant in other trials and have led to changes in treatment strategies in various parts of the world.35,36 Another trial has been published recently comparing cisplatin- to non–cisplatin-based chemotherapy.37 In that study of 441 patients, there was no difference between the response rates produced by cisplatin and docetaxel compared with those produced by gemcitabine and docetaxel combinations (35% v 33%). As a secondary end point, there was also no difference in survival (median, 10 v 9.5 months; 42% v 39% at 1 year). Severe neutropenia, vomiting, and diarrhea were more frequent with cisplatin and docetaxel; QoL was not assessed. Some aspects of trial planning, unfortunately, make the results of this study difficult to interpret with respect to its statistical aspects (see correspondence relating to37), and the lack of a QoL assessment does not allow interpretation of this crucial matter. Preliminary results of the EORTC trial 0897538 indicate that survival time is shorter with a paclitaxel plus gemcitabine combination as compared with more standard PG and cisplatin plus paclitaxel combinations (median survivals, 6.9, 8.8, and 8.1 months, respectively). In contrast, in a study conducted by a Spanish cooperative group39 median survivals were similar in the standard arm (PG) and in an experimental arm including sequential doublets of GemVin and ifosfamide plus vinorelbine; in the latter arm, only response rate (24%) was lower compared with the standard arm (41%). A retrospective analysis of a large European study comparing a standard doublet (cisplatin and vindesine) versus an innovative doublet (PV) versus a single-agent treatment with vinorelbine recently indicated that cisplatin-based treatments are not more effective than single-agent vinorelbine in patients with poor performance status.40 However, these data come from a subgroup retrospective analysis and thus should be taken into consideration only to plan future prospective trials. In addition, contrasting evidence has been produced by Socinski et al,32 who found that prolonged (up to eight cycles) carboplatin and paclitaxel treatment was more effective than shorter (four cycles) treatment only in patients with poor performance status. A definitive agreement on whether cisplatin can be removed from its role as a key drug in the palliative treatment of advanced NSCLC cannot be reached until additional trials are published and, possibly, data are pooled to increase the statistical power of survival comparisons. Our data show that a combination of gemcitabine and vinorelbine is similar to standard cisplatin-based regimens with respect to palliation as assessed by response rate and QoL, and is less toxic, producing statistically significant advantages in several QoL indices that are mostly affected by treatment toxicity (vomiting, appetite, and hair loss). It should be emphasized, however, that primary analysis of this trial is based on a 2-month observation period; this could be a limitation, although we believe that any analysis beyond this time would be affected by a relevant selection bias because of the short life expectancy of advanced NSCLC patients. We also observed disadvantages in progression-free survival and overall survival (the latter were not statistically significant) that do not affect QoL during the first 2 months of treatment. Decisions regarding chemotherapy implementation in advanced NSCLC require consideration of risk-benefit ratios (including QoL, anticipated toxicity, and realistic efficacy benefits). Physicians and patients are known to have different perceptions of the relative value of chemotherapy41 and appropriate discussion between patient and physician of any treatment plan is essential. In clinical practice, physicians and patients might consider gemcitabine plus vinorelbine as a therapeutic option when there are concerns regarding the anticipated toxicity of chemotherapy after careful consideration of available data.
The following coauthors and institutions participated in this study. Italy: C. Gridelli, A. Rossi, P. Maione, E. Barletta, R.V. Iaffaioli, Oncologia Medica B, National Cancer Institute; A. Illiano, M. Esposito, C. Battiloro, G. Tufano, UOS Chemioterapia, DH pneumoncologico, VI divisione Ospedale Monaldi; A. Lamberti, F. Piantedosi, L. Brancaccio, V. Pontillo, V Divisione Oncologia Pneumologica, Ospedale Monaldi; S. Cigolari, V. Angelini, III Cattedra di Medicina Interna, Università Federico II; N. Normanno, Experimental Oncology, National Cancer Institute; C. Gallo, G. Signoriello, Medical Statistics, Second University; F. Perrone, M. Di Maio, E. De Maio, Clinical Trials Unit, National Cancer Institute, Napoli; S.F. Robbiati, DH Oncologico, Ospedale Civile, Rovereto (TN); L. Manzione, D. Bilancia, D. Germano, Oncologia Medica, Azienda Ospedaliera S. Carlo, Potenza; S. Barbera, F. Renda, II Pneumologia, Ospedale Marianosanto, Cosenza; L. Frontini, M. Cabiddu, S. Zonato, Ospedale S. Paolo; E. Piazza, V. Filipazzi, Oncologia Medica, Ospedale L. Sacco, Polo Universitario; P. Foa, Oncologia Medica, Policlinico