- Mechanisms of Action:
- 5-Fluorouracil (5-FU):
- Converted intracellularly to:
- Fluorodeoxyuridine monophosphate (FdUMP), which forms a ternary complex with thymidylate synthase (TS) and reduced folate:
- Blocks deoxythymidine monophosphate (dTMP) synthesis, leading to “thymineless death”
- Fluorodeoxyuridine monophosphate (FdUMP), which forms a ternary complex with thymidylate synthase (TS) and reduced folate:
- Other metabolites (fluorouridine triphosphate, FUTP; fluorodeoxyuridine triphosphate, FdUTP):
- Misincorporate into RNA and DNA, contributing to cytotoxicity
- Leucovorin:
- Enhances TS inhibition
- Converted intracellularly to:
- Methotrexate (MTX):
- Antifolate:
- That inhibits dihydrofolate reductase (DHFR)
- Intracellular polyglutamation increases potency and extends inhibition to other folate-dependent enzymes:
- Impairing purine and pyrimidine synthesis:
- Leading to cell death
- Impairing purine and pyrimidine synthesis:
- Antifolate:
- 5-Fluorouracil (5-FU):
- Indications in Head and Neck Squamous Cell Carcinoma (HNSCC):
- 5-Fluorouracil (5-FU):
- Induction therapy:
- Used in docetaxel + cisplatin + 5-FU (TPF) regimen:
- Which improved progression-free survival (PFS) and overall survival (OS) vs. cisplatin + 5-FU (PF) in TAX 323 / 324
- Used in docetaxel + cisplatin + 5-FU (TPF) regimen:
- Concurrent chemoradiation (CRT):
- Carboplatin + 5-FU with radiation therapy (RT):
- Is an option for cisplatin-ineligible patients
- Carboplatin + 5-FU with radiation therapy (RT):
- Recurrent / Metastatic (R/M):
- Backbone of the EXTREME regimen (platinum + 5-FU + cetuximab):
- Which improved OS compared to platinum + 5-FU alone
- Induction therapy:
- Methotrexate (MTX):
- Single-agent palliative therapy:
- Historically a standard for recurrent / metastatic HNSCC:
- Often given weekly intravenous (IV) 40 mg/m², with activity and tolerability in frail or heavily pretreated patients
- Combination therapy:
- Sometimes paired with cetuximab in cisplatin-unfit patients
- Single-agent palliative therapy:
- 5-Fluorouracil (5-FU):
- Adverse Effects and Management:
- 5-Fluorouracil (5-FU):
- Mucositis, diarrhea, myelosuppression, hand-foot syndrome (HFS):
- Supportive care; oral cryotherapy may reduce mucositis (bolus 5-FU)
- Cardiotoxicity (vasospasm, ischemia):
- Discontinue 5-FU
- Treat as vasospastic angina with nitrates and / or calcium channel blockers
- Neurotoxicity (cerebellar syndrome, hyperammonemic encephalopathy):
- Stop 5-FU
- Hydrate, correct metabolic derangements
- Dihydropyrimidine dehydrogenase (DPD) deficiency:
- Screen with DPYD testing where available:
- Poor metabolizers should avoid fluoropyrimidines
- Antidote:
- Uridine triacetate (Vistogard) within 96 hours of overdose or early severe toxicity
- Screen with DPYD testing where available:
- Mucositis, diarrhea, myelosuppression, hand-foot syndrome (HFS):
- Methotrexate (MTX):
- Mucositis, myelosuppression, hepatotoxicity:
- Monitor complete blood count (CBC) and liver function tests (LFTs); hold dose for grade ≥3 toxicity.
- Folinic acid (leucovorin) rescue may be used for high-dose or severe toxicity
- Renal elimination:
- Requires dose adjustment in renal impairment
- Avoid interactions with trimethoprim-sulfamethoxazole (TMP-SMX), nonsteroidal anti-inflammatory drugs (NSAIDs), proton pump inhibitors (PPIs), and some penicillins, which increase MTX toxicity
- Mucositis, myelosuppression, hepatotoxicity:
- 5-Fluorouracil (5-FU):
- Key References:
- Vermorken JB et al., NEJM 2007; Posner MR et al., NEJM 2007; Lorch JH et al., Lancet Oncol 2011 – TPF vs PF in induction therapy.
- Vermorken JB et al., NEJM 2008 – EXTREME regimen in R/M HNSCC.
- NCCN Guidelines: Head and Neck Cancers, 2025 Insights.
- Amstutz U, Froehlich TK, Largiadèr CR. Clin Pharmacol Ther 2011 – DPD deficiency and 5-FU toxicity.
- US FDA Label: Uridine triacetate (Vistogard).
Specenier P, Vermorken JB. Oral Oncol 2009 – Methotrexate in head and neck cancer.
Rodrigo Arrangoiz MS, MD, FACS, FSSO 