Adjuvant low-dose IL2 plus IFNα in operable renal cell carcinoma: a phase III, randomized, multicenter trial

INTRODUCTION AND AIMS: In non-metastatic, resected renal cell carcinoma, the standard approach is observation but about 30% of the patients develop metastases during the 5 years following nephrectomy. No trials have so far demonstrated any benefit with the use of adjuvant therapies. Immunotherapy with low-dose IL2 plus IFNα is effective and well tolerated in patients with metastatic RCC. We investigated whether this immunotherapeutic approach may prevent the occurrence of metastases and prolong recurrence-free survival (RFS) in patients with operable RCC. METHODS: We enrolled patients with a biopsy-proven diagnosis of RCC, age <75, previous nephrectomy and no residual disease. Exclusion criteria were the presence of autoimmune diseases and severe arrhythmias. The patients were stratified according to the tumour stage and grade, and then randomized to treatment or observation. Treatment consisted of repeated cycles of IL2 and IFNα: IL2 was administered s.c. 5 days per week (1*106 IU/m2, twice daily on days 1 and 2 and once daily on days 3-5) and IFNα i.m. twice weekly (1.8*106 IU/m2, once a day on days 3 and 5); each immunotherapy cycle consisted of four consecutive weeks. The cycles were repeated every four months during the first 2 years and every 6 months for the following 3 years (total, 12 cycles during 5 years). RESULTS: A total of 310 patients were enrolled between 1996 and 2006, 7 were not eligible because of acute coronary disease: 151 patients were randomized to treatment and 152 to observation. The characteristics of the patients were comparable in the two groups. The median follow-up was 52 months, and the median number of immunotherapy cycles 6 per patient (range 0-16). 77 patients (25.4%) had disease recurrence and 59 (19.5%) died during the study period. RFS was longer in the treatment than in the observation arm, but the difference did not reach statistical significance (hazard ratio, HR 0.81, 95% CI 0.51-1.27, p=0.36). No differences were observed in overall survival. Subgroup analysis showed that the effect of immunotherapy was relevant in patients with age<60 y (p=0.13), tumour grade 1-2 (p=0.14), T3a tumours (p=0.16), and negative lymph nodes (p=0.07). Interaction analysis showed that immunotherapy significantly prolonged RFS in patients with two or more of the above factors (HR 0.44, 95% CI 0.24-0.82, p=0.002). Treatment-related toxicity was mainly limited to WHO grades 1-2. CONCLUSIONS: Adjuvant immunotherapy with low-dose IL2 and IFNα does not prolong RFS in the whole population of patients with operable RCC. However, age<60, negative lymph nodes, T3a and grade 1-2 are predictive of benefit and, in the presence of two or more of these factors, immunotherapy significantly prevents disease recurrences