Cisplatin, gemcitabine, and paclitaxel in locally advanced or metastatic non-small-cell lung cancer: a phase I-II study. Southern Italy Cooperative Oncology Group.

PURPOSE: Because both cisplatin-paclitaxel and cisplatin-gemcitabine combinations are generally considered to be among the most active regimens in non-small-cell lung cancer (NSCLC) patients, this study aimed to determine the maximum-tolerated dose (MTD) of paclitaxel when combined with fixed doses of cisplatin and gemcitabine in advanced NSCLC patients and aimed to define the therapeutic activity of this new regimen. PATIENTS AND METHODS: From October 1996 to September 1998, 75 patients with stage IIIB-IV NSCLC, who were either chemotherapy-naive (65 patients) or who had been pretreated (10 patients), received fixed doses of cisplatin (50 mg/m(2)) and gemcitabine (1,000 mg/m(2)) and escalating doses of paclitaxel in a 1-hour infusion, all on days 1 and 8, every 3 weeks. RESULTS: Five different paclitaxel doses were tested, for a total of 275 cycles delivered. The escalation was stopped at the paclitaxel dose of 75 mg/m(2) in pretreated patients, whereas it continued to 150 mg/m(2) in chemotherapy-naive patients. A total of 65 chemotherapy-naive patients were treated. A paclitaxel dose of 125 mg/m(2) was recommended for phase II, and a total of 39 patients were treated at this level, for a total of 158 cycles delivered. No treatment-related deaths occurred. Five patients were hospitalized because of sepsis, and packed RBC transfusion was required in 13 patients. Grade 4 neutropenia and thrombocytopenia occurred in 23 (31%) and eight (11%) patients, respectively. Overall, 74 of the 75 patients were assessable for response. Four complete (CR) and 38 partial (PR) responses were recorded, for an overall response rate (ORR) of 57%. Three of the ten pretreated patients achieved a PR, compared with four CRs and 35 PRs in the 64 chemotherapy-naive patients (ORR, 61%). Thirty-eight of 39 patients included in phase II were assessable for response and quality of life (QOL) (one patient's disease was not measurable). Two CRs and 24 PRs were recorded in this group, for an ORR of 68% (95% confidence interval, 51% to 82%). The QOL score improved in 27 of 38 (71%) patients. The median survival time was 15 months in the 65 chemotherapy-naive patients, but it had not yet been reached in the 39 patients included in phase II, for whom the 1-year projected survival was 70%. CONCLUSION: The cisplatin-gemcitabine-paclitaxel combination is a feasible and well-tolerated approach in advanced NSCLC patients. Both a major response and a QOL improvement can be obtained in a high proportion of patients, with a median survival time exceeding 1 year. A phase III trial comparing this combination with other effective regimens is under way.

Cisplatin, gemcitabine and vinorelbine in locally advanced or metastatic non-small-cell lung cancer: a phase I study.

PURPOSE: The objective of this study was to determine the maximally tolerable doses (MTDs) of vinorelbine (VNR) and gemcitabine (GEM) when combined with a fixed dose of cisplatin (CDDP). PATIENTS AND METHODS: Chemotherapy-naive patients with stage IIIB-IV non-small-cell lung cancer (NSCLC) received a fixed dose of CDDP (50 mg/m2) and escalating doses of VNR (starting from 20 mg/m2) and GEM (starting from 800 mg/m2) on days 1 and 8, every three weeks. The single escalation of GEM alone, by 200 mg/m2 at each step, was initially planned up to a dose of 1,200 mg/m2, to be followed by increments of the VNR dose of 5 mg/m2 at each step. RESULTS: Thirty-one patients were enrolled at five different dose levels. The escalation was stopped at level 4 (GEM 1,200 mg/m2 and VNR 25 mg/m2) since two of six patients of this cohort showed dose-limiting neutropenia at treatment cycle 1. Two different dose levels, GEM 1,200 mg/m2 + VNR 20 mg/m2, and GEM 1,000 mg/m2 + VNR 25 mg/m2 were fairly well tolerated. No treatment-related deaths occurred. Neutropenia was the main toxic effect, occurring in 76% of the total of 116 cycles delivered, and in 24% of them was of grades 3 or 4. A total of eight patients (26%) experienced grade 4 neutropenia lasting more than seven days; in five of them it occurred in the first course. Neutropenic fever was observed in four cases. Grade 4 thrombocytopenia occurred in only two patients. Non-hematologic toxicity was a minor problem in all patients but was never dose-limiting. No complete responses were obtained, but sixteen out of 31 (52%) patients achieved partial responses. The median duration of response was 20 (range 6-56+) weeks, while at a nine-month median follow-up, the median survival time has not yet been reached. To date, 18 patients are still alive. The one-year projected survival for all patients was 51%. CONCLUSIONS: Our results show that CDDP, VNR and GEM can be safely given together without substantial reductions in their individual dose intensities. In our opinion, the dose level of GEM 1,000 mg/m2 + VNR 25 mg/m2 given in combination with CDDP 50 mg/m2 on days 1 and 8 of a three-week cycle can be recommended for phase II trials, since it provides a better balance in dose intensity of GEM and VNR. A phase II randomised study is underway to establish the activity of this new regimen (at the above-cited dose level) in chemo-naive NSCLC patients.

Cisplatin-topotecan-paclitaxel weekly administration with G-CSF support for ovarian and small-cell lung cancer patients: a dose-finding study.

PURPOSE: Paclitaxel (PTX) and topotecan (TPT) have shown promising antitumor activity in both ovarian cancer (OC) and small-cell lung cancer (SCLC) patients. This phase I study was aimed at determining the maximum tolerable dose (MTD) of TPT given weekly over 30 min in combination with fixed doses of cisplatin (CDDP) and (PTX), and with G-CSF support. PATIENTS AND METHODS: Forty-four patients with OC (19) or SCLC (25), either chemo-naïve (20) or pretreated (24) received CDDP 40 mg/m2, PTX 85 mg/m2 (one-hour infusion) and escalating TPT doses (starting from 0.75 mg/m2) in a 30-min infusion in weekly administration. Filgrastim 5 mg/kg was administered on days 3 to 5 of each week. RESULTS: Eight different dose levels were tested for a total of 295 delivered cycles. The dose escalation was interrupted at the TPT dose of 2.50 mg/m2. No toxic deaths occurred in this study. Grade 3 to 4 neutropenia, thrombocytopenia, and anemia occurred in 15 patients (36 cycles), seven patients (15 cycles), and four patients (five cycles), respectively. Severe vomiting and diarrhoea occurred in seven and four patients. Peripheral neuropathy was recorded in 11 patients (42 cycles), but it was never severe. An overall 11 of 19 (58%) OC and 11 of 25 (44%) SCLC patients obtained objective responses. Eight patients showed complete responses (three OC and three SCLC). Among the 20 chemo-naïve patients, 9 of 11 (82%) OC and seven of nine (78%) SCLC responded. CONCLUSIONS: The CDDP/TPT/PTX weekly administration with filgrastim support represents a well-tolerated and active therapeutic approach in both chemo-naïve and pretreated OC and SCLC patients. A weekly dose of TPT of 2.25 mg/m2 is recommended for the phase II study.