Mature Results of a Prospective Randomized Trial Comparing a Three-Weekly with an Accelerated Weekly Schedule of Cisplatin in Advanced Ovarian Carcinoma

In a retrospective analysis of a series of clinical trials by Levin and Hryniuk in 1987, the average relative dose intensity of first-line chemotherapy for advanced ovarian cancer correlated significantly with clinical response and survival, and cisplatin was the only drug for which the outcome correlated with the individual drug relative dose intensity. There was a need to test whether and to what extent this evidence would be confirmed in a prospective evaluation. In this study 101 patients with advanced ovarian carcinoma were randomized to receive the same total dose of cisplatin but at the conventional 3-weekly schedule (CTWS) (100 mg/m2 every 3 weeks for six cycles) (51 patients) or at an experimental accelerated weekly schedule (AWS) (100 mg/m2 every week for two triplets of three cycles separated by a 5-week interval) (50 patients). To benefit from a multidrug regimen at the same extent, patients in both arms sequentially received four cycles of doxorubicin and cyclophosphamide. The median follow-up period of this study is 9.7 years. In 42 and 40 patients of the two arms having evaluable response, the clinical complete response rates to cisplatin were 14% and 22% and the complete plus partial response rates were 48% and 55% in the CTWS and in the AWS arm, respectively. These differences were not statistically significant. However, the survival curves were similar during the first 2 years but clearly diverged thereafter in favor of the AWS arm (p= 0.07). At 5 years, 12% and 30% of the patients were still alive in the CTWS and in the AWS arm, respectively. Hematologic toxicity was not relevant in either arm of the study. Nonhematologic toxicity, especially ototoxicity, was substantial and significantly higher in the AWS arm. Although statistically nonsignificant, this AWS regimen of cisplatin is associated with long-term better survival compared to the CTWS regimen in advanced ovarian carcinoma. This accelerated approach administering cisplatin should be further investigated, especially in patients with low residual disease after primary surgery.