ADDITION OF DACARBAZINE OR CISPLATIN TO INTERFERON-ALPHA INTERLEUKIN-2 IN METASTATIC MELANOMA - TOXICITY AND IMMUNOLOGICAL EFFECTS

The combination of chemotherapy and immunotherapy seems to improve res ponse rate in metastatic melanoma. We investigated the effects on toxi city and immunological effects of a single dose of dacarbacin (DTIC; 8 50 mg/m(2)) or cisplatin (CDDP; 100 mg/m(2)) added to subsequent immun otherapy with interferon-alpha (IFN-alpha) and interleukin-2 (IL-2). T welve patients, who did not respond to IFN-alpha/IL-2 alone were studi ed. Six received DTIC and IFN-alpha/IL-2, and six received CDDP and IF N-alpha/IL-2. DTIC did not add significant toxicity except for nausea. Significant thrombocytopenia was observed in two patients after CDDP. Although CDDP led to grade 3 nephrotoxicity in two patients, the IL-2 -induced fluid retention was less severe than with IFN-alpha/IL-2 alon e. Pharmacokinetics of IL-2 were not altered by DTIC, but higher IL-2 serum levels were found in patients with grade 3 nephrotoxicity after CDDP. The IL-2-related induction of secondary mediators (interferon-ga mma, tumour necrosis factor-alpha, soluble CD25) was not impaired by c hemotherapy and the induction of neopterin was significantly higher af ter addition of CDDP. One partial response was observed after addition of DTIC to IFN-alpha/IL-2, and one after addition of CDDP. The additi on of a single dose of DTIC or CDDP to IFN-alpha/IL-2 is fairly well t olerated and does not abolish induction of secondary mediators. Random ized trials are necessary to test the clinical efficacy.