A multicentre randomised phase III trial in chemotherapy-naive patients with advanced non-small-cell lung cancer (NSCLC) was undertaken to compare the therapeutic activity and toxicity of a cisplatin/carboplatin-etoposide-vinorelbine combination with that of a cisplatin-etoposide regimen. Patients with advanced (stage IIIB-IV) NSCLC were randomised, after stratification for stage (IIIB-IV) and performance status (0-1 and 2), to receive either (A) CDDP 40 mg m(-2) + VP16 100 mg m(-2) on days 1-3 as standard treatment or (B) CBDCA 250 mg m(-2) on day 1 + CDDP 30 mg m(-2) on days 2 and 3 + VP16 100 mg m(-2) on days 1-3 + NVB 30 mg m(-2) on day 1. Therapy was recycled on day 29 in both arms. We hypothesised a 15% minimum increment in the response rate with the experimental regimen over the 25% expected activity rate of the standard regimen. A two-stage design was chosen, which permitted the early termination of the trial (after the accrual of 52 patients in each arm) if the difference in response rates between the two regimens was less than 3% at the end of the first stage. A total of 112 patients (arm A = 57, arm B = 55) were enrolled in the study (53 with stage IIIB and 59 with stage IV) of which 105 eligible patients were evaluable for response on an 'intention to treat' basis. Seven patients were excluded because they did not fulfil the inclusion criteria. Fifteen responses were observed in arm A (28%, 95% CI = 17-42) and 13 (one complete) in arm B (25%, 95% CI = 13-37). On multivariate logistic analysis, treatment did not affect the response rate, while stage IV and performance status 2 were significantly associated with a lower probability of response. Median survivals were similar in the two arms (31 vs 27 weeks). The experimental regimen was associated with an extremely poor median survival in patients with poor performance status (21 weeks). On Cox analysis, treatment failed to show a significant impact on survival: stage IV (relative risk = 1.6, CI = 1.0-2.6, P = 0.036) was the only prognostic variable significantly associated with a worse survival outcome and, although poor performance status adversely affected survival, this effect did not reach the level of statistical significance (relative risk = 1.6, CI = 0.98-2.5; P = 0.063). There were no significant differences in non-haematological toxicities between the two arms, although three patients in the control arm had to discontinue the treatment because of the persistence of severe nephrotoxicity (two patients) or neurotoxicity (one patient). In contrast, a significant increase in both neutropenia and thrombocytopenia was observed in the experimental arm. Four treatment-related deaths were registered in arm B (two due to neutropenic sepsis, one to myocardial failure and one to acute renal failure) compared with one toxic death (acute renal failure) in arm A. In view of these results, the trial was stopped and the null hypothesis (<15% increase in response rate with the experimental regimen) has been accepted. Therefore, our combination does not deserve further evaluation as first-line treatment in advanced NSCLC patients. As our data suggest that an aggressive chemotherapy might have a negative impact on survival of patients with poor performance status, trials to evaluate the activity of new regimens should be conducted separately for each subset of patients with different performance status.

Seventy previously untreated patients with advanced NSCLC were randomised, after stratification for stage (IIIB vs. IV) and Performance Status (0-1 vs. 2), to receive either treatment A: CDDP 40 mg/m(2) + VP16 100 mg/m(2) day 1-3 (37 patients); or treatment B: CBDCA 250 mg/m(2) day 1 + CDDP 30 mg/m(2) day 2, 3 + VP16 100 mg/m(2) day 1-3 (33 patients). Therapy was recycled on day 29 in both arms. The two arms were well balanced for the main pretreatment characteristics. Sixty-six patients (32 with Stage IIIB and 34 with Stage IV disease) were evaluable for toxicity and response (arm A = 34, arm B = 32), while four ineligible patients were excluded from analysis. Acute toxicity was assessed at recycling. Non-hematologic toxicity was higher in arm. A. However, the reduction of nephrotoxicity (9% vs. 23%) in arm B was lower than expected. Leukopenia (15 vs. 5 patients) or thrombocytopenia (7 vs. 0 patients) of any grade affected more patients of arm B. Moreover, Grade 3-4 leukopenia (six patients) or thrombocytopenia (four patients) was observed only in arm B. Seventeen patients responded: 11/33(32%; 95% C.I. = 17-50%) in arm A, and 6/32 (19%; 95% C.I. = 7-36%) in arm B. Median survival times of 40 and 34 weeks, respectively, were reported in arm A and B. Stage IIIB and squamous cell histology were associated with a higher probability of response, In conclusion, the partial replacement of CDDP with CBDCA in combination with VP16 slightly improves the tolerance of the treatment in terms of nephro- and neurotoxicity; however, it induces a significant increase in hematologic toxicity, In view of this unfavourable toxicologic profile and of the discouraging response rate observed, this regimen cannot be recommended as standard treatment in advanced NSCLC.

