PHASE-II TRIAL OF CISPLATIN, FLUOROURACIL, AND PURE FOLINIC ACID FOR LOCALITY ADVANCED HEAD AND NECK-CANCER - A PHARMACOKINETIC AND CLINICAL SURVEY

Purpose: To analyze clinical and pharmacokinetic data cisplatin (CP)/fluorouracil (FU)/l folinic acid (l FA) chemotherapy administered as first-line treatment to locally advanced head and neck cancer patients. Patients and Methods: Thirty-nine patients (35 men and four women; median age, 60 years; six stage III and 33 stage IV) received CP on day 1 (100 mg/m(2)) followed by lFA (200 mg/m(2)/d x 5) plus FU (500 mg/m(2)/d x 5) administered by continuous venous infusion (three cycles planned). Mean plasma concentrations of FU, lFA, and 5-methyltetrahydrofolate (5MTHF) over the cycle were computed. Results: Clinical response was assessable for 33 patients. Response rates on the primary tumor site (n = 33) were 63.7% complete responses (CRs), 24.2% partial responses (PRs), and 12.1% treatment failures. Response rates on lymph nodes (n = 27) were 40.7% CRs, 37.1% PRs, and 22.2% treatment failures. The most frequent toxicity was mucositis (36.2% of cycles grade 3 to 4). Grade 3 to 4 nausea-vomiting, diarrhea, neutropenia, and thrombocytopenia occurred in 6.7%, 1.9%, 13.3%, and 1% of cycles, respectively, Pharmacokinetic analysis showed a wide interpatient variability for both FU (mean, 1.01 mu mol/L; range, 0.16 to 2.09), lFA (mean, 1.89, mu mol/L; range, 0.52 to 7.88) and 5MTHF plasma concentrations (mean, 3.85 mu mol/L; range, 1.30 to 8.11). A significant correlation was demonstrated between FU concentration and hemotologic toxicity grade, mucositis grade, and nausea-vomiting/diarrhea grade. Regarding tumor response, patients who failed to respond significantly exhibited lower FU and total folate concentrations than patients with a CR or PR. Conclusion: This study highlights the efficacy of CP/FU/lFA in head and neck carcinoma and establishes the clinical importance of coupled FU/FA pharmacokinetics to predict pharmacodynamic variability.