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Journal of Clinical Oncology, Vol 22, No 12 (June 15), 2004: pp. 2348-2356 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.10.576 Randomized Phase III Study of Gemcitabine and Vinorelbine Versus Gemcitabine, Vinorelbine, and Cisplatin in the Treatment of Advanced Non-Small-Cell Lung Cancer: From the German and Swiss Lung Cancer Study GroupFrom the University Hospital Hamburg-Eppendorf, University Hospital Magdeburg, Hospital Hofheim, Nordwest Hospital Frankfurt, Franziskus Hospital Flensburg, Hospital Chemnitz, University Hospital Kiel, Marien Hospital Hamm, Hospital Köln-Merheim, University Hospital Lübeck, St Hildegardis Hospital Mainz, University Hospital-Knappschaftskrankenhaus Bochum, Hospital Hanau, and the German Cancer Research Center Heidelberg, Germany Address reprint requests to Eckart Laack, MD, Department of Oncology and Hematology, University Hospital Hamburg-Eppendorf, Martinistrasse 52, D-20246 Hamburg, Germany; e-mail: laack{at}uke.uni-hamburg.de
PURPOSE: To evaluate whether cisplatin-based chemotherapy (gemcitabine, vinorelbine, and cisplatin [GVP]) prolongs overall survival in comparison to cisplatin-free chemotherapy (gemcitabine and vinorelbine [GV]) as first-line treatment in patients with advanced non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Between September 1999 and June 2001, 300 patients with NSCLC stage IIIB with malignant pleural effusion or stage IV disease were randomly assigned to receive GV (gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks) or GVP (gemcitabine 1000 mg/m2 + vinorelbine 25 mg/m2 on days 1 and 8 + cisplatin 75 mg/m2 on day 2 every 3 weeks). Primary end point of the study was overall survival. RESULTS: Two hundred eighty-seven patients (GV, 143 patients; GVP, 144 patients) were eligible for analysis. At the time of analysis, April 15, 2002, 209 patients (GV, 103 patients; GVP, 106 patients) of 287 patients had died (73%). No statistically significant difference was observed for overall survival (P = .73; median survival, 35.9 versus 32.4 weeks; 1-year survival rate, 33.6% versus 27.5%) as well as for event-free survival (P = .35; median time-to-event, 19.3 versus 22.3 weeks) between GV and GVP. Two hundred fourteen patients were assessable for best response. The overall response rates were 13.0% for GV versus 28.3% for GVP (P = .004; complete responders, 0% versus 3.8%; partial responders, 13.0% versus 24.5%). Hematologic and nonhematologic toxicity was significantly lower in the GV treatment arm compared with GVP. No statistically significant difference in quality of life was observed. CONCLUSION: In this phase III study, the cisplatin-based GVP regimen showed no survival benefit as first-line chemotherapy in advanced NSCLC when compared with the cisplatin-free GV regimen, which was substantially better tolerated.
More than 1.3 million new cases of lung cancer occur worldwide every year. In the United States and in Western Europe, lung cancer is the most frequent cause of death among malignant tumors. Treatment of patients with non-small-cell lung cancer (NSCLC) is a particular challenge in oncology because more than one third of patients have distant metastases at diagnosis,1 allowing only palliative treatment. A meta-analysis indicated that chemotherapy significantly improves survival and symptom control compared with best supportive care in stage IV NCSLC patients.2 The analysis of single agents revealed that of all conventional cytotoxic drugs, only cisplatin produces significant benefit compared to best supportive care.2 However, substantial toxicity impaires the advantages in survival and symptom control of cisplatin-containing regimens. Thus, there is an obvious need for at least equally active but better tolerated agents to optimize therapy of metastatic and advanced NSCLC. Since the 1990s, new agents were investigated in advanced NSCLC. These agents include the nucleoside analog gemcitabine, the vinca-alkaloid vinorelbine, the taxanes paclitaxel and docetaxel, the camptothecin-derivatives irinotecan and topotecan, and the benzotriazin derivative tirapazamine. These agents have extended the therapeutic approach for patients with metastatic NSCLC. They have all been incorporated into a number of combination chemotherapeutic regimens, many of which included either cisplatin or carboplatin. As yet, no standard chemotherapy exists for patients with advanced NSCLC. The Eastern Cooperative Oncology Group study 1594 compared in a randomized phase III trial four different platin-based chemotherapy regimens (paclitaxel plus cisplatin, docetaxel plus cisplatin, gemcitabine plus cisplatin, paclitaxel plus carboplatin) and did not identify a superior regimen that could be recommended as a standard therapy.3
Gemcitabine and vinorelbine are two of the most extensively evaluated newer cytotoxic agents. Each is characterized by favorable toxicity profiles and is better tolerated than platinum-based regimens.4-8 The combination of gemcitabine and vinorelbine has demonstrated promising activity and mild toxicity in some phase II trials.9-14 In a randomized phase III trial (Multicenter Italian Lung Cancer in the Elderly Study [MILES]), the combination of gemcitabine and vinorelbine was not more effective than single-agent gemcitabine or vinorelbine in elderly patients ( The role of cisplatin in the era of new and well tolerated cytotoxic agents is still under discussion. Thus, we conducted a multicenter randomized phase III trial to evaluate whether cisplatin-based chemotherapy gemcitabine, vinorelbine, and cisplatin (GVP) prolongs overall survival in comparison to cisplatin-free chemotherapy gemcitabine and vinorelbine (GV) as first-line treatment in patients with advanced NSCLC.