AIMS AND BACKGROUND:The treatment of elderly patients with metastatic solid tumours is still a debated problem. Patients over 75 years are generally excluded from combination chemotherapy trials because of higher toxicity. Several clinical studies have shown that weekly low dose epirubicin is a well tolerated and effective treatment for elderly cancer patients (breast, prostate, lung).METHODS:We report a study of patients aged between 75 and 85 years affected by metastatic anthracyclines-sensible carcinomas, to assess the tolerance of epirubicin given weekly at a dose of 25 mg/m2.RESULTS:25 patients (13 males, 12 females; ECOG P.S. 0-2) entered the study and were evaluable for side effects. One-hundred and ninety-six cycles of therapy have been administered. Side effects were never severe. Mucositis (9 patients), leucopenia (7 patients), anemia (5 patients) were usually of grade 1 or 2. Grade 1 cardiotoxicity (tachycardia) was observed in only one case. Grade 3 toxicity consisted in anemia (1 patient) and mucositis (1 patient), while grade 4 toxicity never occurred. Nineteen patients were evaluable for response: 0 CR, 4 PR (1 lung, 3 breast), 8 SD (3 lung, 3 breast, 2 prostate) have been observed. Compliance was encouraging and the majority of patients showed a decrease in symptoms and an improvement in performance status.CONCLUSIONS:Weekly low-dose epirubicin is a very well tolerated treatment in elderly cancer patients. In view of the negligible toxicity encountered, it could be of utility to test this regimen in patients aged 75 years or older, affected by anthracyclines-sensible metastatic tumors, also to assess activity.

Purpose This phase II study was undertaken to define the toxicity and therapeutical activity of a Fotemustine-DTIC-IFN combination in patients (pts) with metastatic melanoma. Methods Treatment consisted of Fotemustine 100 mg/m2 i.v. d 1, DTIC 250 mg/m2 d 2–5 every 3 weeks. IFN 3 MUI was administered i.m. 3 times a week throughout the chemotherapy administration. Results At the time of this analysis (08–03–1995) 35 pts (20 M, 15 F; age range 24–75 years; 26 chemotherapy-naive; 26 with visceral or SNC involvement) have been treated for a total of 125 courses. Twenty-six pts are presently evaluable for response (3 non-eligible for major protocol violation, and 6 too early). One CR and 5 PR have been observed for a 23% ORR [95% C.I. 9–44]. The patient with CR had skin, lymph nodal and renal involvement at beginning of the treatment. Toxicity 32 pts are evaluable for toxicity for a total of 122 courses. The treatment has been generally well tolerated. Toxic deaths have not been registered Leucopenia and thrombocytopenia of grade 3–4 have been observed in only 2.5% and 6.5% of the total delivered courses respectively. Grade 3 anemia occurred in one patient. IFN-related fever occurred in 11.5% of the courses and was always mild. Conclusions Fotemustine–DTIC–IFN combination seems a well tolerated and quite effective treatment for patients with metastatic melanoma. Since we chose a 35% ORR as target activity level, and considered 20% ORR as the lowest level of interest, at least 7 responses in 31 evaluable pts are required in the first -stage of the trial to continue the accrual to a total of 53 pts. This phase II study was undertaken to define the toxicity and therapeutical activity of a Fotemustine-DTIC-IFN combination in patients (pts) with metastatic melanoma. Treatment consisted of Fotemustine 100 mg/m2 i.v. d 1, DTIC 250 mg/m2 d 2–5 every 3 weeks. IFN 3 MUI was administered i.m. 3 times a week throughout the chemotherapy administration. At the time of this analysis (08–03–1995) 35 pts (20 M, 15 F; age range 24–75 years; 26 chemotherapy-naive; 26 with visceral or SNC involvement) have been treated for a total of 125 courses. Twenty-six pts are presently evaluable for response (3 non-eligible for major protocol violation, and 6 too early). One CR and 5 PR have been observed for a 23% ORR [95% C.I. 9–44]. The patient with CR had skin, lymph nodal and renal involvement at beginning of the treatment. 32 pts are evaluable for toxicity for a total of 122 courses. The treatment has been generally well tolerated. Toxic deaths have not been registered Leucopenia and thrombocytopenia of grade 3–4 have been observed in only 2.5% and 6.5% of the total delivered courses respectively. Grade 3 anemia occurred in one patient. IFN-related fever occurred in 11.5% of the courses and was always mild. Fotemustine–DTIC–IFN combination seems a well tolerated and quite effective treatment for patients with metastatic melanoma. Since we chose a 35% ORR as target activity level, and considered 20% ORR as the lowest level of interest, at least 7 responses in 31 evaluable pts are required in the first -stage of the trial to continue the accrual to a total of 53 pts.