Multiple drug chemotherapy combined with multiple fractions per day (MFD) radiotherapy in an experimental solid tumor model

Abstract

A series of multi-drug chemotherapy studies combined with multi fractions per day (MFD) radiotherapy have been carried out in an experimental solid tumor model to provide information on how drugs contribute in combinations, both for effect on tumor and with regard to host toxicity. Twenty-five different combinations of cyclophosphamide (CP) and 5-fluorouracil (FU) were evaluated in this initial study. All tumors received a total dose of 6000 cGy of radiation given in multiple fractions per day for three courses one week after combined chemotherapy. Doses of each drug in the combinations ranged from 25 to 100% of the LD10 (150 mg/kg or .9 mg/m2) of each drug when given as a single agent. Proportional hazards analysis of the survival data yielded optimal doses of 132.8 mg/kg FU and 115.0 mg/kg CP, that is, approximately 3/4 of the LD10 of each drug in the combination. The group close to the optimum combination had a median GD of 295.3 days. Among the 5 rats in this group there were 4 partial responses and 1 cure for a 100% response rate. Excessive toxicity occurred in the group given the highest doses of FU and CP along with the 6000 cGy radiotherapy. These experimental cancer treatment studies in well defined solid tumor models demonstrate how the quantitative inter-relationship between anti-tumor effects and host toxicity to tumor burden and total therapeutic dose chemotherapy (single or multiple combinations) and radiotherapy alone or in combination can be obtained. These major determinants on treatment outcome are difficult or impossible to determine in clinical studies.(ABSTRACT TRUNCATED AT 250 WORDS)