This was a multicenter, prospective, open label, randomized phase III trial. All eligible patients gave written informed consent before entering this study. The study was approved by local ethic committee and the protocol committee of the German Cancer Society.
Eligibility Criteria
Patients were excluded from the study if they had previous cancer in the last 5 years (except adequately treated basal cell carcinoma of the skin or carcinoma-in-situ of the cervix), pre-existing sensory or motor neuropathy greater than WHO grade 1, a history of myocardial infarction, coronary heart disease
Treatment Schedule All patients received gemcitabine 1000 mg/m2 and vinorelbine 25 mg/m2 on days 1 and 8 every 3 weeks. Gemcitabine was given as a 30-minute infusion followed 1 hour later by vinorelbine (15-minute infusion). To protect the vein in which vinorelbine was infused and to prevent the development of phlebitis, 250 mL of 0.9% saline was given immediately after the vinorelbine infusion. Patients who were randomly assigned into the GVP arm received cisplatin 75 mg/m2 in addition on day 2 every 3 weeks. Cisplatin was given on day 2 as a 1-hour infusion with standard pre- and posthydration. All cytotoxic drugs were administered as an intravenous infusion in 0.9% saline. A combination of metoclopramide and dexamethasone was given on days 1 and 8 and a combination of an HT3-antagonist and dexamethasone was administered on day 2, 15 to 30 minutes before starting chemotherapy to prevent nausea and vomiting. The use of granulocyte-colony-stimulating factor and the substitution of RBCs or platetets was left to an individual decision of the physician.
Treatment Evaluation
Survival—Primary End Point by Design The study was designed as a superiority trial to evaluate whether cisplatin-based GVP chemotherapy prolongs overall survival in comparison to cisplatin-free GV chemotherapy as first-line therapy. The planned sample size was 260 patients (130 per treatment arm) in order to detect a difference in 1-year survival, increasing from 25% in the GV group to 45% in the GVP group with a power of at least 80% at a level of significance of 5%. In order to compensate for possible unforeseen dropout, a total of 300 patients were randomly assigned in the trial. At the time of evaluation (April 2002; 103 of 143 patients had died in the GV arm and 106 of 144 patients had died in the GVP arm), the study had a power of 91.1% to detect a difference in 1-year survival rate of 15% (ie, 25% in the GV and 40% in GVP arm) at a significance level of 5%; respectively, a power of 76.6% to detect a 10% difference in the 1-year survival rate of 25% assumed for GV.
Response, Time-to-Event, and Toxicity To detect acute hematologic toxicity, blood cell count with differential was performed weekly, and chemistry analysis was performed at the beginning of each cycle. Nonhematologic acute toxicity was assessed weekly. Toxicity was evaluated according to WHO criteria at the end of each cycle for the past treatment period. Tumor response rates in the two arms were compared using Fisher's exact test. Maximal toxicities observed per patient during treatment were analyzed with the Cochran-Armitage trend test, taking into account the categoric grading of toxicity according to WHO criteria.
Quality of Life (QoL)
Statistical Analysis Methods
The secondary end points response, toxicity, and QoL were evaluated using nonparametric statistical methods as described above. A Statistical analyses were performed using the statistical packages SAS (SAS Institute, Cary, NC) for Windows Version 8, R Version 1.6.2 (http://www.r-project.org), and StatXact Version 5.0.3 (Cytel Software Corporation, Cambridge, MA). P values of less than .05 were considered statistically significant.
