Long-term immunotherapy with low-dose interleukin-2 and interferon-alpha in the treatment of patients with advanced renal cell carcinoma

Abstract

Background: The objective of this study was to evaluate response, toxicity, and immunologic effects of an original immunotherapy schedule based on repeated cycles of low doses of recombinant interleukin-2 (rIL-2) and recombinant interferon-alpha (rIFNalpha) in patients with metastatic renal cell carcinoma (mRCC).

Methods: Fifty patients who underwent nephrectomy received therapeutic cycles consisting of subcutaneous rIL-2 for 5 days per week and intramuscular rIFNalpha twice weekly for 4 consecutive weeks. The cycle was regularly repeated indefinitely at 4-month intervals in all patients, irrespective of their response. rIL-2 (1 x 10(6) IU/m(2)) was administered every 12 hours on Days 1 and 2 and once per day on Days 3-5 of each week; rIFNalpha (1.8 x 10(6) IU/m(2)) was given on Days 3 and 5. Toxicity was graded according to the World Health Organization (WHO) criteria. Forty percent of the patients had only one metastatic disease site at the time of treatment. The Kaplan-Meier method was used to estimate survival, and an analysis of variance was used to evaluate the effects on leukocytes and lymphocyte subsets over time.

Results: A total of 241 cycles were administered. One patient achieved a complete response, and five patients achieved a partial response. Five patients had stable disease, and 30 patients had progressive disease. Nine patients were not evaluable for response. The overall response rate was 12% (95% confidence interval, 3-21%) on the basis of an intent-to-treat analysis. The 36-month survival probability for all 50 patients was 47%. Treatment-related toxicity was limited to WHO Grades 1 and 2. Both lymphocyte and eosinophil levels significantly increased after all cycles (by 42% and 353%, respectively). The treatment also induced significant increases in the CD25 positive (24%), CD56 positive (28%), and CD3 negative/CD56 positive (54%) lymphocyte subsets.

Conclusions: Long-term, repeated treatment with low doses of rIL-2 and rIFNalpha is feasible in patients with mRCC. The schedule induces clinical response rates and survival probabilities are similar to those obtained using higher doses.