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Purpose: A phase III randomized trial was carried out to compare two schedules of the vinorelbine (VNR)-cisplatin (CDDP) regimen in patients with locally advanced unresectable poor prognosis stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoints were overall survival (OS) and analysis of toxicity, while secondary endpoints included response rates, time-to-progression (TTP) and quality of life (QoL)., Patients and Methods: Eligible patients were randomized to receive: (a) VNR 25mg/m(2) on day 1, 8 and 15 plus CDDP 100mg/m(2) on day 1 every 4 weeks or (b) VNR 30 mg/m(2) on day 1 and 8 plus CDDP 80 mg/m(2) on day 1 every 3 weeks. All patients were chemotherapy-naïve and had an ECOG performance status (PS) of 0-1., Results: Overall 278 patients were enrolled into the trial. Overall response rate was 34% (95% CL 26-42%) in the weekly VNR/CDDP arm, and 32% (95% CL 24-40%) in patients treated with day 1-8 VNR/CDDP without any statistically significant difference. Median TTP was 4.5 and 4.6 months respectively for weekly VNR/CDDP arm and the day 1-8 VNR/CDDP one. This difference was not statistically significant (log-rank test, p=0.818). Median OS was 9.45 and 10 months respectively for weekly VNR/CDDP arm and the day 1-8 VNR/CDDP one without statistically a significant difference (log-rank test, p=0.259). The 1- and 2-year survival rates were 31 and 36%, and 10 and 11% respectively. The incidence of severe neutropenia (34% versus 68%; p=0.0001) and of febrile neutropenia (5% versus 12%; p=0.026), as well as the rate of therapy omissions (10% versus 24%; p=0.0037) were higher in the weekly VNR/CDDP arm than in the day 1-8 VNR/CDDP one. The weekly VNR/CDDP regimen was associated with a lower received dose intensity in a statistically significant fashion (9% versus 22%; p=0.0001) and with a lower non-statistically significant quality of life score as compared to the day 1-8 VNR/CDDP schedule., Conclusions: The combination of day 1-8 VNR plus CDDP every 3 weeks is less toxic and better tolerated than the regimen of weekly VNR plus CDDP every 4 weeks. The two schedules are equivalent in terms of overall response rate, median time-to-progression and overall survival. The combination of VNR on day 1-8 plus CDDP every 3 weeks may be considered as a reference regimen for the treatment of patients with advanced disease and those who deserve a postoperative therapy, and for future studies.

Purpose: we carried out a phase III randomized trial to compare vinorelbine-cisplatin regimen to gemcitabine-cisplatin regimen, and to a sequential administration of gemcitabine-ifosfamide followed by vinorelbine-cisplatin or the opposite sequence of vinorelbine-cisplatin followed by ifosfamide-gemcitabine according to the 'worst drug rule' hypothesis in patients with locally advanced unresectable stage IIIB or metastatic stage IV non-small cell lung cancer. The primary endpoint was survival parameters, while secondary endpoints included analysis of response rates and toxicity., Patients and Methods: patients were randomized to receive: (a) gemcitabine 1000 mg/m(2) on days 1, 8 and 15 plus ifosfamide 1500 mg/m(2) on days 8-12 with mesna uroprotection (GI regimen) followed by vinorelbine 25 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 (GI --> VC regimen); (b) the opposite sequence (VC --> GI); (c) vinorelbine plus cisplatin as above described (VC regimen); or (d) gemcitabine 1400 mg/m(2) on days 1 and 8 plus cisplatin 100 mg/m(2) on day 8 (GC regimen). All regimens were given every 4 weeks. All patients were chemotherapy naive and had a ECOG PS 0-2., Results: 400 patients were enrolled into the trial. Interim analysis after inclusion of 243 patients showed that ORR were 19% in the GI --> VC arm, 32% in the inverse sequence arm (CV --> GI), 42% in the VC arm, and 30% in the GC arm. The VC arm was statistically superior over the GI --> VC arm (p = 0.0074), but not over the other regimens. Median TTP was 3.1 months in the GI --> VC arm versus 5.0 months in the VC --> GI arm (p = 0.014). For these reasons the GI --> VC and VC --> GI arm were closed since the 'worst drug rule' hypothesis was rejected. Accrual in the VC and GC arms continued up to 140 and 138 patients respectively. Final ORR were 44% for the VC regimen (4 CR), and 34% for the GC regimen (1 CR). This difference was statistically significant (p = 0.032). OS was 9.0 and 8.2 months, respectively, with no statistically significant difference. The 1-year survival rate was 24 and 20%, respectively for VC and GC regimens. As expected the incidence of phlebitis was higher in the VC arm, while thrombocytopenia, flu-like syndrome and asthenia were more frequent in the GC arm., Conclusions: the results of this trial indicate that the combination of vinorelbine and cisplatin and that of gemcitabine and cisplatin are equivalent in terms of median TTP and OS, although the vinorelbine-cisplatin regimen is associated with a higher ORR. Both regimens may be considered as reference treatments for future studies. Moreover, our data reject the 'worst drug rule' hypothesis of sequential treatments in NSCCL at least with the combination used in this study., (Copyright 2002 Elsevier Science Ireland Ltd.)

