Quantitative estimation of the thermal dose-modifying factor for cis-diamminedichloroplatinum (CDDP) in tumour-bearing dogs

Abstract

A statistical method for estimating clinical toxicity was used to determine a theoretical isoeffect dosemodifying factor for dogs with disseminated or refractory neoplasia treated with cis-diammine dichloroplatinum (II) plus whole-body hyperthermia or CDDP alone. CDDP was administered every 3 weeks with vigorous saline hydration to 54 dogs (CDDP alone n=21, CDDP/WBH n = 33) that were eligible for entry into this non-randomized study. CDDP was administered during the plateau phase of WBH in dogs receiving combined therapy. Acute toxicity included myelosuppression (CDDP n=7; CDDP/WBH n=5), nephrotoxicity (CDDP n= 1, CDDP/WBH n= 1) and respiratory distress (CDDP/WBH n=2). Eight dogs experienced chronic renal dysfunction as a result of CDDP (n=2) or CDDP/WBH (n=6). A theoretical thermal dose-modifying factor was determined for both acute and cumulative toxicity by comparing the maximum tolerated dose of each treatment group. The maximum tolerated dose (MTD) of CDDP WBH was defined as that dose producing a 50% incidence of moderate acute toxicity or acute plus mild chronic toxicity as estimated from logistic regression analysis of the toxicity data. The MTD (standard error) of CDDP/WBH for acute toxicity only was 54.6 (4.3) mg/M² and for CDDP alone the MTD was 73.6 (40) mg/M². Thus, the iso effect dose-modifying factor for acute toxicity was 1.35 (0.12). The MTD (SE) of CDDP/ WBH for cumulative toxicity (acute plus chronic toxicity) was 46.4 (2.7) mg/M² and for CDDP alone waas 70.0 (2.9) mg/M². The isoeffect dose-modifying factor for total cumulative toxicity was 1.5 (0.1). The 95% confidence intervals are 1.297–1.717. The statistical procedures used in this study are generally applicable to phase I clinical studies and may provide a useful means for inter treatment comparison of toxicity. Using these techniques we concluded that WBH enhances toxicity of CDDP such that a dose reduction is necessary in order to achieve a clinically meaningful iso effect.