DAILY ALTERNATING ADMINISTRATION OF HIGH-DOSE INTERFERON-ALPHA-2B ANDINTERLEUKIN-2 BOLUS INFUSION IN METASTATIC RENAL-CELL CANCER - A PHASE-II STUDY

Background. Both interleukin-2 (IL-2) and alpha-interferon (alpha-IFN) have some efficacy in renal cell cancer (RCC) as single agents. Addit ionally, there is some evidence for additive or synergistic antitumora l activity of IL-2 and alpha-IFN in vitro and possibly in vivo. Based on these data, the authors initiated a Phase II trial with a combinati on of recombinant IL-2 (rIL-2) and recombinant alpha-IFN (alpha-rIFN) in advanced RCC. Methods. Thirty-six assessable patients with metastat ic RCC were entered in this Phase II trial using a daily alternating s chedule of alpha-rIFN and rIL-2. Over a period of 14 days the patients received daily alternating treatment with 10 X 10(6) IU/m2 of recombi nant alpha-2b-interferon subcutaneously and 18 X 10(6) IU/m2 of rIL-2 as a 1-hour intravenous infusion. This treatment schedule was repeated every sixth week up to a maximum of four cycles. After the second cyc le, patients were examined for response. Patients with stable disease or better received two additional cycles of therapy. Patients with pro gressive disease were available for other strategies. Results. Thirty- six patients entered the trial and were assessable for toxic effects. Thirty of 36 patients completed at least two cycles and were assessabl e for response. Nine patients achieved an objective response: 2 had co mplete responses (CR) and 7 had partial responses (PR). Three patients had a minor response. No effect was observed in patients with local r elapse or bone metastases. A relapse-free survival length of 6 months or longer was seen in both patients with CR (12, 23+ months) and in fo ur of seven patients with PR (6, 7, 12,12 months). The toxicity was mo derate and included fever and nausea in most patients, and hypotension , fatigue, skin rash, and arthralgia in a minority of the patients. No Grade 4 and only occasionally Grade 3 toxicity was observed. Fluid re tention was negligible. The monitoring of immunologic parameters showe d a significant rebound lymphocytosis including cytotoxic (CD56+) cell s; in responders the peak of lymphocytosis occurred up to 1 week later than in nonresponders. Peripheral lymphocytes obtained after therapy showed only a slight increase of natural killer cell and lymphokine-ac tivated killer cell activity. During therapy, there was a great releas e of secondary cytokines as tumor necrosis factor-alpha, gamma-interfe ron, and interleukin-6, with a peak level 2-4 hours after rIL-2 infusi on. Conclusions. In conclusion, daily alternating administration of al pha-rIFN and rIL-2 is effective in RCC with less toxicity, and the res ponse rate is comparable to those of other immunotherapeutic schedules , including adoptive immunotherapy and combinations of high-dose IL-2 and alpha-IFN.