RELATIONSHIP BETWEEN FLUOROURACIL SYSTEMIC EXPOSURE AND TUMOR RESPONSE AND PATIENT SURVIVAL

Purpose: The aim of this study was to analyze the link between fluorouracil (FU) systemic exposure and tumor response and overall survival. Patients and Methods: One hundred eighty-six patients (162 men, 24 women) with head and neck cancer were studied. All received cisplatin plus FU for three cycles as first-line chemotherapy. The treatment consisted of cisplatin (100 mg/m2 intravenously [IV]) followed by a 5-day continuous venous infusion of FU (1 g/m2/d). The median follow-up duration for the 104 patients alive was 24 months. For each cycle, we calculated the area under the curve over the duration of pharmacokinetic follow-up (AUC(0-105 h)) for plasma FU. For each patient, we analyzed the averaged AUC(0-105 h) and the averaged total dose for the three cycles. Results: The response rate was 30% complete responses (CRs), 22% partial responses (PRs) more than 75%, 25% PRs less than 75%, and 23% no response (NR). Medians for averaged AUC and dose per cycle were 27,906 ng/mL · h (first through third quartile, 25,398 to 31,060) and 7,000 mg (first through third quartile, 6,200 to 7,833), respectively. The tumor response was significantly linked to tumor stage (P < .001) and to averaged AUC (P = .05), but not to averaged dose. Analysis of parameters (continuous variable) expressing FU treatment intensity showed that dose did not influence survival contrary to the AUC (P = .001). The AUC remains significant (P = .025) in a multivariate analysis including tumor stage, demonstrating that the greater the FU systemic exposure, the longer the survival. Conclusion: These results strengthen the interest of individual FU dose adaptation based on pharmacokinetics.