Phase-1 trial of high-dose intravenous cisplatin with simultaneous intravenous sodium thiosulfate

Previous pharmacological and clinical data have suggested that it is possible to increase significantly the dose of "active" cisplatin delivered systemically by the simultaneous administration of intravenous sodium thiosulfate. In order to define more critically the toxicity and potential efficacy of this therapeutic approach, 36 patients with a variety of solid tumors and limited pretreatment were entered into a phase-1 trial of high-dose intravenous cisplatin plus sodium thiosulfate. The maximally tolerated dose of cisplatin was found to be 200 mg/m2, excessive renal toxicity being observed at a dose of 225 mg/m2 (6/14 courses associated with serum creatinine rise to greater than 2.0 mg-%). Following several courses of high-dose cisplatin, peripheral neuropathy becomes the limiting toxicity (9/15 patients receiving at least three courses of cisplatin at greater than or equal to 150 mg/m2 experienced at least grade-1 neuropathy). Significant ototoxicity developed after only one or two treatment courses, but with continued treatment hearing loss appeared to stabilize in the moderately severe range in most patients. Major responses (PR/CR) were observed in 7/27 evaluable patients. We conclude that cisplatin can be administered at a dose at 200 mg/m2 as a 2-h infusion (with simultaneous sodium thiosulfate) with significant but acceptable toxicities and without evidence of loss of anti-neoplastic activity (secondary to the presence of thiosulfate). However, owing to the development of neurotoxicity most patients will be unable to receive more than three courses of this high-dose treatment regimen.