Radiation and 5-Fluorouracil: A Controlled Clinical Study

Abstract

Clinical and experimental studies have demonstrated that the pyrimidine analog, 5-fluorouracil (FU), may exert considerable antitumor effect (4). Further therapeutic advantages might be gained by combining this drug with another agent such as ionizing radiation. An important consideration in assessing the possible advantages of combination therapy, however, is the comparison of the efficacy of the individual agents with their effects when combined. The purpose of this investigation was to compare the effects of x-irradiation and FU when administered separately and in combination in the treatment of patients with advanced neoplastic disease. Methods Because the variability of tumors in different patients is great, the most suitable study was considered to be the measurement of changes in multiple metastases within individual patients. Experimentally controlled observations of comparable lesions treated with different modalities could thereby be achieved. The parameters were the regression rates of multiple metastatic tumors which were treated with x-irradiation alone, FU alone, and a combination of the two agents. The patients selected had multiple metastases measurable by calipers either directly or upon serial roentgenograms (3). The criteria were as follows: 1. Two or more metastatic lesions. 2. Distribution in similar structure, i.e., lungs, lymph nodes, subcutaneous tissue, skin. 3. Metastases measurable directly or by radiographic means. 4. Histology of primary lesion known. Radiation can be spatially localized, but intravenously administered FU is distributed throughout the body. Therefore, the measurements of the effects of radiation alone and the effects of combined therapy within an individual patient could be determined only by temporal separation of the two agents. This variable of time was compensated for by reversing the sequence of administration of the agents, as demonstrated in the two treatment designs in Table I. Care was taken that all physical factors of radiation technic within each patient were identical for the lesions receiving radiation alone and radiation combined with FU. Technics varied depending upon circumstances of site, type of tumor, and volume of exposure. In general, the radiation doses administered were planned to produce incomplete tumor regression, ranging from 1,000 to 2,500 r calculated at the site of the tumor in from four days to three weeks. Orthovoltage and mega-voltage (2 Mev) x-ray generators were used. Rapid intravenous injections of FU, in daily doses of from 7.5 to 15 mg. per kilogram (mg.∕kg.), of actual weight, and not exceeding a total dose of 1 gram, were given for five consecutive days.