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© 2003 American Society for Clinical Oncology Cisplatin Plus Gemcitabine Versus a Cisplatin-Based Triplet Versus Nonplatinum Sequential Doublets in Advanced Non–Small-Cell Lung Cancer: A Spanish Lung Cancer Group Phase III Randomized Trial
From the Division of Medical Oncology, Arnau de Vilanova Hospital; Division of Medical Oncology, General University Hospital, Valencia; Division of Medical Oncology, Puerta de Hierro Hospital; Division of Medical Oncology, La Princesa Hospital; Division of Medical Oncology, San Carlos University Hospital; Preventive Medicine Department, Autonomous University, Madrid; Division of Medical Oncology, University Hospital, Zaragoza; Division of Medical Oncology, Germans Trias i Pujol Hospital, Badalona; Division of Medical Oncology, Mar Hospital; Division of Medical Oncology, Durán i Reynals Hospital; Division of Medical Oncology, Valle de Hebrón Hospital, Barcelona; Division of Medical Oncology, San Juan Hospital, Reus; Division of Medical Oncology, Arquitecto Marcide Hospital, El Ferrol; Division of Medical Oncology, León Hospital, León; Division of Medical Oncology, Miguel Servet Hospital, Zaragoza; Division of Medical Oncology, Elche University Hospital, Alicante; Division of Medical Oncology, Arnau de Vilanova Hospital, Lérida; Division of Medical Oncology, Provincial Hospital, Castellón; and Division of Medical Oncology, Cruces Hospital, Bilbao, Spain. Address reprint requests to Vicente Alberola Candel, MD, Hospital Arnau de Vilanova, San Clemente 12, 46015 Valencia, Spain; email: alberola_vicara{at}gva.es or Rafael Rosell, MD, Institut Catala d’Oncologia, Hospital Germans Trias i Pujol, Ctra Canyet, Sln, 08916 Budalona, Barcelona, Spain; e-mail: rrosell{at}ns.hugtip.scs.es.
Purpose: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non–small-cell lung cancer (NSCLC). Patients and Methods: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m2 day 1 plus gemcitabine 1,250 mg/m2 days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m2 day 1 plus gemcitabine 1,000 mg/m2 and vinorelbine 25 mg/m2 days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m2 plus vinorelbine 30 mg/m2 days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m2 days 1 and 8 plus ifosfamide 3 g/m2 day 1, every 3 weeks for three cycles (GV–VI). Results: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV–VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV–VI, 27%; CG v GV–VI, P = .003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV–VI, 27%; P < .05); neutropenic fever (CG, 4%; CGV, 19%; GV–VI, 5%; P < .0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV–VI, 3%; P = .0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV–VI, 6%; P < .0001). Conclusion: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.
NON–SMALL-CELL LUNG cancer (NSCLC) is moderately sensitive to currently available cytotoxic drugs. Patients treated with cisplatin-based regimens showed a 27% reduction in risk of death compared with best supportive care,1 equivalent to a 10% absolute improvement in 1-year survival or a 1.5-month increase in median survival. These relatively modest results have led to the development of several novel cytotoxic drugs for the treatment of NSCLC. Investigation of these drugs has centered on platinum-based doublets or triplets and, less frequently, on nonplatinum-based doublets. Cisplatin plus gemcitabine (CG) yielded a significantly better response, time to progression, and median survival than cisplatin alone.2 Response rate with CG was also better than with cisplatin plus etoposide,3 and with cisplatin, mitomycin, and ifosfamide.4 Time to progression was also better with CG than with cisplatin plus etoposide3 but not with cisplatin, mitomycin, and ifosfamide.4 Several other combinations have also been tested,5–7 and a relatively small Italian trial found that the addition of vinorelbine to CG (CGV) improved survival over both CG and cisplatin plus vinorelbine.8 A later German phase II study also reported similar survival with CGV.9 Toxicity in all of these studies4–9 was tolerable. However, a small phase II study that reported almost the same results8,9 with CGV found a significant level of hematologic toxicity (21% febrile neutropenia and 9% treatment-related deaths).10 Intriguingly, a randomized study of CGV versus gemcitabine plus vinorelbine (GV) reported a significantly better response for CGV but without differences in survival and with more acceptable toxicity in the GV arm, which led the authors to conclude that cisplatin is not essential for NSCLC treatment.11 Noncisplatin combinations have also been tested. A phase II study of gemcitabine, ifosfamide, and vinorelbine reported a high response rate with a time to progression of 7 months and a median survival of 11 months; however, a high rate febrile neutropenia was reported.12 The GV combination has been examined in phase II studies,13,14 with response rates of approximately 39%, time to progression of 4.2 months, median survival of 9 months, 1-year survival of 31%, and low toxicity. Although less extensively tested, the vinorelbine plus ifosfamide (VI) combination has also yielded similar results,15 with low toxicity. Encouraging phase II trial results prompted us to hypothesize that a sequential administration of two nonplatinum doublets could overcome drug resistance and improve survival when compared with a reference cisplatin doublet. On the basis of this reasoning, the Spanish Lung Cancer Group conducted a phase III randomized trial in advanced NSCLC comparing CG with CGV and sequential doublets of GV followed by VI (GV–VI). The primary end point was overall survival, and secondary end points compared response rate, time to progression, and toxicity.
