Dihydropyrimidine dehydrogenase (DPD) deficiency and side effects in cancer patients

Introduction

Cancers are ranked among diseases with increasing prevalence every year. According to statistics, the number of cancer patients is projected to increase to 12 million by 2030 globally [1] . They are the cause of a large number of deaths with various risk factors and preventive and therapeutic strategies. Cancer treatment involves different approaches, including surgery, radiotherapy, cellular or monoclonal immunotherapy, oral targeted therapies, biotherapies and cytotoxic chemotherapy. These therapeutic strategies involve different protocols with different products. Regarding chemotherapy, most protocols contain fluoropyrimidine-based products (5fluorouracil), which are molecules with a narrow therapeutic index and many toxicities. They are not only used in metastatic situations, but also increasingly in adjuvant situations, i.e. for patients treated for a localized tumor at risk of relapse [2] . The metabolism of fluoropyrimidine products depends primarily on the activity of the dihydropyrimidine dehydrogenase (DPD) enzyme, involved in the degradation of natural pyrimidines. Indeed, it ensures the initial and limiting step of pyrimidine catabolism, thus involved in the degradation of chemotherapy drugs containing 5-FU or its analogues. Actually, more than 80% of the 5-FU administered is catabolized by DPD [3] . A deficiency of this enzyme can cause side effects in patients treated with these products. This study was conducted within that context to highlight the presence or absence of side effects in cancer patients undergoing fluoropyrimidine-based chemotherapy.

Methodology

A survey sheet was drafted to collect relevant data: This includes the patient's first and last name, date of last chemotherapy, products used, clinical signs noted after a chemotherapy session…; for those who have already started their treatment. In these patients, a blood sample was taken on EFTA tube and centrifuged at 4000 revolutions per minute for 8 minutes. Uracil (U) and Dihydrouracil (UH2) parameters were determined using the HPLC method after extraction. All results and epidemiological characteristics were reported using Excel 2016. The interpretation of the results was carried out with the following cut-off values: Interpretation of uracil (U) concentration:  U< 16 ng/mL: no DPD deficiency  16 < U <150 ng/mL: presence of partial DPD deficiency  U>150 ng/mL: presence of complete DPD deficiency  Interpretation of the UH2/U report:  UH2/U >13: no DPD deficit  1<UH2/U<10: presence of partial DPD deficiency  UH2/U < 1: Presence of complete DPD deficiency

Results

In our study population, we identified 29 patients who had not yet started chemotherapy whereas 74 had already started. Of those who started chemotherapy, 92% had side effects and only 8% were found without symptoms. On average, the uracil concentration measured in patients was 17.44±1.65 ng/ml. For dihydrouracil, the average measured in these patients was 177.95±5.62 ng/ml. Regarding the ratio of dihydrouracil to uracil, we found an average of 12.6±0.48. When it comes to uracil levels according to side effects, we found:  For patients with U < 16 ng/ml, 45 had side effects while 20 did not.

 For patients with uracil levels between 16 and 150 ng/ml, 24 had side effects and 14 did not.  For patients with U >150 ng/ml, only one patient experienced side effects. For the ratio of dihydrouracil to uracil:  For patients with UH2/U >13, 25 experienced side effects while 12 did not.

 For patients with a UH2/U between 1 and 10, 43 experienced side effects and 22 did not.  For patients with UH2/U < 1, only one patient experienced side effects. The DPO status shows that:  Among patients without DPD deficiency, 22 experienced side effects (21.4%) and 12 did not (11.7%).

 Of those with partial DPD deficiency, 46 experienced adverse effects (44.7%) and 22 did not (21.3%).  For patients with total DPD deficiency, only one patient experienced side effects. In patients who have already started chemotherapy, we found that 92% developed symptoms after taking medication, and this has been illustrated by many studies.

For the UH2/U ratio in our study population, the mean value was 12.6±0.48 with a standard deviation of 4.91±0.95. The lowest and highest values of this ratio were 0.2 and 28.1, respectively. Indeed, the mean uracil (U) was 17.44±1.65 ng/ml with a standard deviation of 16.64±3.23 ng/ml. The lowest and highest values for uracil were 5.8 ng/mL and 165.79 ng/mL. Compared to Caroline Calderon's results, the mean UH2/U in the patients was 10.70 +/-4.60 with the lowest value 0.74 and the highest value 24.61. For the same study, the mean uracil was 12.81 +/-7.81 ng/mL with the lowest value 3.87 ng/mL and the maximum value 62.38 /ml [4] . Among patients with uracil values below 16 ng/ml, 43.6% had side effects, in the following proportion:  Vomiting in 17 patients (16.5%)  Diarrhea in 12 patients (11.6%)  Dizziness in 4 patients (3.8%)  Fatigue in 12 patients (11.6%)  Headache, general malaise, nausea, limb pain, body aches  tremors, hot flashes, hair loss, dermatological problems In this population, uracil U < 16 ng/ml was not significantly associated with the occurrence of side effects, as 19.4% of patients did not experience side effects. For uracil values between 16 and 150 ng/ml, patients had side effects in the following proportion:  Vomiting in 9 patients (8.7%)  Diarrhea in 2 patients (1.9%)  Dizziness in 3 patients (2.9%)  Fatigue in 7 patients (6.8%)  Pain on the left side of the heart, nausea, diarrhea, loss of saliva, loss of appetite, pain on the left side

We found a significant association with the occurrence of severe toxicities when uracilemia is ≥ 16 ng/ml. Indeed, the 2017 study on 550 patients by Meulendjiks et al. [5] showed a clear correlation between uracil levels ≥ 16 ng/ml and early severe toxicity. In the same perspective, Boisdron-Celle et al. had similar results in 2006 [6] . In contrast to the studies by With et al. (2022) [7] , their results showed a lack of a significant association between the occurrence of side effects and DPD status. For uracil levels above 150 ng/ml, we found that 0.01% of patients had side effects such as general fatigue, chest pain, constipation, and lack of appetite. These results can also be interpreted based on the UH2/U ratios which show that 25 patients experienced side effects when the UH2/U ratio >13, 43 with a ratio between 1 and 10 and one patient with a ratio of less than 1. DPD status based on side effects reveals that 22 patients (21.4%) experienced side effects in the absence of DPD deficiency, 46 patients (44.7%) with partial deficiency and 1 patient (0.9%) with complete deficiency. According to the Hagiwara study, DPD deficiency was noted in the presence of many grade 3 side effects during the first cycle of chemotherapy in a 64-year-old patient [8] . These results have been confirmed by several authors, all corroborating the fact that the incidence of level III, IV or V side effects is higher in patients with partial DPD deficiency [9,10] .

Conclusion

The association between uracil concentrations and side effects showed that uracil levels above 150 ng/ml were consistently associated with serious side effects, such as vomiting, diarrhea and general fatigue. Similarly, a UH2/U ratio greater than 13 was also correlated with an increase in symptoms, thus corroborating the use of this ratio as an indicator of toxicity.

References

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