RANDOMIZED PHASE-II TRIAL OF BCDT [CARMUSTINE (BCNU), CISPLATIN, DACARBAZINE (DTIC) AND TAMOXIFEN] WITH OR WITHOUT INTERFERON-ALPHA (IFN-ALPHA) AND INTERLEUKIN (IL-2) IN PATIENTS WITH METASTATIC MELANOMA

The purpose of this study was to evaluate in a randomized phase II tri al the efficacy and toxicity of combination biochemotherapy compared w ith chemotherapy alone in patients with metastatic melanoma. Sixty-fiv e patients with metastatic melanoma (ECOG performance status 0 or 1) w ere randomized to receive intravenous BCNU 100 mg m(-2) (day 1, altern ate courses), cisplatin 25 mg m(-2) (days 1-3), DTIC 220 mg m(-2) (day s 1-3) and oral tamoxifen 40 mg (BCDT regimen) with (n = 35) or withou t (n = 30) subcutaneous interleukin 2 (IL-2) 18 x 10(6) iu t.d.s. (day -2), 9 x 10(6) iu b.d. (day -1 and 0) and interferon 2 alpha (IFN-alp ha) 9 MU (days 1-3), Evidence for immune activation was determined by flow cytometric analysis of peripheral blood lymphocytes. Treatment wa s repeated every 4 weeks up to six courses depending on response. The overall response rate of BCDT with IL-2/IFN-alpha was 23% [95% confide nce interval (CI) 10-40%] with one complete response (CR) and seven pa rtial responses (PR), and for BCDT alone 27% (95% CI 12-46%) with eigh t PRs; the median durations of response were 2.8 months and 2.5 months respectively. Sites of response were similar in both groups. There wa s no difference between the two groups in progression-free survival or overall survival (median survival 5 months for BCDT with IL-2/IFN alp ha and 5.5 months for BCDT alone). Although 3 days of subcutaneous IL- 2 resulted in significant lymphopenia, evidence of immune activation w as indicated by a significant rise in the percentage of CD56- (NK cell s) and CD3/HLA-DR-positive (activated T cells) subsets, without any ch ange in the percentage of CD4 or CD4 T-cell subsets. Toxicity assessme nt revealed a significantly higher incidence of severe thrombocytopeni a in patients treated with combination chemotherapy than with chemothe rapy alone (37% vs 13%, P = 0.03) and a higher incidence of grade 3/4 flu-like symptoms (20% vs 10%) and fatigue (26% vs 13%). The addition of subcutaneous IL-2 and IFN alpha to BCDT chemotherapy in a randomize d phase II trial resulted in immune activation but did not improve res ponse rates in patients with metastatic melanoma, and indeed may incre ase some treatment-related toxicity.