Patients Eligible patients had to have a histologically or cytologically confirmed diagnosis of NSCLC, and stage IIIB (pleural effusion or not amenable to radiation therapy) or stage IV disease according to the International Staging System for lung cancer. Other eligibility criteria included no prior chemotherapy; bidimensionally measurable disease; age between 18 and 75 years; Eastern Cooperative Oncology Group (ECOG) performance status (PS)  2; adequate hematologic function (WBC > 3,500/µL, platelet count > 100,000/µL, and hemoglobin > 10 g/L); and adequate hepatic and renal function (bilirubin < 1.5 mg/dL, AST and ALT < 3 x upper limit of normal, and creatinine < 1.5 x upper limit of normal). Prior radiation therapy at asymptomatic sites was allowed, provided that the irradiated area was not the only source of measurable disease and that radiation therapy had been completed before chemotherapy was initiated. Patients were not eligible if they had active infection, hypercalcemia, or uncontrolled systemic disease; were pregnant or breast-feeding; or had symptomatic CNS metastasis, or second malignancy other than carcinoma-in-situ of the cervix or basal cell skin carcinoma. Written informed consent was obtained from all patients. The protocol was approved by the ethical review boards of all participating centers and by the Spanish Health Authorities.
Study Design and Statistical Methods The randomization process was performed centrally by random permutated blocks within strata methods. Patients were stratified according to disease stage (IIIB v IV), baseline PS (0 to 1 v 2), and center.
Treatment Schedule Cycles were delayed if a minimum neutrophil count of 1.5 x 109/L and a minimum platelet count of 100 x 109/L was not maintained on day 1. Chemotherapy doses on day 8 were adjusted depending on neutrophil and platelet counts on that day. If granulocyte count was 1.0 to 1.49 x 109/L or platelet count was 75 to 99 x 109/L, gemcitabine and vinorelbine levels were reduced by 25%; if granulocyte count was 0.5 to 0.99 x 109/L or platelet count was 50 to 74 x 109/L, gemcitabine and vinorelbine levels were reduced by 50%. Below these levels, gemcitabine and vinorelbine were omitted.
Before each cycle, serum creatinine, calculated creatinine clearance, and serum electrolytes, including magnesium, were analyzed. If the serum creatinine concentration was
Baseline and Treatment Evaluations During the study, clinical examinations, blood counts, and biochemistry blood tests were performed before each cycle. Toxicity was graded according to the Cancer and Leukemia Group B criteria. Response to treatment was assessed according to standard World Health Organization response criteria17 after two complete cycles and after study discontinuation. Survival was calculated from the date of random assignment to the date of death. If a patient was not dead, survival was censored at the time of the last visit. Time to progression was calculated from the date of random assignment to the date of progression or death. If a patient had not progressed, time to progression was censored at the time of the last visit.
