The Heterogeneous Impact of Prediagnostic Folate Intake for Fluorouracil-Containing Induction Chemotherapy for Head and Neck Cancer

SIMPLE SUMMARY: To our knowledge, this is the first study to suggest that an association between prediagnostic folate intake and head and neck squamous cell carcinoma (HNSCC) survival significantly differs based on fluorouracil (FU)-containing chemotherapy. In the FU-containing chemotherapy group, a higher folate intake was significantly associated with better overall survival; however, no apparent association between prediagnostic folate intake and survival was observed in definitive treatment without an FU-containing chemotherapy group. Fluorouracil exerts its antitumor activity by inhibiting folate-mediated one-carbon metabolism; therefore, our finding indicates that in the carcinogenic process, the folate status causes HNSCC to be heterogeneous in terms of one-carbon metabolism. ABSTRACT: Fluorouracil (FU) exerts its antitumor activity by inhibiting folate-mediated one-carbon metabolism. Evidence that folate may play a role in the carcinogenic process via folate-mediated one-carbon metabolism has given rise to the hypothesis that pre-diagnostic folate intake may induce heterogeneous chemosensitivity to FU-containing induction chemotherapy (IC) in head and neck cancer. To assess this hypothesis, we conducted a cohort study to investigate whether the association between prediagnostic dietary folate intake and cancer survival differed between treatment regimens with and without FU-containing IC in 504 cases of locally advanced (stage III/IV) HNSCC, using an epidemiologic database combined with clinical data. In total, 240 patients were treated with FU-containing IC followed by definitive treatment, and 264 patients were treated with definitive treatment alone. Definitive treatment is defined as (1) the surgical excision of a tumor with clear margins, with or without neck lymph node dissection; or (2) radiotherapy with or without chemotherapy. In the overall cohort of the FU-containing IC group, a higher folate intake was significantly associated with better overall survival (adjusted hazard ratios (HRs) for the highest compared to the lowest folate tertiles (HR(T3-T1)) = 0.42, 95%CI, 0.25–0.76, P(trend) = 0.003). Conversely, no apparent association between prediagnostic folate intake and survival was observed with definitive treatment alone (HR(T3-T1): 0.83, 95%CI, 0.49–1.42, P(trend) = 0.491)). A consideration of the cumulative dose of FU-containing IC showed that the survival impact of prediagnostic folate intake differed statistically significantly by treatment regimen (Pinteraction = 0.012). In conclusion, an association between prediagnostic folate intake and HNSCC survival significantly differed by FU-containing IC. This finding indicates that in the carcinogenic process, folate status causes HNSCC to be heterogenous in terms of one-carbon metabolism.