Patient Characteristics From September 1999 to June 2001, 300 patients were entered in this multicenter study. One hundred fifty-two patients were randomly assigned into the GV treatment arm and 148 patients into the GVP treatment arm. Thirteen randomly assigned patients (4.3%) did not fulfill the eligibility criteria and were excluded from the full analysis set. Four patients had a stage IIIB disease without malignant pleural effusion, one patient was staged as stage IIIA disease, two patients had brain metastases, two patients did not have NSCLC (one patient had small cell lung cancer and one patient a malignant melanoma), two patients revealed a Karnofsky performance status of lower than 70%, one patient did not fulfill the eligibility criteria concerning tumor size, and one patient refused treatment after randomization. Therefore, 287 patients were assessable for analysis (143 patients in GV treatment arm, 144 patients in GVP treatment arm; Fig 1).
Patient characteristics of both treatment arms are listed in Table 1. Patients in both treatment arms had a median age of 61 years (GV, 60.8 years; range, 41.0 to 75.9; GVP, 61.1 years; range, 40.6 to 75.9). Besides age, the study was also well balanced for sex, stage, histologic type, and Karnofsky performance status.
Survival At the time of analysis (April 15, 2002), 209 of 287 eligible patients (72.8%) had died (GV arm, 103 patients; GVP arm, 106 patients). A difference of 15% in 1-year survival between both treatment arms could be detected with a power of at least 87% at a level of significance of 5%. The median follow-up was 70.7 weeks for the whole patient population (GV arm, 70.3 weeks; GVP arm, 74.3 weeks). The median survival time for patients in the GV arm was 35.9 weeks and for patients in the GVP arm, 32.4 weeks. The 1-year survival rate for the 143 patients who were treated with GV was 33.6% (95% CI, 26.3 to 42.9%), and for the 144 patients who were treated with GVP the survival rate was 27.5% (95% CI, 20.9 to 36.1%). The log-rank test showed no statistically significant difference between both treatment arms with regard to overall survival (P = .73; Fig 2). Also, no significant difference was observed between women and men (P = .50), between stage IIIB disease with malignant pleural effusion and stage IV disease (P = .50), between the different histologic types (P = .57), and the different histologic grading (P = .61). Patients with a Karnofsky performance status of 90% or 100% revealed a significantly longer overall survival than those patients with a Karnofsky performance status of 70% or 80% (P = .003; Fig 3). This result was confirmed in a multivariate analysis where Karnofsky performance status was the only significant factor among the baseline patient characteristics of this study.
At time of analysis, 242 of 287 assessable patients (84.3%) had an event (progression or death; GV, 122 patients; GVP, 120 patients). The median time to event for patients in the GV arm was 19.3 weeks compared to 22.3 weeks for patients in the GVP arm (Fig 4). Patients in the GV arm had a 1-year event-free survival rate of 20.4% (95% CI, 14.6% to 28.6%), and 21.9% in the GVP arm (95% CI, 16.0 to 29.9%), which was not significantly different (P = .35).
Tumor Response Two hundred fourteen of the 287 patients (74.6%) were assessable for best response after at least two treatment cycles. Best response could not be determined for 73 patients (GV, 35 of 143 [24.5%]; GVP, 38 of 144 [26.4%]). Twelve patients died early, 27 patients dropped out before evaluation of response, and in 34 patients, either baseline or assessments after two cycles are missing or the lesions were not measured in two dimensions. The overall response rate, including complete and partial responders, was 13.0% (14 partial responders of 108 patients; 95% CI, 7.3% to 20.8%) in the GV arm and 28.3% (four complete and 26 partial responders of 106 patients; 95% CI, 20.0% to 37.9%) in the GVP arm. The overall response rate in the GV arm was statistically significantly lower (P = .004) than in the GVP arm (Table 2).
No significant difference in response was observed between women (10 responders of 56 women) and men (34 responders of 158 men; P = .77), between stage IIIB with malignant pleural effusion (nine responders of 29 patients), and stage IV disease (35 responders of 185 patients; P = .31), and between the different histologic types (P = .52) (25 responders of 111 patients with adenocarcinoma; 17 responders of 68 patients with squamous cell carcinoma; two responders of patients with other histologic types). Patients with a Karnofsky performance status of 90% or 100% had no significantly higher response rate (28 responders of 122 patients) than those patients with a Karnofsky performance status of 70% or 80% (16 responders of 92 patients; P = .28).