Patient Characteristics From September 1998 to July 2000, 570 patients were enrolled in the study. Thirteen patients were ineligible because of unconfirmed histology (three patients), inadequate stage (four patients), prior chemotherapy (two patients), previous diagnosis of cancer (two patients), withdrawal of consent (one patient), and concurrent acute complication before chemotherapy (one patient).
For all randomly assigned patients, median age was 59 years, with a clear predominance of males (87%). Forty-four percent had squamous cell carcinoma, 41% had adenocarcinoma, and 9% had large cell carcinoma. Twenty-one percent had stage IIIB and 79% had stage IV disease. Eighty-five percent had PS 0 to 1, and 15% had PS 2. Baseline characteristics were well balanced across treatment groups (182 CG, 188 CGV, 187 GV–VI). The characteristics of the 557 eligible patients are listed in Table 1
Chemotherapy Administration The overall median number of cycles administered per patient was four. Thirty-two percent of CG, 30% of CGV, and 30% of GV–VI patients received the planned six cycles of chemotherapy. Twenty-seven percent of CG, 24% of CGV, and 35% of GV–VI patients withdrew from the study because of progressive disease. Ten percent of CG, 18% CGV, and 8% of GV–VI patients withdrew because of toxicity (CGV v GV–VI, P = .0002; Table 2  ). The weekly dose of gemcitabine reached 1,168 mg/m2, 888 mg/m2, and 974 mg/m2 for CG, CGV, and GV–VI, respectively; a reduction of 7%, 11%, and 2% in the planned doses, respectively. Vinorelbine dose-intensity was 22.2 mg/m2 for CGV and 30 mg/m2 for GV–VI.
Response Rate and Time-to-Event Measures The overall response rate for all randomly assigned patients was 37%. Overall response rates for each arm were CG, 42%; CGV, 41%; and GV–VI, 27% (CG v CGV, P = .4; CG v GV–VI, P = .003; CGV v GV–VI, P = .001; Table 3 ). There were eight complete responses (CG, four; CGV, three; and GV–VI, one). The proportion of patients with either objective response or stable disease was similar across the three treatment groups (CG, 64%; CGV, 60%; GV–VI, 60%). The response rate was slightly higher in females (43%) than in males (34%; P = .07). PS was a significant prognostic factor for response (Table 4). The response rate in patients with CNS metastases (29%) was not different from that obtained in patients with other metastatic sites.
The median follow-up was 8.3 months, and as of July 2002, 415 patients (74.5%) had died (CG, 127 [69.8%]; CGV, 137 [72.9%]; GV–VI, 151 [80.7%]). Median survival for all eligible patients was 8.5 months (95% confidence interval [CI], 7.7 to 9.2). Median survival was 9.3 months for CG, 8.2 months for CGV, and 8.1 months for GV–VI (Fig 1 ). These differences were not statistically significant. Median survival was longer in females (8.7 months) than in males (7.2 months; P = .04). PS was a significant prognostic factor for median survival; patients with PS = 0 to 1 attained a median survival of 9.4 months, compared with 4.7 months in patients with PS = 2 (P = .0001). Patients with less than 5% weight loss had a median survival of 9.4 months, whereas for those with more than 5% weight loss, median survival was 7.1 months (P = .04). There was no difference in median survival according to disease stage: 8.7 months for stage IIIB and 8.6 months for stage IV (Table 4 ).
Median time to progression for all patients was 5.7 months. Median time to progression was similar across the three treatment arms: 6.3 months (95% CI, 5.2 to 7.2) for CG, 6.7 months (95% CI, 4.3 to 6) for CGV, and 5.5 months (95% CI, 4.7 to 6.4) for GV–VI (Fig 2 ).
The proportion of patients surviving 1 and 2 years was 35% and 13%, respectively. The 1-year survival rates were 38% for CG, 33% for CGV, and 34% for GV–VI; the 2-year survival rates were 13% for CG, 16% for CGV, and 11% for GV–VI.
Toxicity
Overall toxicities are listed in Table 5
The main differences in nonhematologic toxicity were observed in nausea and vomiting, which were higher in both cisplatin-based treatment groups (CG, 22%; CGV, 32%; GV–VI, 6%; P < .00001). Other differences in nonhematologic toxicity were not significant (Table 5 ).
