Purpose: Preclinical studies have demonstrated significant synergistic tumor cell death when gemcitabine is combined with radiation therapy. The optimal mode for concomitant delivery of drug and radiation therapy remains to be determined. A phase I/II study was undertaken to establish the maximum tolerated dose of infusional gemcitabine when combined with radiation therapy in advanced gastrointestinal malignancies and to assess the response to treatment.
Materials and methods: Twenty-five patients with advanced or recurrent gastrointestinal malignancy were entered in this dose-escalation study. The initial dose of gemcitabine was 50 mg/m2 as a 24-hour continuous intravenous infusion given weekly x 3 with concurrent radiation therapy. The patients were given a week off chemotherapy after the third injection. The radiation therapy was continued during that week. Gemcitabine was thereafter resumed weekly for another 3 weeks or until the patient completed the radiation therapy (whichever was earlier). Five patients were treated at each dose level. The dose of the drug was escalated in increments of 50 mg/m2 if the toxicity was acceptable at the previous level until the maximum tolerated dose was established. Thirteen patients with advanced unresectable colorectal cancer and 12 patients with advanced unresectable pancreaticobiliary cancers were enrolled on the study. Radiation was delivered at 180 cGy/fraction to a total dose of 4000 cGy +/- boost. Because toxicity was severe at the 150 mg/m2 dose level, three additional patients were entered at this dose level. The dose was then dropped to 125 mg/m2, and five more patients were entered at this dose level. Two additional patients were then added in order to assess toxicity. Patient follow-up ranged from 4 to 22 months, and the median was 8 months.
Results: All patients were evaluable for toxicity. The doses of 50 and 100 mg/m2 were well tolerated, but at 150 mg/m2, six of eight patients experienced grade 3 or greater toxicity. The dose was de-escalated to 125 mg/m2, and three of seven patients showed grade 3 diarrhea and weight loss. Clinical tumor response was evaluable in 20 patients. Ten patients had a complete clinical response (50%), five patients had a partial response (25%), three patients had no response, and two patients had progression of disease. No patients experienced late toxicities related to either gemcitabine administration or radiation therapy. Twelve patients are currently alive.
Conclusion: Based on these results, it appears that the maximum tolerated dose for weekly 24-hour infusion of gemcitabine combined with radiation therapy is 100 mg/m2. Gemcitabine appears to be a potent radiation sensitizer, and when combined with radiation therapy, it has shown encouraging tumor responses. In this study, we found an overall response rate of 75% in patients with locally advanced stage of disease. Further evaluation of gemcitabine at 100 mg/m2 is being undertaken in preparation for a confirmatory multi-institutional phase II study.