Placebo-associated remissions in a multicentre, randomized, double-blind trial of interferon gamma-1b for the treatment of metastatic renal cell carcinoma

Objective To determine the validity of using an historical maximum spontane ous regression rate (reportedly 0-1.1% in those with lung metastases after nephrectomy) in clinical trials of treatments for patients with metastatic renal cell carcinoma (RCC), as the eligibility criteria for most studies wi ll select patients with better performance status (and thus excluding those who are unlikely to respond) and more modern staging methods would potenti ally reduce the number of false-positives. Patients and methods A multicentre randomized,placebo-controlled, double-bl ind trial was recently completed in which 197 patients with metastatic RCC from 17 study centres across Canada were randomized to receive placebo or r ecombinant interferon gamma-1b (60 mu g/m(2)) subcutaneously once every 7 d ays until disease progression. All tumour responses were validated by an in dependent response committee unaware of the treatment. Results The median (95% confidence interval) overall response rate (complet e, CR, and partial, PR) for those on interferon-gamma was 4 (1.4-11.5)% and for those on placebo was 6 (2.5-13.2)% (P = 0.75). In the six patients who were receiving placebo the CR and PR (three each) was considered to repres ent spontaneous remission. Of these six patients (aged 44-64 years) five ha d undergone nephrectomy, one a tumour embolization, four had clear cell car cinoma and one an adenocarcinoma, and all had regression of lung and/or lym ph node metastases. Conclusion The lack of efficacy of interferon-gamma in this trial underline s the importance of continued research to identify alternative therapeutic agents or combinations of agents in phase II studies. However, the threshol d response rate for initiating phase III trials should be increased to 18% in the phase II trials, i.e. three times the response rate on placebo.