In vitro and in vivo evaluation of the combination of cisplatin and its analogue carboplatin for platinum dose intensification in ovarian carcinoma.

BACKGROUND

Cisplatin and its analogue carboplatin have been shown to cause dose-dependent growth inhibition throughout a wide dose range in the ovarian cancer cell lines OVCAR-3, 2780, HTB-77, and CRL-1572 tested. Cisplatin was 30 times more effective than carboplatin. The combination of both substances led to a less-than-synergistic effect, as was revealed by an isobologram in the OVCAR-3 cell line. Because of the different toxicity pattern, cisplatin and carboplatin theoretically are ideal candidates for combination chemotherapy in platinum-sensitive tumors.

METHODS

In a Phase II study, the efficacy, the toxicity profile, and the feasibility of combining both substances were assessed in 20 previously untreated patients with ovarian cancer. The regimen consisted of carboplatin (300 mg/m2) on day 1, followed by cisplatin (100 mg/m2) on day 2 every 4 weeks.

RESULTS

A total of 81 cycles were administered (median, 4 cycles; range, 1-6 cycles); four patients experienced complete remission and three experienced clinical partial remissions. Limiting toxicities were thrombocytopenia, leukopenia, and ototoxicity. The mean (+/- standard deviation [SD]) carboplatin and cisplatin dose intensities (DI) reached during the first four cycles of therapy were 58 mg/m2/week (+/- 18 mg/m2/week) and 21 mg/m2/week (+/- 7 mg/m2/week), respectively, which corresponded closely to the projected DI of 75 and 25 mg/m2/week, respectively. Based on the equivalence ratio of 4:1, the DI of carboplatin has been converted into the respective cisplatin DI, resulting in a total DI estimate. The overall DI of 37 mg/m2/week (+/- 14 mg/m2/week) was close to the projected one of 44 mg/m2/week.

CONCLUSIONS

Combining cisplatin with carboplatin was found to represent a feasible and efficacious therapeutic strategy for increasing platinum dose intensity.