Purpose: To compare a regimen of vinorelbine and cisplatin (VC) to the combination of mitomycin, vindesine, and cisplatin (MVP) in patients with stage IIIB or stage IV non-small cell lung cancer (NSCLC). The main endpoits were analysis of objective response rates, toxicity, time to progression, and overall survival., Patients and Methods: 247 eligible patients were randomized to receive (a) vinorelbine 25 mg/m(2) intravenous bolus on days 1 and 8 plus cisplatin 100 mg/m(2) on day 1 every 4 weeks, or (b) mitomycin c 8 mg/m(2) i.v. on day 1, vindesine 3 mg/m(2) i.v. on days 1, 8, 15 and 22, plus cisplatin 100 mg/m(2) on day 1 every 4 weeks. In subsequent cycles vindesine was given every other week. For both treatments a maximum of six cycles was planned. Patients with performance status 0-2 according to the ECOG scale were enrolled. Response and toxicity were evaluated according to the WHO criteria. Analysis of clinical efficacy was performed according to an intent-to-treat analysis., Results: No statistically significant differences in clinical efficacy were observed between the two chemotherapy regimens. The overall objective response rates were 39% (95% CL, 31-49%) in the VC arm and 42% (95% CL, 33-51%) in the MVP arm (P=0.13). Median time to progression was 4.2 and 4.5 months for the MVP arm and the VC arm, respectively. Median overall survival was 7 months in the VC arm and 8 months in the MVP one (log-rank test, P=0.898). These differences were not statistically significant. However, leukopenia and thrombocytopenia were significantly higher in the MVP arm than in the VC (P=0.0001; P=0.0002). Grade 3 alopecia was more frequent in the MVP arm than in the VC one (P<0.001), which was associated with higher rate of phlebitis (P=0.037)., Conclusion: Data achieved in this study suggest that the vinorelbine-cisplatin doublet is similar to the three-drug MVP regimen in term of overall response rate, time to progressive disease, and overall survival. However, hematological toxicity and alopecia are more frequent and severe in the MVP regimen which therefore appears to be less tolerable than the VC regimen. The combination of vinorelbine and cisplatin may be considered as a reference treatment for future studies on the treatment of advanced NSCLC.

A phase II study in patients with stage IIIB/IV non-small cell lung cancer (NSCLC) was carried out to evaluate the clinical activity and toxicity of the chemotherapeutic combination of gemcitabine+vinorelbine (GEM/VNR). Forty-five patients (40 male, 5 female) with a median age of 67 years (range 37-73) and a median ECOG performance status of 1 (range 0-2) were enrolled into the trial. Twenty patients had stage IIIB (two positive supraclavicular nodes and 20 cytologically positive pleural effusion), and 25 had stage IV NSCLC. GEM 1000 mg/m(2) diluted in 250 cc(3) of normal saline was administered iv on days 1, 8, and 15, while VNR was given 30 mg/m(2) on days 1 and 8 every 4 weeks. The median number of courses/patient was 4 (range 3-7). According to an intent-to-treat analysis 2 (4%) patients had a complete response and 16 (36%; 95% CL 22-52%) had a partial response for an overall response rate of 40% (95% CL 26-56%). Twelve (27%) patients had stable disease and 15 (33%) were considered as treatment failures. Median overall survival of the whole series was 8+ months with 33% of patients alive at 1 year. Toxicity was generally mild. WHO grade 3-4 neutropenia was recorded in 22% of cases, grade 1-3 liver toxicity in 6% of patients and neutropenia-unrelated fever in 9%. This multicentre phase II study suggests that the GEM/VNR combination regimen is an active and well tolerated regimen in patients with stage IIIB/IV NSCLC. Larger studies comparing cisplatin-based regimens to new schedules without cisplatin are warranted.

Thirty-five patients affected by stage III-IV non-small-cell lung carcinomas were treated with ifosfamide 3 gr/m2 plus MESNA as uroprotector on day 1 and vinorelbine 25 mg/m2 i.v. bolus on day 1 and 8. This cycle was repeated every 21 days. Over a total of 35 evaluable patients, the overall response rate was 34% (95% CL 18-54%). One patient experienced a complete response with a duration of 7.2+ months, and 11 patients a partial response with a mean duration of 5.9+ months. Seven patients had no change and 16 improved. The overall survival was 7.6+ months. Over a total of 145 cycles, the most frequent toxicity was myelosuppression, but grade 3 leukopenia and grade 2 thrombocytopenia were seen only in 14% and 9% of cases, respectively. Only one patient suffered grade 4 leukopenia. Gastrointestinal toxicity was minimal; only five patients (14%) complained of grade 3 vomiting. This combination regimen can be safely given on an outpatient regimen, but it is relatively active in advanced non-small-cell lung cancer. However, it should be noted that >50% of the patients in this series had a performance status of <80 and >50% were older than 65 years.

Thirty consecutive patients with stage IIIB-IV non small cell lung cancer were treated with a combination of cisplatin 80 mg/m2 on day 1 plus vinorelbine 25-30 mg/m2 on days 1, 8. This cycle was repeated every 3 weeks. The overall response rate was 46%, with 1 patient showing a complete response and 13 patients (43%) a partial response with a mean duration of 8.4+ months. Six patients had a stabilization and 10 progressed. The main toxicities were represented by myelosuppression and nausea/vomiting. Grade 3 leukopenia was seen in 33% of cases, grade 2 thrombocytopenia in 12%, and phlebitis in the injection vein in 16%. Mild constipation was also recorded. The combination of cisplatin plus vinorelbine is quite effective in advanced non small cell carcinoma of the lung, and may be safely given on an outpatient basis.