Randomized trial of initial therapy with melphalan versus cisplatin-based combination chemotherapy in patients with advanced ovarian carcinoma: initial and long term results--Eastern Cooperative Oncology Group Study E2878.

BACKGROUND: Following surgical debulking, most patients with international Federation of Gynecology and Obstetrics (FIGO) Stage III or IV carcinoma of the ovary receive treatment with combination chemotherapy. However, the optimal postsurgical therapy for ovarian carcinoma remains to be defined.
METHODS: To define better the role of initial therapy with a cisplatin-based chemotherapy regimen, the Eastern (Cooperative Oncology Group (ECOG) initiated a randomized, Phase III trial, EST 2878, comparing initial therapy with a single, orally administered alkylating agent, melphalan, versus a complex regimen employing cyclophosphamide, hexamethylmelamine, doxorubicin, and cisplatin (CHAD). Women who failed treatment with melphalan were crossed-over to treatment with CHAD minus the cyclophosphamide (HAD). Study endpoints included response to therapy, time to treatment failure, and overall survival.
RESULTS: Between October, 1978, and November, 1980, EST 2878 accrued 253 patients with advanced epithelial carcinoma of the ovary. There were 118 eligible patients initially treated with melphalan and 126 with CHAD. Two patients experienced lethal toxicities, including gastrointestinal hemorrhage (1 patient) and neutropenic sepsis (1 patient), and 22 patients experienced life-threatening toxicities, including hematologic toxicity (21 patients) and anaphylaxis (1 patient). Response to treatment and clinical complete response rates were higher in women receiving CHAD (60% and 38%, respectively) versus melphalan (42% and 21%, respectively) (P = 0.037 and P = 0.024, respectively), but these differences were confined to women older than 50 years of age. Likewise, time to treatment failure was significantly longer in women receiving CHAD (P = 0.014), but the difference was again confined to women older than 50 years of age and to women suboptimally debulked at the time of surgery. Survival did not differ between the two arms (median survivals of 17.5 months with initial melphalan therapy and 19.5 months with CHAD), probably because women treated initially with melphalan received salvage therapy with HAD). Twenty-three patients survived longer than 10 years. Among 18 long term survivors who had retrospective pathologic review, 8 had borderline tumors of the ovary.
CONCLUSIONS: In women with advanced ovarian cancer, initial therapy with a cisplatin-based combination chemotherapy regimen resulted in higher clinical complete response rates and longer time to failure compared with initial therapy with a single, oral alkylating agent; however, the benefits of this approach were confined to women older than 50 years of age at diagnosis, and there was no significant difference in survival.

RCT Entities:   Population Interventions Outcomes