A PHASE I-II STUDY OF ORAL DOXIFLURIDINE PLUS RADIOTHERAPY IN RADIOSENSITIVE TUMORS OF THE PELVIC REGION

Aims and backround: Fluoropyrimidines have shown synergic effects in c ombination with radiotherapy in several tumor types. Doxifluridine is a novel 5-fluorouracil (5-FU) prodrug which is transformed into 5-FU i n neoplastic tissue. This would imply enhancement of radiotherapy by 5 -FU in neoplastic tissue, where the drug is concentrated higher than i n surrounding healthy tissues. Methods: A phase I-II study was carried out on 10 patients with radiosensitive tumors of the pelvic area (4 u terine carcinomas). Escalating doses of oral doxifluridine were admini stered in combination with standard radiotherapy to assess the efficac y and toxicity profile of the combined treatment. The 9 evaluable pati ents (3 groups of 3 patients each) received oral doxifluridine, at dal ly doses of 500, 750, or 1000 mg, for 6 consecutive weeks in combinati on with a standard (1.8-2.0 Gy) dose of radiotherapy. Assessment of ph ysical and laboratory parameters was made at baseline, then weekly up to the end of the treatment and at follow-up. Results: At the final ev aluation, one patient with a diagnosis of uterine carcinoma showed a c omplete response that lasted 10 weeks. One patient had a partial respo nse, and 7 patients had no change. The most frequent adverse events we re gastrointestinal: 27 episodes of mild to moderate nausea/vomiting a nd diarrhea. Three patients complained of severe diarrhea of 5-7 days duration: all patients spontaneously recovered. There were no signific ant changes in laboratory or clinical parameters, and no serious toxic ity requiring reduction or interruption of the radiotherapy. Conclusio ns: The maximum tolerated dose of oral doxifluridine in combination wi th standard radiotherapy was assessed at 1000 mg/patient/day (equivale nt to 36-38 g monthly, previously reported as mTD in phase I studies).