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 (HRT3-T1) = 0.42, 95%CI, 0.25–0.76, Ptrend= 0.003). Conversely, no apparent association between prediagnostic folate intake and survival was observed with definitive treatment alone (HRT3-T1: 0.83, 95%CI, 0.49–1.42, Ptrend= 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.
氟尿嘧啶（FU）通过抑制叶酸介导的一碳代谢发挥其抗肿瘤活性。有证据表明叶酸可能通过叶酸介导的一碳代谢在致癌过程中发挥作用，由此提出假说：诊断前叶酸摄入量可能导致头颈癌对含FU诱导化疗（IC）的化疗敏感性存在异质性。为验证该假说，我们利用流行病学数据库结合临床数据，对504例局部晚期（III/IV期）头颈部鳞状细胞癌（HNSCC）患者进行队列研究，探讨诊断前膳食叶酸摄入量与癌症生存期的关联在含FU的IC治疗方案与不含该方案之间是否存在差异。其中240例患者接受含FU的IC治疗后进行根治性治疗，264例患者仅接受根治性治疗。根治性治疗定义为：（1）肿瘤手术切除且切缘阴性，伴或不伴颈部淋巴结清扫；（2）放疗，伴或不伴化疗。在含FU的IC组整体队列中，较高叶酸摄入量与更好的总生存期显著相关（最高与最低叶酸三分位数组调整后风险比（HRT3-T1）= 0.42，95%CI 0.25–0.76，趋势P值=0.003）。相反，在单纯根治性治疗组中未观察到诊断前叶酸摄入量与生存期存在明显关联（HRT3-T1：0.83，95%CI 0.49–1.42，趋势P值=0.491）。进一步考虑含FU的IC累积剂量时发现，诊断前叶酸摄入量对生存期的影响在不同治疗方案间存在统计学显著差异（交互作用P值=0.012）。综上所述，诊断前叶酸摄入量与HNSCC生存期的关联因是否采用含FU的IC而存在显著差异。这一发现表明，在致癌过程中，叶酸状态通过一碳代谢途径导致HNSCC具有异质性。
肿瘤(癌症)患者之家