Rationales for intraperitoneal chemotherapy: Chemosensitivity testing and pharmacokinetic considerations—Clinical experience with intraperitoneal chemotherapy

Abstract

Background To facilitate drug selection for regional chemotherapy, we defined the concentration response behavior, and the dependence of drug cytotoxicity on time, using the 2 human colorectal carcinoma cell lines HT29 and NMG 64/84. In addition, the drugs' cytotoxic potencies for regional chemotherapy after a single drug exposure were preclinically defined with in vitro phase II studies, using single cell suspensions of human solid tumor biopsies in the Human Tumor Colony Assay (HTCA). Methods The drugs Doxorubicin (ADM), Cis-Platinum (CDDP), Epidoxorubicin (EPI), 5-FU, 5-FUDR, Mitomycin C (MMC), and Mitroxantrone (NOV) were incubated at increasing concentrations up to 1000 μg/ml at 10, 30, 60, 360, and 1440 min with the cell lines. These drugs, as well as Vindesine (VDS) and Mafosfamide (MAF) were also tested in the HTCA at increasing concentrations. The HTCA response rates at 1 μg/ml (5-FU and MAF at 10μg/ml) and at 10μg/ml (5-FU and MAF at 100 μg/ml were used for in vitro phase II comparisons of the drugs' potential clinical activities. Results All test drugs showed a time and concentration dependent cytotoxicity against the cell lines. Based on the cytotoxicity test results with HT29 and NMG 64/84, specific times were recomended for clinical therapy with each drug. In the HTCA, the drugs differed in their activities at both concentrations. The HTCA results, which are clinically more relevant, showed that a 10 times higher concentration of the drug resulted in an increase of in vitro response rates by a factor of 2.1±0.7 (1.1 to 3.7). NOV was the drug which had a high cytotoxicity against the cell lines, a high HTCA-phase II activity (82% response at 10 μg/ml), and clinical pharmacological advantages for intraperitoneal regional chemotherapy (IPRC). Therefore we used NOV for IPRC at 10μg/ml and with a minimal instillation time of 3 h and obtained a clinically relevant response (CR+ PR) in 56% of the patients with malignant ascites (N=16). In peritoneal carcinosis (N=11) these response rate was 45% with questionable clinical relevance. Conclusions In vitro tests with cell lines and with tumor cell suspensions in the HTCA helped to define the pharmacological basis for the drugs' use in regional chemotherapy. Mitoxantrone and its treatment concentration of 10 μg/ml were successfully identified by HTCA phase II tests for IPRC.