Post-Study Therapy
In advanced NSCLC, novel doublets of cisplatin or carboplatin combined with paclitaxel, docetaxel, gemcitabine, or vinorelbine have generally achieved better response rates than more traditional combinations.3,4,18,19 Between 1996 and 2000, 2,795 patients were included in four randomized studies that examined which of these doublets might confer greater survival benefit: 1,155 patients in the ECOG trial20 and a total of 1,640 patients in three separate European randomized trials21,22 (including this study). In none of these studies was any survival differences found between paclitaxel, docetaxel, gemcitabine, and vinorelbine doublets. In the four-arm ECOG trial20 that compared cisplatin plus paclitaxel (24-hour infusion) with cisplatin plus gemcitabine, cisplatin plus docetaxel, and carboplatin plus paclitaxel (3-hour infusion), there were no differences in survival, although time to progression was significantly higher in the cisplatin plus gemcitabine arm than in the cisplatin plus paclitaxel arm (4.5 v 3.5 months, respectively; P = .002). In the Scagliotti et al21 study of cisplatin plus gemcitabine versus carboplatin plus paclitaxel versus cisplatin plus vinorelbine, no differences in response, time to progression, or survival were observed among the three arms. In the Van Meerbeeck et al22 study that compared cisplatin plus paclitaxel, cisplatin plus gemcitabine, and gemcitabine plus paclitaxel, there were no significant differences in response or median survival, although both response rate (31.8%, 36.8%, and 27.7%, respectively) and median survival (8.1, 8.9, and 6.7 months, respectively) were slightly lower in the gemcitabine plus paclitaxel arm. A significant difference was found in time to progression in favor of the cisplatin plus paclitaxel arm in comparison with the gemcitabine plus paclitaxel arm (4.2 v 3.5 months; P = .044). Finally, in this study, the patients in the noncisplatin sequential doublets group (GV–VI) had a significantly lower response rate than both the CG (P = .003) and the CGV (P = .001) treatment groups; no benefit was demonstrated for sequential doublets. Although median survival was slightly higher in the CG group, there were no significant differences between the treatment arms (Table 3 ). These findings contrast with those of the Italian study8 that compared cisplatin, gemcitabine, and vinorelbine with cisplatin plus gemcitabine and cisplatin plus vinorelbine. In this small group of patients (N = 104), the triplet significantly improved median survival (P < .05). In a previous phase II trial, the Spanish Lung Cancer Group had tested a paclitaxel plus gemcitabine combination23 and found a response rate of 32%, median survival of 9.9 months, and acceptable toxicity. Two Greek randomized trials24,25 indicated that platinum- and nonplatinum-based doublets attained similar response rates and survival. No major differences were observed between cisplatin plus docetaxel and gemcitabine plus docetaxel,24 or between carboplatin plus paclitaxel and gemcitabine plus paclitaxel.25 Median survival was 10.4 months for carboplatin plus paclitaxel, compared with 9.8 months for gemcitabine plus paclitaxel; response rates were 28% and 35%, respectively; time to progression was 6.3 and 6.1 months, respectively.25 These results contrast with those obtained by Van Meerbeeck et al,22 in which time to progression was significantly better in the cisplatin plus paclitaxel arm than in the gemcitabine plus paclitaxel arm (P = .04). In this study, the CG combination delivered every 3 weeks was well tolerated, with 34% of patients requiring dose reduction on day 8. Grade 3 to 4 neutropenia was observed in 32% of the patients, but only 4% developed neutropenic fever. In contrast, with the CGV triplet, 24% of patients suffered neutropenic fever, although it was not life threatening, and dose reductions were required in 44% of patients. The GV–VI sequential doublets showed the best toxicity profile. In light of our data and the contradictory findings of other studies, cisplatin plus gemcitabine doublets can be recommended as first-line treatment for metastatic NSCLC. The addition of vinorelbine to this combination does not improve response or survival, although it substantially increases the toxicity burden. The benefit of noncisplatin combinations is still unproven, given the significantly lower response observed in this study and the significantly shorter time to progression in the Van Meerbeeck et al study.22
