Lack of impact of platinum dose intensity on the outcome of ovarian cancer patients: 10-year results of a prospective randomised phase III study comparing carboplatin–cisplatin with cyclophosphamide–cisplatin

Abstract

This prospective multicentre phase III trial was conducted to assess whether increased platinum dose intensity (DI) by combining carboplatin with cisplatin has an impact on overall survival (OS) and progression-free interval (PFI) compared with the standard combination of cyclophosphamide and cisplatin in patients with epithelial ovarian cancer. A total of 253 patients with epithelial ovarian cancer of stages International Federation of Gynecology and Obstetrics (FIGO) IC–IV were randomised to receive either cyclophosphamide (600 mg/m2, intravenously (i.v.), day 1) and cisplatin (100 mg/m2, i.v., day 2) (n=125) as the standard regimen or carboplatin (300 mg/m2, i.v., day 1) and cisplatin (100 mg/m2, i.v., day 2) (n=128), every 28 days for six courses. The median follow-up was 6.0 years. 124 patients randomised to the platinum dose-intensified arm and 123 patients randomised to the standard arm met all of the eligibility criteria. Patient characteristics were well balanced between the two treatment groups. All eligible patients randomised were included in the analysis of OS and PFI. The median OS of the standard and platinum dose-intensified arms were 41.2 (95% Confidence Interval (CI): 29.2–50.7) and 43.0 months (95% CI: 34.3–63.2), respectively (P=Non-significant (N.S.). The median PFI in the standard arm was 29.7 (95% CI: 17.4–41.7) versus 23.1 months (95% CI: 17.8–35.4) in the platinum dose-intensified arm, respectively (P=N.S.). Toxicity, comprising leucopenia, granulocytopenia, thrombocytopenia, anaemia, emesis and nausea, was statistically significantly higher in the platinum dose-intensified arm than in the standard arm. Unexpectedly, no statistically significant differences were found between the 2 arms’ overall neuro- and ototoxicity. When converting carboplatin-platinum into cisplatin-platinum on the basis of an equivalence ratio of 4:1, patients in the platinum dose-intensified arm received a total platinum dose 1.58 times the platinum dose of the standard arm. With 35.0 mg/m2/week being administered, the total platinum DI of the dose-intensified arm was statistically significantly (P<0.0001) higher than that of the standard regimen (with 22.0 mg/m2 being administered). Calculating the average administered relative dose intensities of the regimens yielded almost identical results with 0.56 and 0.58 for the standard and experimental arms, respectively. Thus, by conventional means, a 1.6-fold increase in the platinum DI could be reached by combining carboplatin and cisplatin without unacceptable morbidity. Nevertheless, this did not translate into any therapeutic benefit for the patient, even in the optimally debulked group of patients for whom dose-intensification would have been expected to be of benefit.