A PHASE-II STUDY OF INTERFERON-ALPHA, INTERLEUKIN-2 AND 5-FLUOROURACIL IN ADVANCED RENAL-CARCINOMA - CLINICAL-DATA AND LABORATORY EVIDENCE OF PROTEASE ACTIVATION

Objective To confirm the activity and evaluate the toxicity of the com bination of subcutaneous interferon-a (IFN-alpha) and interleukin-2 (I L-2) with intravenous 5-fluorouracil (5-FU) in patients with advanced and recurrent renal carcinoma and of performance status 0-2. Additiona lly, to examine protease, complement and neutrophil activation as pote ntial mediators of IL-2 toxcity. Patients and methods Fifty-fine patie nts were treated in an 8-week cycle with IFN-alpha (6 MU/m(2) on day 1 in weeks 1 and 4 and thrice weekly in weeks 2-3, and 9 MU/m(2) thrice weekly in weeks 5-8) IL-2 (20 MU/m(2) on days 3-5 in weeks 1 and 4 an d 5 MU/m(2) thrice weekly in weeks 2-3) and 5-FU (750 mg/m(2) on day 1 of weeks 5-8). Patients responding to the first cycle were eligible t o continue with further cycles. Toxicity and effects on quality of lif e were assessed using World Health Organization criteria and the Rotte rdam Symptom Checklist and Hospital Anxiety and Depression Scale, Seru n levels of C3a, prekallikrein and elastase-rr,proteinase inhibitor (e lastase-alpha(1)-antitrypsin) were assayed in a subset of patients bef ore, during and after the administration of high-dose IL-2 in week 1. Results There were partial remissions in nine patients, with responses in 24% (95% CI 10-38%) of evaluable patients and 16% of all patients. Amongst 25 evaluable patients who had undergone nephrectomy, the resp onse rate was 32% (95% CI 14-50%), whereas there was only one response amongst 22 patients who had not undergone nephrectomy. The median sur vival for patients with stable disease or partial remission exceeded 2 2 months. Outcome and survival were related to performance status, num ber of sites of metastases and nephrectomy. This group of patients was of relatively poor performance status and 18 patients (36%) failed to complete one 8-week treatment cycle. Cardiovascular and renal toxicit ies were less than those seen with intravenous IL-2 schedules but 44% of patients experienced at least one grade III toxicity and only 14% r eported less than two grade II toxicities, Plasma levels of elastase-a lpha(1) proteinase inhibitor exceeded the normal range in three of sev en patients tested before treatment and increased in all seven patient s after treatment with IL-2. The same three patients had raised levels of C3a before treatment and in all patients examined, C3a increased a fter treatment with IL-2, In contrast, plasma prekallikrein concentrat ions were below normal before treatment and decreased further afterwar ds. Conclusions This study confirms the activity of this regimen in pa tients of good performance status, with limited sites of disease and i n those who are fit for nephrectomy, but also showed that treatment wa s associated with considerable toxicity. The administration of IL-2 is associated with protease activation which may be a suitable target fo r pharmacological intervention in attempts to ameliorate toxicity.