Amifostine and chemotherapy-related thrombocytopenia

Thrombocytopenia is a manifestation of hematopoietic toxicity that, at present, can be treated only with platelet transfusions. Thrombocytopenia is a dose-limiting toxicity for carboplatin, mitomycin-C, and other agents, and becomes dose limiting when granulocyte colony-stimulating factor or granulocyte-macrophage colony-stimulating factor are used with some chemotherapeutic regimens; thus, strategies to reduce thrombocytopenia are needed. While clinical trials have begun using hematopoietic growth factors that have shown promising preclinical effects on thrombocytopenia, alternative approaches to modifying therapy-related thrombocytopenia are also being developed. Amifostine is a pro-drug that is metabolized to a thiol, WR-1065, which functions to selectively protect normal tissues from the toxic effects of ionizing radiation, alkylating agents, platinating agents, and other cytotoxic compounds. Results from a randomized clinical trial have shown that amifostine reduces mitomycin-induced thrombocytopenia in patients with refractory colorectal cancer. The results of phase I studies of the combination of amifostine and carboplatin suggest that amifostine could modify the toxicity of the platinum compound. Two randomized clinical trials using amifostine and carboplatin have also been reported. In one, the median platelet nadir of all cycles was lower in the amifostine-treated patients; in the other, more profound thrombocytopenia was produced by a higher carboplatin dose, but platelet recovery was more rapid in the amifostine-treated patients. In both of these trials, survival of non-small cell lung cancer patients who received both amifostine and carboplatin was longer than in those treated with carboplatin alone, suggesting that amifostine does not inhibit the antitumor effects of carboplatin. Further studies of amifostine with carboplatin and combination chemotherapy regimens in which thrombocytopenia is dose limiting should be undertaken, as should clinical investigations of amifostine in conjunction with hematopoietic growth factors.