A 38-year-old woman with metastatic colorectal cancer is being evaluated for 5-fluorouracil (5-FU) toxicity after developing severe hand–foot syndrome and mucositis. Which investigation would be most appropriate to identify patients at risk for severe 5-FU toxicity due to dihydropyrimidine dehydrogenase (DPD) deficiency?

## DPD Deficiency and 5-FU Toxicity **Key Point:** Dihydropyrimidine dehydrogenase (DPD) is the rate-limiting enzyme that catabolises 80–90% of administered 5-FU. DPD deficiency (partial or complete) leads to severe, potentially fatal 5-FU toxicity due to impaired drug clearance and accumulation. ## Pathophysiology of DPD Deficiency 1. **Complete DPD deficiency** (rare, ~1 in 500–1000): Profound 5-FU accumulation; contraindication to 5-FU 2. **Partial DPD deficiency** (heterozygous DPYD mutations, ~3–5% of population): Increased toxicity risk; dose reduction recommended 3. **Normal DPD activity**: Standard 5-FU dosing tolerated **Mnemonic:** **DPD** = **D**ihydropyrimidine **P**hosphoribosyl **D**ehydrogenase (enzyme that breaks down 5-FU) ## Why Genetic Testing (DPYD) is the Investigation of Choice **High-Yield:** DPYD gene mutation testing is the gold standard for identifying DPD deficiency because: 1. **Prospective identification**: Can be done before 5-FU administration to prevent toxicity 2. **Genetic basis**: Identifies the molecular defect (e.g., DPYD*2A, DPYD*13 variants) 3. **Clinical utility**: Guides dose reduction or alternative chemotherapy selection 4. **Cost-effective**: Single genetic test prevents severe, life-threatening toxicity 5. **Regulatory approval**: Major oncology guidelines (ASCO, ESMO, NCCN) recommend DPYD testing before 5-FU use **Clinical Pearl:** The FDA and EMA now recommend DPYD testing before 5-FU/capecitabine initiation. Patients with DPYD deficiency should receive 50% dose reduction or avoid 5-FU entirely. ## Comparison with Other Investigations | Investigation | Role | Limitation | |---|---|---| | **DPYD genetic testing** | Identifies DPD deficiency; guides dosing | Gold standard; prospective | | **Plasma 5-FU levels** | Monitors drug exposure | Reactive (after toxicity occurs); not predictive | | **Liver function tests** | Assesses hepatic metabolism | Non-specific; does not identify DPD deficiency | | **Uracil-to-dihydrouracil ratio** | Reflects DPD activity indirectly | Research tool; not routinely available; less specific than genetic testing | ## Clinical Algorithm ```mermaid flowchart TD A[Patient scheduled for 5-FU/Capecitabine]:::outcome --> B[DPYD genetic testing]:::action B --> C{DPYD mutation present?}:::decision C -->|No mutation| D[Standard 5-FU dosing]:::action C -->|Heterozygous| E[50% dose reduction]:::action C -->|Homozygous/Complete deficiency| F[Avoid 5-FU; use alternative]:::urgent D --> G[Monitor for toxicity]:::action E --> G F --> H[Consider TAS-102 or other agents]:::action ```