Capecitabine

Impact of genetic variation on response to therapy

Capecitabine is a fluoropyrimidine-based chemotherapy that functions as an orally administered precursor of the cytotoxic moiety 5-fluorouracil. The DPYD gene encodes dihydropyrimidine dehydrogenase (DPD), a key enzyme involved in catabolism of 5-fluorouracil. DPD deficiency is most often caused by inherited variants of the DYPD gene.

The SmPC for capecitabine provides special warnings and precautions in use related to DPYD gene variants and DPD deficiency which are summarised as follows:

• DPD activity is the rate limiting step in the catabolism of 5-fluorouracil. Patients with DPD deficiency are therefore at increased risk of fluoropyrimidine-related toxicity, including stomatitis, diarrhoea, mucosal inflammation, neutropenia and neurotoxicity.
• Patients with complete DPD deficiency are at high risk of life-threatening or fatal toxicity and must not be treated with capecitabine.
• Patients with partial DPD deficiency are at increased risk of severe and potentially life-threatening toxicity. A reduced starting dose of capecitabine should be considered to limit this toxicity. In the absence of serious toxicity, subsequent doses may be increased with careful monitoring.

The MHRA advises that patients with known complete DPD deficiency should not be treated with capecitabine, and that a reduced starting dose should be considered for patients with partial DPD deficiency.

Testing recommendations

The SmPC states that phenotype and/or genotype testing prior to the initiation of treatment with capecitabine is recommended.

The MHRA advises that all patients should be tested for DPD deficiency before initiation of treatment with medicines containing capecitabine.

Therapeutic recommendations

Treatment should be initiated and managed under the supervision of a specialist cancer physician. 

Consult specialist resources for detailed information on dosing, response measures, and dose titration. 

The UK Systemic Anti-Cancer Therapy Board (2024) have produced guidance on a personalised medicine approach for fluoropyrimidine-based therapies which is summarised as follows: 

DPYD metaboliser status unknown 

• All patients due to receive fluoropyrimidine based therapy should have a DPD test [DPYD genotype test] prior to starting treatment.
• Treatment should only be commenced prior to a genotype test in exceptional circumstances following a multidisciplinary discussion and where the benefit is thought to outweigh the risk.

DPYD Normal metabolisers 

Some examples of DPYD genotypes include (see note): No reduced function variant/No reduced function variant

• No reduced function variants identified.
• Normal DPD activity and normal risk of fluoropyrimidine toxicity.
• Use at standard dose. 

DPYD Intermediate metabolisers: Activity score 1.5

Some examples of DPYD genotypes include (see note): c.2846A>T/No reduced function variant, c.1129–5923C>G/No reduced function variant.

• DPD activity reduced to 50-75% of that of normal metabolisers.
• Increased risk of severe or even fatal toxicity.
• Reduce starting dose to 50% of target dose.
• Monitor for efficacy and titrate accordingly to a maximum of 75% of target dose (see further information). Users should follow local treatment protocols on incremental dose changes.
• If no toxicity is observed at a dose of 75%, a further increment to a maximum of 85% of target dose may be possible, but caution is advised. 

DPYD Intermediate metabolisers: Activity score 1.0 

Some examples of DPYD genotypes include (see note): c.1905+1G>A/No reduced function variant, c.557A>G/557A>G, c.1129–5923C>G/557A>G, c.2846A>T/557A>G. 

• DPD activity reduced to 30-50% of that of normal metabolisers. 
• Increased risk of severe or even fatal toxicity.  
• Reduce starting dose to 50% of target dose or consider alternate therapy.  
• Monitor for toxicity and titrate accordingly to a maximum of 75% of target dose (see further information). Users should follow local treatment protocols on incremental dose changes.  

DPYD Poor metabolisers: Activity score 0.5 

Some examples of DPYD genotypes include (see note): c.1905+1G>A/2846A>T, c.1905+1G>A/1129-5923C>G, c.1679T>G/557A>G

• DPD activity reduced to 10-25% of that of normal metabolisers.
• Increased risk of severe or even fatal toxicity.
• Avoid use of fluoropyrimidine therapy.
• Consider alternate therapy.

DPYD Poor metabolisers: Activity score 0 

Some examples of DPYD genotypes include (see note): c.1905+1G>A/1905+1G>A, c.1679T>G/1679T>G, c.1905+1G>A/1679T>G

• Complete DPD deficiency (predicted 0% DPD activity).
• Significantly increased risk of life-threatening or fatal toxicity.
• Do not use fluoropyrimidine therapy.
• Use alternate therapy.

Note: This is a limited list of examples of DPYD genotypes. The UK Systemic Anti-Cancer Therapy Board (2024) guidance provides a more comprehensive list.

The genotype term “No reduced function variant” has been used in this monograph to indicate a genotype where no reduced function variants have been found. Local laboratory reporting terminology may vary.

Further information

The absence of a loss of function DPYD variant being identified does not exclude fluoropyrimidine-associated toxicity related to other genetic (e.g., rare variants in DPYD or other genes) or non-genetic (e.g., renal function, co-morbidities) factors.

To maintain effectiveness of treatment, dose titration based on toxicity or therapeutic drug monitoring over subsequent cycles is important. The UK Systemic Anti-Cancer Therapy Board (2024) states that there is little data around specific increment levels to increase by, but a recommendation would be to take a pragmatic approach and increase by 10-12.5% per cycle assuming no, or clinically acceptable, toxicity after two treatment cycles. It is recommended that there are, at most, two stepwise increments. Users should follow local treatment protocols on incremental dose changes and alternate therapies where appropriate.

Due to challenges in sequencing, some DPYD assays test a nearby genetic variant c.1236G>A as a proxy for the decreased function variant c.1129-5923C>G, as both variants are normally present together, also referred to as the “HapB3 haplotype”. In rare cases, the decreased function variant c.1129-5923C>G or the nearby variant c.1236G>A may be present individually and so this method of testing may result in either a false positive or false negative result for the decreased function variant c.1129-5923C>G.

References

Amarox Limited (2024). Capecitabine 150 mg film-coated tablets SmPC. Available at: https://www.medicines.org.uk/emc/product/14590/smpc (Accessed online 15 May 2025).

MHRA Medicines and Healthcare products Regulatory Agency (2020). 5-fluorouracil (intravenous), capecitabine, tegafur: DPD testing recommended before initiation to identify patients at increased risk of severe and fatal toxicity. Drug Safety Update. Available at: https://www.gov.uk/drug-safety-update/5-fluorouracil-intravenous-capecitabine-tegafur-dpd-testing-recommended-before-initiation-to-identify-patients-at-increased-risk-of-severe-and-fatal-toxicity (Accessed online 15 May 2025).

The UK Systemic Anti-Cancer Therapy Board (2024). Personalised Medicine Approach for Fluoropyrimidine-based Therapies v2 September 2024. Available at: https://www.uksactboard.org/publications (Accessed online 15 May 2025).

Clinical Pharmacogenetics Implementation Consortium (CPIC^®) (2024). CPIC^® Guideline for Dihydropyrimidine Dehydrogenase Genotype and Fluoropyrimidine Dosing. January 2024 update (edited March 2024). Available at: https://cpicpgx.org/guidelines/guideline-for-fluoropyrimidines-and-dpyd/ (Accessed online 15 May 2025).