An ongoing prospective randomized comparison of interleukin-2 regimens for the treatment of metastatic renal cell cancer

PURPOSE: This article compares the pharmacokinetics, toxicity, and clinical efficacy of high-dose intravenous, low-dose intravenous, and intermediate-dose subcutaneous recombinant interleukin-2 (rIL-2) regimens in patients with measurable metastatic renal cell carcinoma. PATIENTS AND METHODS: This trial began as a two-arm randomized study comparing two bolus intravenous rIL-2 regimens. High-dose (720,000 IU/kg) and low-dose (72,000 IU/kg) rIL-2 were administered every 8 hours for up to 15 consecutive doses. Later, a third arm of outpatient subcutaneous rIL-2 (week 1:250,000 IU/kg/day for 5 of 7 days; weeks 2-6: 125,000 IU/kg/day for 5 of 7 days) was added, and only concurrently randomized patients were compared. A sample of patients underwent pharmacokinetic studies of serum IL-2 levels following their first dose. Accrual to this study is ongoing and results are preliminary. RESULTS: In the two-arm comparison of high-dose versus low-dose intravenous rIL-2, 116 and 112 patients have been randomized, respectively, and the median follow- up is 52 months. Low-dose rIL-2 induced significantly less hypotension, thrombocytopenia, malaise, pulmonary toxicity, and neurotoxicity than high- dose rIL-2. The initial overall response rate (partial plus complete responses) was 19% with high-dose rIL-2 and 10% with low-dose rIL-2. Responses to high-dose rIL-2 tended to be more durable. With 54 to 56 patients randomized per arm in the three-arm comparison, the high-dose intravenous, low-dose intravenous, and subcutaneous outpatient rIL-2 regimens have produced response rates of 16%, 4%, and 11%, respectively. Subcutaneous rIL-2 therapy was infrequently associated with grade 3 or 4 toxicity (similar to low-dose intravenous rIL-2 therapy). Survival data remain incomplete with median follow-up in the three-arm trial at 27 months. DISCUSSION: The optimal IL-2 regimen for treating metastatic renal cell carcinoma is not known. Alternative regimens with much less acute toxicity than high-dose IL-2 can cause regression of renal cell carcinoma, but duration of therapy, chronicity of symptoms, and quality-of-life issues may be important in properly evaluating the tolerability of different regimens. Because the main benefit of IL-2 therapy is not its initial response rate but its induction of durable, complete responses, further accrual and follow-up will be necessary to compare properly the impact of these regimens on patient survival.