Toxicity Information on toxicity during treatment was missing in some cases (especially neutrophils on day 15 of a cycle) and varying from parameter to parameter. Hematologic toxicity (ie, neutropenia, anemia, and thrombocytopenia) was significantly (P < .00001, respectively) more frequent and more severe on arm GVP than on arm GV (Table 3 and Table 4). GVP also induced significantly more relevant alopecia (P < .00001), vomiting/emesis (P < .00001), diarrhea (P = .01), and elevation of serum creatinine (P < .00001), whereas a more frequent and more severe elevation of transaminases occurred in patients in the GV arm (P < .00001; Table 4).
Treatment delays of 7 or more days occurred in 220 of all 1,125 administered cycles (GV, 64 of 554 patients; GVP, 156 of 571 patients). The predominant cause of treatment delays was hematologic toxicity (neutropenia, 97 of 220 patients; thrombocytopenia, 13 of 220 patients; leukopenia, 17 of 220 patients, anemia, one of 220 patients; nonhematologic toxicity, 73 of 220 patients; missing information, 19 of 220 patients). Significantly more patients had a delay of 7 or more days in arm GVP than in the GV arm (79 v 42 patients; P < .00001). Toxicity caused 17 patients to go off study (GV, four patients; GVP, 12 patients). In addition, four treatment-induced deaths occurred (GV arm, one patient; GVP arm, three patients). Two of these deaths were due to sepsis and pneumonia during neutropenia, respectively.
Second-Line Chemotherapy One hundred two (35.5%) of 287 patients received a second-line chemotherapy (GV, 60 of 143 patients [42.0%]; GVP, 42 of 144 patients [29.2%]).
Quality of Life
In addition, sum scores of the factors of main interest (pain, short-windedness, fatigue, and global health) were analyzed. For all tests of the sum scores, no statistically significant difference between the treatment arms could be seen (Table 6).
In this randomized phase III study, the cisplatin-based triplet combination GVP chemotherapy did not prolong overall survival in patients with advanced NSCLC in comparison to the cisplatin-free doublet GV chemotherapy as first-line chemotherapy. The cisplatin-induced higher response rate had no impact on survival. This might be explained by a short duration of response. The GV regimen was applied in an out-patient setting and was substantially better tolerated than the cisplatin-based GVP regimen, whereas no significant differences were observed in QoL between both arms. A randomized phase III trial comparing paclitaxel plus carboplatin with paclitaxel alone has demonstrated that the doublet chemotherapy significantly improves survival and tumor response in comparison to single-agent chemotherapy.19 The role of cisplatin in the era of new and well tolerated cytotoxic agents is still controversially discussed. Up to now, several randomized studies comparing cisplatin-based and cisplatin-free chemotherapy regimens in NSCLC have been published with different results.4-6,20-24 The EORTC lung cancer group performed a randomized phase III trial in advanced NSCLC comparing the three chemotherapy regimens paclitaxel and cisplatin, gemcitabine and cisplatin, and paclitaxel and gemcitabine.20 Four hundred eighty patients entered this trial. Seventy-nine percent of these patients had stage IV disease and 21% had stage IIIB disease. The cisplatin-free regimen paclitaxel and gemcitabine had a lower median survival (6.9 v 8.1 v 8.8 months), a lower 1-year survival rate (26.5% v 35.5% v 32.6%), and a lower response rate (27% v 31% v 36%) than the two cisplatin-based regimens.20 However, Georgoulias et al21 observed in their randomized phase III study that docetaxel and cisplatin versus docetaxel and gemcitabine had similar efficacy (response rate, 32.4% v 30.2%) and survival data (median survival, 10 v 9.5 months; 1-year survival rate, 42% v 38%) in both treatment arms, while the cisplatin-free regimen showed less toxicity. Four hundred forty-one patients with stage IIIB or IV disease were included onto this trial. In a three arm phase III trial comparing vinorelbine plus cisplatin with vindesine plus cisplatin and vinorelbine as a single agent in 612 patients, the survival data of the vinorelbine monotherapy were similar to those of the combination chemotherapy cisplatin and vindesine (median survival, 31 v 32 weeks).4 Patients in the vinorelbine and cisplatin arm, however, had a longer median survival and higher 1-year and 2-year survival rates. A further randomized phase III trial compared a gemcitabine monotherapy with cisplatin plus vindesine.22 No significant differences between both therapies were reported in terms of response rate (20.2% v 20%), median time to progression (9.2 v 13.7 weeks), median survival (6.7 v 5.5 months), and 1-year survival rate (22% v 19.3%). The gemcitabine monotherapy induced less frequent and