A clinical trial of procarbazine plus vincristine plus bis-chloroethyl-nitrosourea plus imidazole carboxamide dimethyl triazeno in metastatic malignant melanoma

Abstract

Only a limited percentage of patients with metastatic malignant melanoma respond to single-agent chemotherapy. Vincristine, procarbazine, imidazole carboxamide dimethyl triazeno (DTIC) and bis-chloroethyl-nitrosourea (BCNU) have been used as single agents by various investigators. A response rate of +/- 20% was seen with vincristine (1-3) and BCNU (3, 4), and a response rate of 20-30% has been observed with DTIC (3, 5-8) and procarbazine (3, 9, 10). Newer agents such as triazeno imidazole carboxamide mustard (TIC mustard) (11), chloroethyl cyclohexyl nitrosourea (CCNU) (12), and chloroethyl methylcyclohexyl nitrosourea (methyl-CCNU) (13) have not so far proved superior. During the last years various drug combinations have been tried in an effort to improve the results of treatment in patients with metastatic malignant melanoma. In 1959 Moon reported objective response in 9 out of 20 patients who received a minimum of two courses of a combination of BCNU and vincristine (14). In a randomized trial performed by Acute Leukemia Group B (15), only 24% responded to this combination as compared to 32% and 29% for two different DTIC schedules. There were 120 patients who entered onto this protocol. A combination of DTIC plus cyclophosphamide plus vincristine was reported to give a 25% response (16). Workers at the Mayo Clinic reported objective response in 4 out of 18 patients treated with a combination of DTIC plus vincristine as compared to 1 out of 19 using CCNU (12). Costanza and co-workers (Eastern Co-Operative Oncology Group study) reported that 12 out of 61 patients responded to treatment with DTIC plus BCNU as compared to 9 out of 51 on DTIC alone (17); while Cohen (18) and co-workers reported that 10 out of 16 patients treated with the triple combination of vincristine plus BCNU plus DTIC showed significant response and concluded that this combined approach in the treatment of disseminated malignant melanoma warranted further study. Preliminary analysis of an Eastern Co-Operative Oncology Group protocol showed no statistical advantage of DTIC plus methyl-CCNU over each drug on its own (19). The present study was undertaken to investigate the possible advantage of combining DTIC plus vincristine plus BCNU plus procarbazine in courses of treatment. All of these agents are of some value on their own and all four have possible different mechanisms of action.