Clinical effects of amifostine (Ethyol) in patients treated with carboplatin.

Amifostine is a compound that has been developed as a radio- and chemoprotectant. It is a prodrug, giving rise to the active thiol, WR-1065. Amifostine has been demonstrated to reduce the toxicity of ionising radiation, alkylating agents and platinum compounds. Preclinical studies have shown that amifostine can reduce the myelosuppression of carboplatin in a murine model tumour system without reducing the efficacy of therapy. In fact, in this model system, the antitumour effects of carboplatin against the OVCAR-3 cell line were actually greater with than without amifostine. Based on these preclinical studies, clinical trials of the combination of carboplatin and amifostine have been undertaken. A phase I trial of carboplatin and amifostine in pretreated patients demonstrated that two doses of amifostine 740 mg/m2/dose may be safely administered with carboplatin. The maximum tolerated dose (MTD) of carboplatin that could be administered with amifostine was 500 mg/m2, suggesting the hypothesis that amifostine increases the MTD of carboplatin from 400 to 500 mg/m2. To test this hypothesis, a randomised trial of carboplatin 500 mg/m2 versus carboplatin 500 mg/m2 plus two doses of amifostine 910 mg/m2/dose has been performed. Analysis of this trial is not complete, but initial results suggest a reduction of first-cycle thrombocytopenia, from a median platelet nadir value of 85 x 10(9) cells/l for carboplatin alone to 144 x 10(9) cells/l for the combination of carboplatin plus amifostine. Similarly, the median first-cycle granulocyte nadir was 1.6 x 10(9) cells/l without amifostine but 2.4 x 10(9) cells/l with the cytoprotectant. Neither of these first-cycle differences was statistically significant, but these effects are being maintained with repeated dosing, so that an increase in delivered cumulative carboplatin dose seems possible with the use of amifostine. These promising data indicate that continued studies of amifostine with carboplatin are justified and that the effects of amifostine on the thrombocytopenia produced by carboplatin-containing combination chemotherapy regimens should be investigated.