INVITRO AND INVIVO EVALUATION OF THE COMBINATION OF CISPLATIN AND ITSANALOG 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 tes ted. Cisplatin was 30 times more effective than carboplatin. The combi nation of both substances led to a less-than-synergistic effect, as wa s revealed by an isobologram in the OVCAR-3 cell line. Because of the different toxicity pattern, cisplatin and carboplatin theoretically ar e ideal candidates for combination chemotherapy in platinum-sensitive tumors. Methods. In a Phase II study, the efficacy, the toxicity profi le, and the feasibility of combining both substances were assessed in 20 previously untreated patients with ovarian cancer. The regimen cons isted 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 admi nistered (median, 4 cycles; range, 1-6 cycles); four patients experien ced complete remission and three experienced clinical partial remissio ns. Limiting toxicities were thrombocytopenia, leukopenia, and ototoxi city. The mean (+/-standard deviation [SD]) carboplatin and cisplatin dose intensities (DI) reached during the first four cycles of therapy were 58 mg/m2/week (+/-10 mg/m2/week) and 21 mg/m2/week (+/-7 mg/m2/we ek), respectively, which corresponded closely to the projected DI of 7 5 and 25 mg/m2/week, respectively. Based on the equivalence ratio of 4 :1, the DI of carboplatin has been converted into the respective cispl atin 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/wee k. Conclusions. Combining cisplatin with carboplatin was found to repr esent a feasible and efficacious therapeutic strategy for increasing p latinum dose intensity.