CISPLATIN CARBOPLATIN PLUS ETOPOSIDE PLUS VINORELBINE IN ADVANCED NON-SMALL-CELL LUNG-CANCER - A MULTICENTER RANDOMIZED TRIAL/

A multicentre randomised phase III trial in chemotherapy-naive patient s with advanced non-small-cell lung cancer (NSCLC) was undertaken to c ompare the therapeutic activity and toxicity of a cisplatin/carboplati n-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 + C DDP 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 exp erimental regimen over the 25% expected activity rate of the standard regimen. A two-stage design was chosen, which permitted the early term ination of the trial (after the accrual of 52 patients in each arm) if the difference in response rates between the two regimens was less th an 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 respo nse on an 'intention to treat' basis. Seven patients were excluded bec ause they did not fulfil the inclusion criteria. Fifteen responses wer e 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 stat us 2 were significantly associated with a lower probability of respons e. Median survivals were similar in the two arms (31 vs 27 weeks). The experimental regimen was associated with an extremely poor median sur vival in patients with poor performance status (21 weeks). On Cox anal ysis, 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 progno stic variable significantly associated with a worse survival outcome a nd, 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 diffe rences in non-haematological toxicities between the two arms, although three patients in the control arm had to discontinue the treatment be cause of the persistence of severe nephrotoxicity (two patients) or ne urotoxicity (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 n eutropenic sepsis, one to myocardial failure and one to acute renal fa ilure) compared with one toxic death (acute renal failure) in arm A. I n view of these results, the trial was stopped and the null hypothesis (<15% increase in response rate with the experimental regimen) has be en accepted. Therefore, our combination does not deserve further evalu ation as first-line treatment in advanced NSCLC patients. As our data suggest that an aggressive chemotherapy might have a negative impact o n survival of patients with poor performance status, trials to evaluat e the activity of new regimens should be conducted separately for each subset of patients with different performance status.