Biochemical modulation in the treatment of advanced cancer: a study of combined leucovorin, fluorouracil, and iododeoxyuridine.
Multiple studies have shown that leucovorin-fluorouracil regimens are modestly superior to fluorouracil alone in the treatment of advanced colorectal cancer. Laboratory data suggest that iododeoxyuridine could further enhance the efficacy of leucovorin-fluorouracil regimens. This report describes the Phase I clinical evaluation of a leucovorin-fluorouracil-iododeoxyuridine chemotherapy regimen. Twenty-four patients received treatment with leucovorin (500 mg/m2), fluorouracil (500 mg/m2), and iododeoxyuridine (escalating doses) on days 1 and 8 of a 21-day cycle. The maximum tolerated dose of iododeoxyuridine was 1200 mg/m2, with a recommended Phase II dose of 1000 mg/m2. Myelosuppression (leukopenia) was dose limiting; other commonly observed treatment toxicities were nausea/vomiting, mucositis, and hyperlacrimation. Although the 1200 mg/m2 dose was tolerated during the initial few cycles of therapy, chronic administration could not be maintained secondary to dose-limiting neutropenia. Since neutropenia was dose limiting, in a follow-up study, 10 patients received a modified regimen (treatment on days 1 and 6 instead of days 1 and 8) with the addition of granulocyte colony-stimulating factor (days 8-19). The addition of granulocyte colony-stimulating factor, however, did not permit further escalation of the iododeoxyuridine dose. Three partial responses and six minor responses were observed. Phase II studies of this regimen are ongoing in advanced colorectal and advanced pancreatic cancer to determine response rates in these diseases.