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/m(2), intravenously (i.v.), day 1) and
cisplatin (100 mg/m(2), i.v., day 2) (n=125) as the standard regimen or
carboplatin (300 mg/m(2), i.v., day 1) and
cisplatin (100 mg/m(2), 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/m(2)/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/m(2) 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.