Reduction of the systemic toxicity of cisplatin by intra‐arterial hepatic route administration for liver malignancies

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Abstract
Cisplatin (CDDP) administration by the intra-arterial hepatic route (i.a.h.) in patients with primary or metastatic liver malignancies could enhance the anti-tumor activity of the drug and reduce its systemic toxicity. The aim of the present study was to compare Pt pharmacokinetics and the toxicity of the circulating drug after i.a.h. versus intravenous (i.v.) administration. CDDP pharmacokinetics was followed-up in 11 i.a.h. courses given to 7 patients with liver malignancies and compared with 19 i.v. courses in 15 patients with cancer of different origins. The Pt level in blood was monitored by sensitive atomic absorption spectrometry. The dose given was in the range of 25–80 mg/m/treatment. For analysis and for comparison purposes, the data from both CDDP treatments were normalized to a standard dose of 35 mg/m2. The mean peak Pt level for i.a.h. treatment was found to be about half of the mean peak value for i.v. administration with a similar dose-independent bi-exponential rate of elimination i.a.h. CDDP treatment was relatively well tolerated with no symptoms of either nephro- or neurotoxicity. For in vitro evaluation of peripheral CDDP toxicity, a sensitive ovarian carcinoma cell line, OV-1063, was used. A cytotoxic effect was recorded only within 2 hr following high-dose i.v. CDDP treatment. A substantial fraction of the drug given by the i.a.h. route was found to be extracted by the liver in the first passage, with reduced drug level in the peripheral blood plasma relative to the dose given. This may explain the apparent diminution of side-effects following i.a.h. CDDP treatment.