A 2019 review discussed multiple mutations in the dihydropyrimidine dehydrogenase (DPD) gene, contributing to the 5-fluorouracil (5-FU) toxicity and inadequate dosages. 5-FU as a uracil analog exhibits its wide antitumor activities primarily through disrupting RNA and DNA synthesis. Given DPD is majorly involved in the metabolism of pyrimidines in the human body, it has the same metabolizing effect on 5-FU, a pyrimidine analog. In-vitro data demonstrated DPD catabolizes more than 80% of the 5-FU into dihydro-fluorouracil. As such, patients with DPD deficiency, either from particle loss of enzymatic activity (3-5%) or complete loss of the activity (0.2%), may have an increased risk of severe polyvisceral 5-FU-induced toxicity (grade 3 or higher). [1]
Recent studies found multiple polymorphisms associated with the DPYD gene that encodes DPD enzymes. Additionally, the genetic variants leading to DPD deficiency appeared to vary in different ethnic groups. Specifically, in the Caucasian population, IVS14+1G>A polymorphism linked to the DPYD* 2A allele was found to be the most frequent among the cancer patients, leading to severe 5-FU toxicity. While specific incidences were not reported, clinical manifestations due to the toxicity of 5-FU included fever, mucositis, stomatitis, nausea, vomiting, and diarrhea. In severe cases, it may lead to neurological abnormalities, such as cerebellar ataxia and changes in cognitive functions. Case reports also observed patients have gone into a coma or developed leukopenia, neutropenia, possibly thrombocytopenia, and anemia. In suspicion of 5-FU toxicity due to DPD deficiency, 5-FU should be stopped immediately, followed by removing traces of the drug with hemodialysis and hemoperfusion. Moreover, the subsequent dosage of 5-FU should be adjusted according to the enzymatic status of the DPD observed during the first treatment as well as the patient’s tolerability. In contrast, the high intratumoral activity of DPD may considerably decrease the cytotoxic effect of 5-FU, causing a therapeutic deficiency. Drugs decreasing DPD catabolic activities, known as DPD inhibitors, can be used along with 5-FU to act as a substrate for DPD. [1]
A 2020 consensus paper developing diagnostic and treatment recommendations for 5-FU-associated toxicities reported around 30% of severe toxicity reactions (WHO grade 3-4), particularly diarrhea, mucositis, hand/foot syndrome, myelosuppression with profound and persistent neutropenia, as well as neurotoxicity, can be explained by DPD deficiency in patients receiving 5-FU, capecitabine, and tegafur, leading to a mortality rate of 0.2-1%. Cardiotoxicity, including electrocardiogram changes, coronary artery spasm, and myocardial damage, occurs less often in a range of 1-10% of treated patients. Recommendations, primarily formulated based on European Medicines Agency (EMA) and European entities, suggest the need to test for the 4 most common genetic DPYD variants before treatment with drugs containing FU. Subsequent decisions on FU therapy and dose adjustments should then be guided by genetic testing activity scores and DPD phenotyping. [2]
A 2011 pharmacogenomic review suggests from the literature that there is a major association between DPD mutations and severe 5-FU-related toxicities, although the wide ranges of treatment settings and variants of DPD mutations make it difficult to highlight specific risks. The overall combined variants contribute to approximately 20% of 5-FU adverse events and may be more prevalent in combination 5-FU therapies compared to monotherapy. Consistent findings from case-control studies seem to implicate polymorphisms c.1905+1G>A, c.1679T>G, c.2846A>T as being linked to severe 5-FU related National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) grade ≥ 3 toxicities. DPD mutations specific to geographic regions may also define local risks for 5-FU toxicity. There are limited data suggesting that the type of 5-FU-based chemotherapy regimen could also potentiate toxicity with certain DPD variants. [3]
A 2000 study evaluated the clinical implications of DPD deficiency in 37 cancer patients with unexpected severe 5-FU-associated toxicity by analyzing the activity of DPD genes and the clinical presentation of patients suffering from severe toxicity following the administration of 5-FU. A decreased DPD activity was detected in the peripheral blood mononuclear cells of 59% of the enrolled subjects. The study also observed a significantly higher proportion of patients with decreased DPD activity suffered grade IV neutropenia compared with patients with normal DPD activity (55% vs. 13%, p= 0.01). Additionally, in patients with low DPD activity, the onset of toxicity occurred twice as fast compared to patients with normal DPD activity (10.0 ± 7.6 vs. 19.1 ± 15.3 days; p<0.05). Except for grade IV neutropenia, no differences in hematological, gastrointestinal, flu-like symptoms or other toxicities were observed between the two groups. A high incidence of mutations in the PDP gene was discovered in 11 of 14 patients, with the splice site mutation IVS14+1G>A being the most abundant one (43%). The findings of this study demonstrated that 57% (8 of 14) of the patients with a reduced PDP activity have a molecular basis for their deficient phenotype. Based on these data, it was suggested that a partial DPD deficiency appears to play a role in developing 5FU-associated toxicities. Taking the common use of 5-FU in therapy, the severe related toxicities in patients with a low activity DPD, and the high frequency of the IVS14+1G>A mutation in DPD-deficient patients into account, it is preferable to routinely analyze the DPD-activity or screening the IVS14+1G>A mutation prior to the initiation of treatment with 5-FU. [4]