The following investigators and institutions were actively involved in the trial: O. Juan, Division of Medical Oncology, Arnau de Vilanova Hospital; D. Almenar, Division of Medical Oncology, Doctor Peset Hospital, Valencia; J.M. Sánchez, Division of Medical Oncology, Germans Trias i Pujol Hospital, Badalona; F. Gómez, Division of Medical Oncology, General Hospital, Albacete; R. García-Gómez, Division of Medical Oncology, Gregorio Marañón Hospital; P. Garrido, Division of Medical Oncology, Ramón y Cajal Hospital; M. Dómine, Division of Medical Oncology, Jiménez Díaz Fundation; J. E. Alés, Division of Medical Oncology, Internaiional Rúber Fundation, Madrid; J. Terrassa, Division of Medical Oncology, Son Dureta Hospital, Palma de Mallorca; F.J. Barón, Division of Medical Oncology, Conxo Hospital, Santiago de Compostela; R. Blanco, Division of Medical Oncology, Terrassa Hospital, Terrassa; R. Barceló, Division of Medical Oncology, Cruces Hospital; P. Martínez, Division of Medical Oncology, Basurto Hospital, Bilbao; M.D. Torregrossa, Division of Medical Oncology, Luïs Alcanyis Hospital, Xàtiva; N. Batista, Division of Medical Oncology, University Hospital, Las Palmas; C. García Girón, Division of Medical Oncology, General Yagüe Hospital, Burgos; I. Moreno, Division of Medical Oncology, Municipal Hospital, Badalona; A. Galán, Division of Medical Oncology, Sagunt Hospital, Sagunto; I. Maestu, Division of Medical Oncology, Virgen de los Lirios Hospital, Alcoy; C. Pallarés, Division of Medical Oncology, Sant Pau Hospital, Barcelona; F. J. Cebas and E. Velez, Division of Medical Oncology, San Millán Hospital, Logroño; C. Jara, Division of Medical Oncology, Alcorcón Fundation, Alcorcón; E. Adrover, Division of Medical Oncology, Virgen de la Luz Hospital, Cuenca; and J. Cassinello, Division of Medical Oncology, General Hospital, Guadalajara.
We thank Joan H. Schiller, MD, from the University of Wisconsin at Madison, Karen Kelly, MD, from the University of Colorado at Denver, and Primo N. Lara, MD, from the University of California at Davis for their constructive comments on earlier versions of this manuscript; Vicente Alberola Jr for technical assistance in data management; and Elizabeth Breedlove and Renée O’Brate for assistance with the manuscript.
Preliminary results of this study were presented at the 37th Annual Meeting of the American Society of Clinical Oncology in San Francisco, CA, May 12–15, 2001.
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8. Comella P, Frasci G, Panza N, et al: Randomized trial comparing cisplatin, gemcitabine, and vinorelbine with either cisplatin and gemcitabine or cisplatin and vinorelbine in advanced non-small-cell lung cancer: interim analysis of a phase III trial of the Southern Italy Cooperative Oncology Group. J Clin Oncol 18:1451–1457, 2000 9. Laack E, Mende T, Dürk H, et al: Gemcitabine, vinorelbine and cisplatin combination chemotherapy in advanced non-small cell lung cancer: A phase II trial. Eur J Cancer 38:654–660, 2002[Medline] 10. Hesketh PJ, Nauman CJ, Hesketh AM, et al: Unfavorable therapeutic index of cisplatin/gemcitabine/vinorelbine in advanced non-small-cell lung cancer. Clin Lung Cancer 4:47–51, 2002[Medline]
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25. Kosmidis P, Mylonakis N, Nicolaides C, et al: Paclitaxel plus carboplatin versus gemcitabine plus paclitaxel in advanced non-small-cell lung cancer: A phase III randomized trial. J Clin Oncol 20:3578–3583, 2002 Submitted December 6, 2002; accepted June 18, 2003.
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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 and Fisher’s exact tests. The Bonferroni multiple-comparison procedure was used to assess differences between treatment arms both in baseline clinical characteristics and in grade 3 to 4 toxicities. Bonferroni P 
1.6 mg/dL but the creatinine clearance was 
