Combined carboplatin and cisplatin. Limited prospects for dose intensification

The relative lack of overlapping toxicities and less-than-complete cross-resistance of tumors treated with both carboplatin and cisplatin may allow these two analogues to be given in combination to exploit platinum dose intensity therapeutics. Early experience with combined platinum regimens, however, found myelosuppression, particularly severe thrombocytopenia, to be dose-limiting. It was postulated that a 2-day interval between carboplatin and cisplatin would allow for near complete clearance of the former before cisplatin administration and a potential gain in dose intensity.

Other carboplatin-cisplatin regimens produced Grade 3-4 toxicity in 20% of patients. By defining 95% confidence limits around this observed rate of Grade 3-4 toxicity, the accrual needs of this study were determined in a two-stage process. Sixteen patients with advanced malignancies were entered onto a trial of 300 mg/m2 of carboplatin on day 1, followed by 125 mg/m2 of cisplatin on day 3 every 28 days. Hematologic and nonhematologic toxicity was closely monitored, including the use of serial audiograms, to allow appropriate dose modification.

A total of 40 courses of combination platinum therapy was administered to 15 patients who were evaluable for toxicity. Higher-than-anticipated ototoxicity and neurosensory toxicity was observed. WHO Grade 3 ototoxicity (hearing loss) was documented in 12 of 15 patients (80.0%, 95% confidence interval [CI]: 52.0-97.0%) and emerged as the dose-limiting side effect of this regimen. High-frequency hearing loss, as demonstrated by conventional audiograms, was universal among all 12 patients who received at least 2 courses of combination platinum therapy (100%, 95% CI: 73.5-100%). Grade 2 or 3 neurosensory toxicity also was observed in 4 of 15 patients. Hematologic toxicity was manageable. WHO Grade 3-4 neutropenia or thrombocytopenia occurred in only 14% and 11%, respectively, of 40 courses. There was no evidence of cumulative marrow toxicity. Calculated dose intensities (mg/m2/week) were 94 +/- 26.0 for carboplatin, 39.3 +/- 12.4 for cisplatin, and 64.0 +/- 19.2 for the combination (expressed as cisplatin equivalents). Objective responses (complete response+partial response) occurred in 8 of 16 subjects (50.0%, 95% CI: 24.7-75.4%), with 1 patient achieving a complete response of 14+months.

The schedule of day 1 carboplatin plus day 3 cisplatin every 4 weeks appeared to allow a higher platinum dose intensity with less myelotoxicity than previously reported schedules combining these two analogues. Ototoxicity, however, was unexpectedly severe and limits future prospects for the use of combined platinum analogues to achieve dose intensification.