less severe toxicity and a significantly better and longer lasting symptom control (clinical benefit, 48.1% v 28.9%) in comparison to the cisplatin-containing chemotherapy.22 Two randomized phase II trials compared a gemcitabine monotherapy with cisplatin and etoposide.5,6 The response rates and median survival times were similar in both regimens in either trial, whereas gemcitabine had a favorable toxicity profile. Comparable to our study, two other study groups investigated the combination of gemcitabine and vinorelbine in randomized phase III trials.23-24 A Spanish lung cancer group conducted a phase III trial comparing cisplatin plus gemcitabine, cisplatin plus gemcitabine plus vinorelbine, and gemcitabine plus vinorelbine followed by ifosfamide plus vinorelbine in 562 patients.23 Similar to our study, only patients with stage IIIB disease with malignant pleural effusion (21%) or stage IV disease (79%) were included. The sequential cisplatin-free doublets induced a lower response rate than the cisplatin-based regimen (24.1% v 41% v 40%). However, the median survival time was not significantly different between the three treatment arms (9.3 v 8.2 v 8.1 months) and the cisplatin-free treatment arm was associated with less frequent and less severe hematologic toxicity.23 Gridelli et al24 performed an international, multicenter, randomized phase III trial to compare gemcitabine plus vinorelbine with cisplatin plus vinorelbine or cisplatin plus gemcitabine. The primary end point of this study was quality of life. Patients with stage IIIB disease with pleural effusion or involved supraclavicular nodes (20%) or stage IV disease (80%) who were younger than 70 years entered the study. Four hundred fifteen of 501 randomly assigned patients were assessable for quality of life analyses. There was no significant difference in general quality of life or functional scales between the two arms after 2 months of treatment. Cisplatin-based chemotherapy improved disease-related symptoms (not significant in multivariate analysis), but worsened appetite, vomiting, and alopecia (significantly). Patients who were treated with a cisplatin-based regimen had significantly more grade 3/4 neutropenia, vomiting, alopecia, and ototoxicity. No significant difference was observed in response rate (25% v 30%) and in median survival (32 v 38 weeks), whereas patients in the cisplatin-based treatment arms had a significantly longer progression-free survival (17 v 23 weeks).24 In conclusion, it is very difficult to compare the data from the various studies for a variety of reasons, including different patient characteristics, different selection criteria, different primary end points and sample sizes, and different combination chemotherapies with different schedules. We think a meta-analysis of randomized trials comparing cisplatin-free and cisplatin-based regimens will help to find an answer to the role of cisplatin in the era of well-tolerated cytotoxic drugs. However, with regard to the relatively short survival time of patients with advanced NSCLC and the palliative therapeutic approach, the choice of therapy should be based on a favorable toxicity profile (no relevant alopecia and vomiting/emesis) and convenience of its administration (ie, out-patient setting). Our phase III trial has demonstrated that the combination chemotherapy gemcitabine and vinorelbine does fulfill these criteria.
The following colleagues also participated in this trial: Riha, Matthiesen (Hospital Coswig); Gerecke, Ittel (Hospital Stralsund); Backes, Preiß (Hospital St Theresia Saarbrücken); Lindemann (University Hospital Magdeburg); AL-Batran (Nord West Hospital Frankfurt); Saal (Franziskus Hospital Flensburg); Schmid (Marien Hospital Hamm); Chemaissani (Hospital Köln-Merheim); Albrecht (St Hildegardis Hospital Mainz); Petz (University Hospital Bochum); Hofstetter, Hirsch (Hospital Offenburg); Bartscht, Raff, Kneba (University Hospital Kiel); Köchling (Hospital Leer); Glasmacher, Hahn, Mey (University Hospital Bonn); Goldmann (Outpatient Clinic Lüneburg); Henrich (Horst-Schmidt-Hospital Wiesbaden); Braig, Höffken (University Hospital Dresden); Hoffmann (Outpatient Clinic Norderstedt); Hechler, Berthold, Schmitt, Scholtze (Theresien Hospital Mannheim); Hesse (Hospital Parchim); Honegger (Hospital Triemli Zürich); C. Laack, Meyer (University Hospital Hamburg-Eppendorf); Wacker-Backhaus, Aumiller (Marien Hospital Hamburg); Drescher (Outpatient Clinic Hamburg); Hoffknecht, Niemann, van Roye (St Martin Hospital Koblenz); Weerda, Bölcskei (Hospital Nürnberg); v. Hirschhausen (Hospital Schweinfurt); Anchisi (Hospital Sion); Struß, Schaberg (Hospital Rotenburg/Wümme); Drost (Hospital Mönchengladbach) Heim (Sonnenberg Hospital Bad Sooden-Allendorf); Kleinsorge (Outpatient Clinic Detmold); Verpoort, Zeller (Outpatient Clinic Hamburg).