Maggiore, Milano; M. D’Aprile, E. Veltri, G. Pistillucci, Oncologia Medica, Ospedale S. Maria Goretti, Latina; G.P. Ianniello, V. Tinessa, Oncologia Medica, Azienda Ospedaliera G. Rummo, Benevento; G. Gasparini, A. Morabito, D. Gattuso, Oncologia Medica, Azienda Ospedaliera Bianchi Melacrino Morelli, Reggio Calabria; S. Fava, A. Calcagno, E. Grimi, Oncologia Medica, Ospedale Civile, Legnano (MI); F. Pari, E. Aitini, Oncologia ed Ematologia, Azienda Ospedaliera C. Poma, Mantova; G. Michetti, M. Oribelometti, Pneumologia, Ospedali Riuniti, Bergamo; S. Romito, F. Carrozza, Oncologia Medica, Ospedale Cardarelli, Campobasso; G. Porcile, F. Castiglione, Oncologia Medica, Ospedale San Lazzaro, Alba (CN); G. Filippelli, L. Dodaro, Oncologia Medica, Ospedale S. Francesco di Paola, Paola (CS); S. Barni, M. Cazzaniga, Oncologia Medica, Azienda Ospedaliera Treviglio–Caravaggio, Treviglio (BG); V. Gebbia, N. Borsellino, Dipartimento Oncologico, La Maddalena SpA; M. Spatafora, Pneumologia, Università di Palermo, Azienda Ospedaliera V. Cervello, Palermo; N. Rossi, DH Oncologia, Ospedale Civile, Polla (SA); L. Isa, Oncologia Medica, Ospedale Serbelloni, Gorgonzola (MI); G. Colantuoni, Oncologia Medica, Azienda Sanitaria S. Giuseppe Moscati, Avellino; A. Aschelter, Oncologia Medica Complementare, Istituto Regina Elena, Roma; Mauceri G., Oncologia Medica, Centro Catanese di Oncologia, Catania; G.M. Corradini, Oncologia Medica, Azienda Ospedaliera G. Salvini, Rho (MI); P. Tralongo, Oncologia Medica Ospedale G. Di Maria, Avola (SR); G. Sita, Oncoematologia (Medicina I), Ospedale Maggiore, Lodi; B. Rho, Pneumologia, Ospedale S. Corona, Azienda Ospedaliera S. Giuseppe Salvini, Garbagnate (MI); G. Nettis, Oncologia (Medicina Interna) Ospedale Regionale Miulli, Acquaviva delle Fonti (BA); C. Pizza, Oncologia Medica, Ospedale Civile, Nola (NA); S. Quattrin, Oncologia Medica, Ospedale Civile S. Maria delle Grazie, Pozzuoli (NA). Oncologia Medica, CRO Regione Basilicata, Ospedale Giustino Fortunato, Rionero in Vulture (PZ); Oncologia Medica, Ospedale S. Gennaro; Istituto di Tisiologia e Malattie Apparato Respiratorio, Seconda Università, Ospedale Monaldi; Oncologia Medica C, National Cancer Institute, Napoli; Oncologia, Azienda Ospedaliera, Ospedali Civili Riuniti, Sciacca (AG); Oncologia Medica, Università, Sassari; Oncologia Medica, Ospedale Mariano Santo, Cosenza; Oncologia Medica, Ospedale S. Andrea, Vercelli; Oncologia Medica, Ospedale, Casalpusterlengo (LO); Servizio di Oncologia, Ospedale Agnelli, Pinerolo (TO); Oncologia Medica e Sperimentale, Istituto Oncologico, Bari; Oncologia Medica, Casa della Divina Provvidenza, Ospedale Cottolengo, Torino; Oncologia Medica, Ospedale S. Bortolo, ULSS 6, Vicenza; Oncologia (Medicina interna), Ospedale Civile, Ariano Irpino (AV); Oncologia, Policlinico Giaccone, Palermo; Pneumologia, Ospedale San Martino, Genova; Medicina, Ospedale Civile, Lagonegro (PZ); Oncologia Medica, Casa di Cura Igea, Milano. Canada: F. Shepherd, R. Feld, Princess Margaret Hospital; R.L. Burkes, Mount Sinai Hospital; Y.H. Rahim, East General Hospital; N. Iscoe, Sunnybrook Regional Cancer Centre; J. Wilson, Humber River Regional Hospital, Toronto; B. Findlay, J. Giesbrecht, P. Hughes, Hotel Dieu Hospital, St Catharines; R. Myers, B. Higgins, S. Fine, Credit Valley Hospital, Mississauga; R. Wierzbicki, Lakeridge Health Oshawa, Durham Regional Cancer Centre, Oshawa; L. Seymour, D. Tu, B. Graham, K. Laing, Dr H. Bliss Murphy Cancer Centre, St. John’s; I. Yaqoob, M. Salim, M. Hussain, Allan Blair Cancer Centre, Regina, SK; V. Hirsh, Department of Oncology, McGill University, Montreal; A. Blais, Centre Hospitalier Regional, Rimouski, PQ; M. Burnell, Atlantic Health Sciences Corp, Saint John Regional Hospital, NB. Hamilton Regional Cancer Centre, Hamilton; Northwestern ON Regional Cancer Centre, Thunder Bay; Windsor Regional Cancer Centre, Windsor; St Joseph Health Centre, Toronto, ON; CancerCare Manitoba (including St Boniface Hospital), Winnipeg, MB; Queen Elizabeth Hospital, Chalottetown, PE; and CUSE–Site Fleurimont, Sherbrooke, PQ.
We thank the Gruppo Oncologico Italia Meridionale (GOIM) for actively participating in the study; and Federika Crudele, Giuliana Canzanella, Fiorella Romano, and Assunta Caiazzo for data management and secretarial services.
Partially supported by Clinical Trials Promoting Group (CTPG), Naples, Italy. The National Cancer Institute of Canada Clinical Trials Group received a grant from Eli Lilly Canada. The coordinating center (Clinical Trials Unit of the National Cancer Institute of Naples) is supported by Associazione Italiana per la Ricerca sul Cancro (AIRC). Cesare Gridelli is member of the speaker’s bureau for Eli-Lilly (Florence, Italy), Pierre-Fabre (Cedex, France), GlaxoSmithKline (Research Triangle Park, NC, USA); Ciro Gallo received honoraria from Glaxo-Smith Kline (Verona, Italy); Frances Shepherd received research funding and honoraria from Eli-Lilly (Scarborough, Ontario, Canada); Francesco Perrone received honoraria from Glaxo-Smith Kline (Verona, Italy).
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test. 
