Phase I study of oxaliplatin in patients with advanced cancer

Summary Oxaliplatin, or trans-1-diaminocyclohexane-platinum, was tested in a phase I study. A total of 44 patients received 116 courses with dose escalation from 45 to 200 mg/m². Neither renal nor hematologic toxicities were observed at doses up to 200 mg/m². Gastrointestinal toxicity was practically constant and often of grade 3–4 on the WHO scale (53% of patients). The dose-limiting toxicity was a peculiar sensory neuropathy; the first neurologic phenomena appeared at a dose of 135 mg/m² and continued thereafter, occurring after 75% of the courses with mild to moderate intensity (WHO grade 1–2 after 67% of the courses). Neurotoxicity was cumulative and six patients developed grade 3 disabling neuropathy after a cumulative dose of 500 mg/m², with walking and handwriting difficulties being slowly regressive in three cases. A peculiar symptom was the influence of temperature, with exacerbation of paresthesias when patients touched cold surfaces. Nerve-conduction studies carried out in six cases showed a predominantly sensory neuropathy with axonal degeneration. No other toxicities were observed, although audiograms were not systematically done. We observed four partial responses that lasted 6–13 months in patients with oesophageal (2 cases), lung (1), and urothelial cancer (1); two of these patients had been pretreated with cisplatin. Since neurologic side effects occur very frequently and may produce a long-lasting sensory neuropathy, for phase II studies we recommend a starting dose of 135 mg/m², with a careful neurologic survey.