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

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.

Keywords: fluorouracil; folate intake; head and neck squamous cell carcinoma; induction chemotherapy.

Figure 1

Mechanism of folate-mediated one carbon metabolism and fluorouracil. Dietary folate intake is converted into 5–10 methylene tetrahydrofolate (THF). Then, 5–10 methylene THF and thymidylate synthesis (TS) induce the methylation of dUMP from dTMP, leading to DNA nucleotide synthesis. The 5-fluorouracil (5-FU) active metabolite fluorodeoxyuridine monophosphate (FdUMP) binds to the nucleotide-binding site of TS and forms a stable ternary complex with TS and 5–10 methylene THF, blocking the access of dUMP to the nucleotide-binding site and inhibiting dTMP synthesis, resulting in DNA damage. dTMP; deoxythymidine monophosphate, FdUMP; fluoro-deoxyuridine monophosphate, dUMP; deoxyuridine monophosphate, SAM; S-adenosylmethionine, SAH; S-adenosylhomocysteine.

Figure 2

Kaplan–Meier survival curves of OS in patients treated with FU-containing IC followed by definitive treatment (A) and by definitive treatment alone (B). (A) Patients with high folate intake (n = 83) had significantly higher OS than patients with low folate intake (n = 81) (5-year OS: 70.8% vs. 50.8% log-rank p =0.020,adjusted HR 0.42, 95%CI, 0.25–0.76, P_trend = 0.003). (B) Patients with high folate intake (n = 86) did not show better OS than patients with low folate intake (n = 86) (5-year OS: 67.6% vs. 58.6%, log-rank p =0.447,adjusted HR 0.83, 95%CI, 0.49–1.42, p for trend = 0.491).

Figure 3

The heterogeneity of the impact of folate intake on OS by FU-containing IC among patients overall (upper) and patients without supplement use (lower). Upper: The difference between the survival impact of folate intake and FU-containing IC did not reached statistical significance (Pinteraction = 0.202); however, the association of folate intake and overall mortality statistically significantly differed between the high-dose FU-containing IC group and the definitive alone group (Pinteraction = 0.012). (lower) Among the patients who were not supplement users, potential heterogeneity in the survival impact of folate between FU-containing IC and definitive treatment alone was revealed (Pinteraction = 0.077), and significant heterogeneity between high-dose FU-containing IC and definitive treatment alone was observed (Pinteraction = 0.004).

Figure 4

Kaplan–Meier survival curves of recurrence-free survival (RFS) in patients treated with FU-containing IC followed by definitive treatment (A), by definitive treatment alone (B), and distant metastasis-free survival (DMFS) for patients treated with FU-containing IC followed by definitive treatment (C) and by definitive treatment alone (D). (A,B) Folate intake showed no apparent association with RFS in either the FU-containing IC group or the definitive treatment alone group, with adjusted HRs for high compared to low folate intake of 0.88 (95%CI, 0.58–1.36, P_trend = 0.596; 5-year-RFS 44.4 (33.0–55.0) vs. 41.2 (30.1–52.2), log-rank p = 0.609, Figure 4A) and 0.82 (95%CI, 0.51–1.30, P_trend = 0.395; 5-year-RFS 57.0 (45.0–67.3) vs. 40.4 (28.4–52.3) log-rank p = 0.351, Figure 4B), respectively. (C,D) A comparison of high with low folate intake showed that patients with a higher intake in the FU-containing IC group had better DMFS, with an adjusted HR of 0.41 (95%CI, 0.25–0.74, P_trend = 0.001; 5-year DMFS, 69.0 (57.3–78.1) vs. 50.1 (38.2–60.8), log-rank p = 0.012; Figure 4C). In contrast, with definitive treatment alone, an association between folate intake and DMFS was not obvious (adjusted HR comparing high with low folate intake = 0.92, 95%CI, 0.55–1.55, P_trend = 0.756; 5-year DMFS 67.3 (55.6–76.6) vs. 54.9 (42.2–65.9), log-rank p = 0.354; Figure 4D).