A phase I-II study of oral doxifluridine plus radiotherapy in radiosensitive tumors of the pelvic region.

Fluoropyrimidines have shown synergic effects in combination with radiotherapy in several tumor types. Doxifluridine is a novel 5-fluorouracil (5-FU) prodrug which is transformed into 5-FU in neoplastic tissue. This would imply enhancement of radiotherapy by 5-FU in neoplastic tissue, where the drug is concentrated higher than in surrounding healthy tissues.A phase I-II study was carried out on 10 patients with radiosensitive tumors of the pelvic area (4 uterine carcinomas). Escalating doses of oral doxifluridine were administered in combination with standard radiotherapy to assess the efficacy and toxicity profile of the combined treatment. The 9 evaluable patients (3 groups of 3 patients each) received oral doxifluridine, at daily doses of 500, 750, or 1000 mg, for 6 consecutive weeks in combination with a standard (1.8-2.0 Gy) dose of radiotherapy. Assessment of physical and laboratory parameters was made at baseline, then weekly up to the end of the treatment and at follow-up.At the final evaluation, one patient with a diagnosis of uterine carcinoma showed a complete response that lasted 10 weeks. One patient had a partial response, and 7 patients had no change. The most frequent adverse events were gastrointestinal: 27 episodes of mild to moderate nausea/vomiting and diarrhea. Three patients complained of severe diarrhea of 5-7 days duration: all patients spontaneously recovered. There were no significant changes in laboratory or clinical parameters, and no serious toxicity requiring reduction or interruption of the radiotherapy.The maximum tolerated dose of oral doxifluridine in combination with standard radiotherpay was assessed at 1000 mg/patient/day (equivalent to 36-38 g monthly, previously reported as mTD in phase I studies).