Daily alternating administration of high-dose alpha-2b-interferon and interleukin-2 bolus infusion in metastatic renal cell cancer. A phase II study

Abstract

Background. Both interleukin‐2 (IL‐2) and alpha‐interferon (α‐IFN) have some efficacy in renal cell cancer (RCC) as single agents. Additionally, there is some evidence for additive or synergistic antitumoral activity of IL‐2 and α‐IFN in vitro and possibly in vivo. Based on these data, the authors initiated a Phase II trial with a combination of recombinant IL‐2 (rIL‐2) and recombinant α‐IFN (α‐rIFN) in advanced RCC. Methods. Thirty‐six assessable patients with metastatic RCC were entered in this Phase II trial using a daily alternating schedule of α‐rIFN and rIL‐2. Over a period of 14 days, the patients received daily alternating treatment with 10 × 106 IU/m2 of recombinant alpha‐2b‐interferon subcutaneously and 18 × 106 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 cycle, patients were examined for response. Patients with stable disease or better received two additional cycles of therapy. Patients with progressive 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 assessable for response. Nine patients achieved an objective response: 2 had complete responses (CR) and 7 had partial responses (PR). Three patients had a minor response. No effect was observed in patients with local relapse 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 four of seven patients with PR (6, 7, 12, 12 months). The toxicity was moderate 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 retention was negligible. The monitoring of immunologic parameters showed a significant rebound lymphocytosis including cytotoxic (CD56+) cells; 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‐activated killer cell activity. During therapy, there was a great release of secondary cytokines as tumor necrosis factor‐alpha, γ‐interferon, and interleukin‐6, with a peak level 2–4 hours after rIL‐2 infusion. Conclusions. In conclusion, daily alternating administration of α‐rIFN and rIL‐2 is effective in RCC with less toxicity, and the response rate is comparable to those of other immunotherapeutic schedules, including adoptive immunotherapy and combinations of high‐dose IL‐2 and α‐IFN.

Natural history and therapy of metastatic renal cell carcinoma

“…bolus injection, the majority of combination therapy patients received s.c. rIL‐2, in contrast with its use a single agent. When taken collectively, these Phase I and II trials yielded response rates of approximately 20% in >1200 patients with metastatic RCC 131, 138, 139, 149, 158, 162‐90…”

Feasibility of prolonged use of interferon‐α in metastatic kidney carcinoma

“…Despite the pause, the response rate of the patients was similar, and survival was even longer compared with previous reports with continuous IFN-␣, 5,6,9,25 IFN-␣, and vinblastine 19 and other combination treatments including interleukin-2. 8,11,24,26 A randomized trial previously has indicated that IFN-␣ increases the survival rate of RCC patients. 19,27 In most previous studies, the duration of the treatment with IFN-␣ has been 6 -12 weeks, 5,15,17 and most responses have been observed within 2 or 4 months of treatment start.…”

New Advances in Interferon Therapy of Cancer

“…Of interest has been the use of low-or intermediate-dose combinations of the two in outpatient regimens. Most of these have been well tolerated, with response rates that have been higher than expected in some cases (Table 3) [69,[81][82][83][84][85][86][87][88][89]. Modifications of this combination have included the use of low-dose infusional or s.c. immunotherapy in combination with chemotherapy, without a demonstrable advantage, and the use of cytokine therapy with IFN-activated tumor-infiltrating lymphocytes.…”