DPD deficiency (DPYD) and fluoropyrimidine chemotherapy

Dihydropyrimidine dehydrogenase, usually shortened to DPD, is an enzyme made mainly in the liver. The DPYD gene holds the instructions for it. Its everyday job is to break down the building blocks uracil and thymine. Fluoropyrimidine cancer medicines are chemically similar to those building blocks, so the same enzyme handles them too.

MedlinePlus Genetics explains that in people with DPD deficiency these cancer medicines accumulate in the body and cause severe reactions. More than fifty different changes in the gene have been linked to the deficiency. Because so many variants exist, the activity of the enzyme runs along a spectrum rather than being simply present or absent.

The medicines of concern are fluorouracil given into a vein, capecitabine tablets and tegafur. They are used in several cancers, including bowel cancer and some breast and stomach cancers, usually as part of a wider regimen. Cancer Research UK describes capecitabine as a tablet swallowed whole with water within thirty minutes of finishing a meal, taken in cycles that vary by cancer type.

A related concern applies to flucytosine. The MHRA notes that flucytosine is a prodrug that turns into fluorouracil in the body, and it should not be used in someone known to have complete DPD deficiency. The same advice says treatment for a serious fungal infection should not be held up while waiting for a DPD result, and testing can be considered if toxicity appears.

The MHRA quotes prevalence figures for Caucasian populations: complete deficiency in roughly 0.01 to 0.5 per cent and partial deficiency in roughly 3 to 9 per cent. Prevalence differs between ethnic groups, and MedlinePlus Genetics notes higher rates of some disease-causing variants in African American populations, so the figures for one group should not be applied to everyone.

The same safety update reported that thirty fatal cases involving known or suspected DPD deficiency had been reported in the UK up to June 2020. That history is the main reason testing before the first dose is now advised, rather than only investigating after someone becomes seriously unwell.

Cancer Research UK says that before capecitabine you have a blood test to check the DPD enzyme, and that low levels mean a higher chance of severe side effects and may call for a lower dose. The MHRA also asks prescribers to enquire about any family history of DPD deficiency.

Hospitals differ in how they carry out the test and how quickly a result returns, so it is reasonable to ask your oncology team how the test is done locally and when you will hear the result. Starting treatment is normally sequenced so the result is known first.

• A complete deficiency result: the fluoropyrimidine is not given, and the team chooses a different regimen.

• A partial deficiency result: the MHRA says a reduced starting dose can be considered, with later doses increased only if there has been no serious toxicity.

• A normal result: treatment starts as planned, with the first cycle watched closely because the MHRA also advises monitoring in the first cycle and after dose increases.

The MHRA lists the typical early problems as sore mouth or mouth ulcers (stomatitis), diarrhoea, inflammation of mucous membranes, a fall in white blood cells (neutropenia) and effects on the nervous system. They generally appear in the first cycle.

Cancer Research UK advises contacting the treatment advice line straight away for a temperature of 37.5 degrees Celsius or above, or below 36 degrees, for a severe skin reaction such as peeling or blistering, and for side effects that are severe or getting worse. If you cannot reach the team and feel seriously unwell, NHS 111 or 999 are the routes for urgent help.

A DPD test narrows the risk but does not remove it. Other causes of severe toxicity exist, including kidney function, interactions and individual variation, which is why the MHRA wording is that severe toxicity may still occur despite a negative result.

It is also worth asking how the team will use a partial-deficiency result. Because the advice allows dose increases when the early cycle goes well, the plan is not necessarily fixed, and the team will usually explain how they will decide.