RANDOMIZED TRIAL OF HIGH-DOSE CHEMOTHERAPY WITH AUTOLOGOUS BONE-MARROW SUPPORT AS ADJUVANT THERAPY FOR HIGH-RISK, MULTI-NODE-POSITIVE MALIGNANT-MELANOMA

Background: Chemotherapy adjuvant to surgery in metastatic melanoma ha s been evaluated in only a few prospective randomized trials. In the t reatment of metastatic melanoma, dacarbazine has response rates of 15% -25% and in several studies, when combined with other alkylating agent s, has yielded even higher response rates. Among the highest response rates are those achieved by using high-dose chemotherapy regimens comb ined with autologous bone marrow support (transplantation). Purpose: W e conducted a prospective randomized clinical trial to test the effica cy of high-dose alkylating agents in combination with autologous bone marrow support given as adjuvant therapy for high-risk stage II (World Health Organization) melanoma. Methods: Thirty-nine patients with met astases involving rive or more lymph nodes were randomly assigned to o ne of two treatment arms within 8 weeks of lymphadenectomy: immediate treatment or observation only. The immediate-treatment arm consisted o f 19 patient who, immediately after random assignment, received high-d ose chemotherapy with alkylating agents, followed 3 days later by rein fusion of autologous bone marrow. The observation arm consisted of 20 patient who were observed until relapse (confirmed by biopsy) and were them treated with the identical high-dose alkylating agent chemothera py followed by reinfusion of autologous bone marrow. Bone marrow was h arvested from the patients under general anesthesia 1-2 weeks prior to chemotherapy and was cryopreserved. Chemotherapy consisted of intrave nous administration of cyclophosphamide (1875 mg/m2 as a 1-hour infusi on daily for 3 days), cisplatin (55 mg/m2 per day by continuous infusi on over the same 72-hour period), and carmustine (BCNU) (600 mg/m2) gi ven immediately after cisplatin on the 4th day as a 2-hour infusion. T he total doses of the three drugs were 5625, 165, and 600 mg/m2, respe ctively. All patients received medical evaluations every 6-12 weeks ov er the study period. Kaplan-Meier estimates were used to determine the time to disease progression on the basis of intent to treat. Results: There was no statistically significant difference in overall survival or in time to disease progression between the two treatment arms. How ever, the median time to progression was 16 weeks in the observation a rm and 35 weeks in the immediate-treatment arm. Conclusions: Immediate adjuvant high-dose chemotherapy with alkylating agents followed by au tologous bone marrow support more than doubled the time to disease pro gression compared with observation alone, though the difference was no t statistically significant. No differences in overall survival were n oted.