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In patients with metastatic renal cell carcinoma response rates of 7-26% have been achieved with immunotherapy. A high response rate of 48% in 35 patients has been reported for treatment with the combination of interferon-alpha (IFN-alpha), interleukin-2 (IL-2) and 5-fluorouracil (5-FU) (Atzpodien et al (1993a) Eur J Cancer29A: S6-8). We conducted a multicentre phase II study to confirm these results. Metastatic renal cell carcinoma patients were treated as outpatients with an 8-week treatment cycle. Recombinant human IL-2 20 MU m(-2) was administered subcutaneously (s.c.) three times a week (t.i.w) in weeks 1 and 4 and 5 MU m(-2) t.i.w. in weeks 2 and 3. Recombinant human IFN-alpha 2a 6 MU m(-2) was administered s.c. once in weeks 1 and 4 and t.i.w. in weeks 2 and 3, and 9 MU m(-2) t.i.w. in weeks 5-8. 5-FU (750 mg m(-2)) was given as a bolus injection intravenous once a week in weeks 5-8. The treatment cycle was repeated once in case of response or minor response. Fifty-two patients entered the study. All had undergone a nephrectomy and had progressive metastatic disease. The median WHO-performance status was 1, the median number of metastatic sites was 2 (range 1-5) and the median time between the diagnosis of the primary tumour and the start of treatment was 12.9 months (range 1-153). Among the 51 patients, including four patients with early progressive disease, who were evaluable for response, the response rate was 11.8% (95% confidence interval (CI) 2.9-20.7%), with no complete responses. Median duration of response was 8.3 (range 3.8-22.4+) months. Median survival was 16.5 (range 1.8-30.5+) months. Grade 3/4 toxicity (WHO) occurred in 29/52 (55.8%) of the patients in cycle 1 and in 6/16 (37.5%) of the patients in cycle 2. It consisted mainly of anorexia, fatigue, nausea, fever and leucocytopenia. We cannot confirm the high response rate in patients with metastatic renal cell carcinoma treated with the combination of IFN-alpha, IL-2 and 5-FU, as described by Atzpodien et al.

Purpose: To analyze the putative relationship between immunotherapy-associated dysthyroidism and the probability of a tumor response., Patients and Methods: A total of 89 consecutive patients with advanced cancer were treated with interleukin-2 (IL2)-based immunotherapy in a prospective study., Results: Twenty patients developed thyroid dysfunction. Repeatedly positive tests for thyroid antibodies developed in 28% of the patients. Twenty-two patients achieved a response. There was no relationship between the formation of antibodies and the probability of response. There appeared to be a trend toward a relationship between thyroid dysfunction and response (P = .23). A strong relationship was found between response on the one hand and cumulative dose of IL2 (P = .01) and treatment duration with IL2 (P = .025) on the other. The frequency of thyroid dysfunction was also significantly correlated with treatment duration (P = .001). After adjustment for cumulative dose of IL2 and treatment duration, no relationship between thyroid dysfunction and response remained (P = .99)., Conclusion: There is no relationship between thyroid dysfunction and the probability of tumor response. Thyroid dysfunction is merely a function of treatment duration and cumulative dose of IL2.

A phase I trial was performed with a new interleukin-2 (IL-2) given as a continuous intravenous infusion in patients with solid tumors. The objectives of the study were to examine the feasibility of administering IL-2 in 4-day cycles for 4 consecutive weeks, and to investigate the response pattern of peripheral blood lymphocytes. Tumor necrosis factor (TNF) and IL-2 serum concentrations were also measured. Prior to this study, IL-2 had been tested at increasing dosages during one 4-day cycle, and it appeared that a dose of 1300 mcg/m2/day was tolerated. However, when this treatment schedule was maintained for 4 consecutive weeks, the maximum tolerated dose was 430 mcg/m2/day. In this schedule, a dose-dependent progressive increase in rebound lymphocyte count occurred after each weekly cycle, resulting in a 5-70-fold increase after the 4th cycle. Serum TNF peak concentrations also showed a tendency to increase during each subsequent cycle, while serum IL-2 peak concentrations showed a paradoxical decrease. Clinical toxicity comprised several events, which, possibly, could be ascribed to autoimmune phenomena. Myocardial infarction as a late toxicity of IL-2 is suggested. One complete response (renal carcinoma) and two partial responses (renal and breast carcinoma) were documented, one of these occurring in a patient who previously had shown a transient response on interferon therapy.