The authors indicated no potential conflicts of interest.
This article is dedicated to Professor Dieter Kurt Hossfeld on the occasion of his 65th birthday.
The trial was supported in part by Lilly Deutschland GmbH, Bad Homburg, and Pierre Fabre Pharma GmbH, Freiburg, Germany. Preliminary results of this study were presented at the 27th European Society for Medical Oncology Congress in Nice, France, October 18-22, 2002. Authors' disclosures of potential conflicts of interest are found at the end of this article.
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9. Isokangas OP, Knuuttila A, Halme M, et al: Phase II study of vinorelbine and gemcitabine for inoperable stage IIIB-IV non-small cell lung cancer. Ann Oncol 10:1059-1063, 1999 10. Bajetta E, Chiara Stani S, De Candis D, et al: Gemcitabine plus vinorelbine as first-line chemotherapy in advanced non-small cell lung carcinoma: A phase II trial. Cancer 89:763-768, 2000[CrossRef][Medline] 11. Lilenbaum R, Cano R, Schwartz M, et al: Gemcitabine and vinorelbine in advanced non-small cell lung carcinoma: A phase II study. Cancer 88:557-562, 2000[CrossRef][Medline]
12. Chen YM, Perng RP, Yang KY, et al: A multicenter phase II trial of vinorelbine plus gemcitabine in previously untreated inoperable (stage IIIB/IV) non-small cell lung cancer. Chest 117:1583-1589, 2000
13. Krajnik G, Mohn-Staudner A, Thaler J, et al: Vinorelbine-gemcitabine in advanced non-small cell lung cancer (NSCLC): An AASLC phase II trial. Ann Oncol 11:993-998, 2000 14. Laack E, Mende T, Benk J, et al: Gemcitabine and vinorelbine as first-line chemotherapy for advanced non-small cell lung cancer: A phase II trial. Eur J Cancer 37:583-590, 2001
15. Gridelli C, Perrone F, Gallo C, et al: Chemotherapy for elderly patients with advanced non-small lung cancer: The Multicenter Italian Lung Cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 95:362-372, 2003
16. Frasci G, Lorusso V, Panza N, et al: Gemcitabine plus vinorelbine versus vinorelbine alone in elderly patients with advanced non-small cell lung cancer. J Clin Oncol 18:2529-2536, 2000 17. Miller AB, Hoogstraten B, Staquet M, et al: Reporting results of cancer treatment. Cancer 47:207-214, 1981[CrossRef][Medline] 18. Fayers PM, Aaronson NK, Bjordal K, on behalf of the EORTC Quality of Life Group: The EORTC QLQ-C30 Scoring Manual, 3rd edition, European Organisation for Research and Treatment of Cancer, Brussels, Belgium, 2001 19. Lilenbaum RC, Herndon J, List M, et al: Single-agent (SA) versus combination chemotherapy (CC) in advanced non-small cell lung cancer (NSCLC): a CALGB randomized trial of efficacy, quality of life (QOL), and cost-effectiveness. Proc Am Soc Clin Oncol 21:1, 2002 (abstr 2) 20. Van Meerbeeck JP, Smit E, Lianes P, et al: An EORTC randomized phase III trial of three chemotherapy regimens in advanced non-small cell lung cancer (NSCLC). Proc Am Soc Clin Oncol 20:308, 2001 (abstr 1228) 21. Georgoulias V, Papadakis E, Alexopoulos A, et al: Platinum-based and non-platinum-based chemotherapy in advanced non-small-cell lung cancer: A randomised multicentre trial. Lancet 357:1478-1484, 2001[CrossRef][Medline]
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23. Alberola V, Camps C, Provencio M, et al: 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. J Clin Oncol 21:3207-3213, 2003
24. Gridelli C, Gallo C, Shepherd FA, et al: 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. J Clin Oncol 21:3025-3034, 2003 Submitted October 24, 2003; accepted March 30, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
70 years) with advanced NSCLC.
1.5x upper normal limit [UNL] and ALT and AST 
2 test was used to compare the treatment delays in both arms. Balance between the two treatment arms was examined by a descriptive statistical analysis. 
