Phase I study of eniluracil, a dihydropyrimidine dehydrogenase inactivator, and oral 5-fluorouracil with radiation therapy in patients with recurrentor advanced head and neck cancer

5-Fluorouracil (5-FU) is an effective enhancer of radiation therapy (RT) in head and neck cancers. Due to rapid, predominantly hepatic metabolism by d ihydropyrimidine dehydrogenase (DPD) and suggested clinical benefit from pr olonged drug exposure, 5-FU is commonly given by continuous infusion. Enilu racil is a novel DPD-inactivator designed to prolong the half-life of 5-FU and provide sustained plasma concentrations of 5-FU with oral dosing. We co nducted a Phase I study of the safety and efficacy of eniluracil given with oral 5-FU in patients receiving concurrent RT for recurrent or advanced sq uamous cell carcinomas of the head and neck. Thirteen patients with recurrent, metastatic, or highrisk (defined as an ex pected 2-year survival rate of <10%) head and neck cancer were enrolled and treated with concomitant chemoradiotherapy on an every-other-week schedule , Eniluracil at a fixed dose [20 mg twice a day (BID)] was given for 7 cons ecutive days (days 1-7), 5-FU and RT were given on 5 consecutive days (days 2-6). One patient was treated with once-daily RT (2.0 Gy fractions). The r emaining patients received hyperfractionated RT (1.5-Gy fractions BID). The initial dose of 5-FU was 2.5 mg/m(2) given BID. Dose escalation in patient cohorts was scheduled at 2.5mg-mg/m(2) increments, with intrapatient dose escalation permitted, Lymphocyte DPD activity and serum 5-FU and uracil con centrations were monitored during two cycles. DPD activity was completely or nearly completely inactivated in all patient s. Sustained, presumed therapeutic concentrations of 5-FU were observed at a dose of 5.0 mg/m(2) given BID. Cumulative dose-limiting myelosuppression (both neutropenia and thrombocytopenia) was observed during the fourth and fifth cycles following administration of 5.0 mg/m(2) 5-FU BID. One patient died of neutropenic sepsis during cycle 4, Other late cycle toxicities incl uded diarrhea, fatigue, and mucositis, Grade 3 mucositis was observed in 4 patients, but no grade 4 mucositis or grade 3 or 4 dermatitis was observed. A second patient death occurred during cycle 1 of treatment, No specific c ause of death was identified. The study was subsequently discontinued. Cumulative myelosupression was the significant dose-limiting toxicity of or al 5-FU given with the DPD-inactivator eniluracil on an every-other-week sc hedule. Clinical radiation sensitization was not observed, based on the abs ence of dose-limiting mucositis and dermatitis. Alternative dosing schedule s need to be examined to determine the most appropriate use of eniluracil a nd 5-FU as radiation enhancers.