TREATMENT OF ADVANCED RENAL-CELL CANCER WITH SEQUENTIAL INTRAVENOUS RECOMBINANT INTERLEUKIN-2 AND SUBCUTANEOUS ALPHA-INTERFERON

Starting from in vitro studies suggesting synergistic antitumour activ ity against renal cell cancer (RCC) of recombinant interlukin-2 (rIL-2 ) and alpha-interferon (IFN), a phase II trial was initiated to test t he clinical activity of this combination. The two cytokines were admin istered sequentially, with the aim of reducing the risk of additive to xicity and enhancing the immunological reaction against the tumour. Th e original treatment schedule consisted of rIL-2 18 x 10(6) U/m(2)/day by continuous intravenous infusion for 120 h days 1-5, and alpha-IFN 2b, at a flat dose of 9 x 10(6) U by subcutaneous or intramuscular inj ection thrice in a week, from day 8 to 28. Treatment was planned to be continued for six or more 28-day cycles, depending on clinical respon se. 12 patients were treated according to this schedule; as some cardi ovascular toxicity was experienced in this set of patients, 11 further patients were treated with half-dose rIL-2 (i.e. 9 x 10(6) U/m(2)/day ). 17 out of 23 enrolled patients completed at least one cycle of trea tment and were evaluated for response. We observed six major responses [one complete response (CR) + five partial responses (PR)] for an obj ective response rate of 35% [95% confidence interval (CI) 17-59%]. 5 a dditional patients achieved stabilisation of disease; one of them reac hed CR after surgical extirpation of a lung mass. Sites of response in cluded lung, nodes and bone. Duration of responses is 12+ months for C R; 17, 16, 12+, 9 and 9 months for PRs. Median survival is 16 months. Response was not significantly different between full-dose and half-do se rIL-2. Considering stable disease (SD) as responses, there seemed t o be a higher chance of response for patients with smaller tumour burd en (P = 0.032). The toxicity of rIL-2 treatment, mainly cardiovascular , was substantial; 9 patients experienced severe cardiotoxicity, consi sting of major arrhythmias, myocardial ischaemia, reduction of ejectio n fraction measured with hart radionuclide scan, and were excluded fro m continuing treatment. Other rIL-2-related toxicities forcing exclusi on from the study were severe thrombocytopenia (1 case), and generalis ed exfoliative dermatitis requiring steroids (1 case). Otherwise, trea tment was well tolerated; rIL-2-related toxicities promptly recovered after rIL-2 discontinuation in the majority of cases, and no treatment -related deaths were reported. The half-dose rIL-2 regimen was signifi cantly less toxic in terms of hypotension (P = 0.014), fever (P = 0.01 4), oliguria (P = 0.042), serum creatinine elevation (P = 0.009) and p rothrombin time elongation (P = 0.038). alpha-IFN was not related to m ajor toxicities. We conclude that the sequential administration of rIL -2 by continuous intravenous infusion and alpha-IFN by intramuscular o r subcutaneous injection following our treatment schedule is feasible and active in RCC. Recombinant IL-2 9 x 10(6) U/m(2)/day seems to be e qually effective and less toxic than 18 x 10(6) U/m(2)/day. However, c ardiovascular toxicity remains a major problem; particularly, arrhythm ias and ischaemic events are poorly predictable and preventable.