Frequency of dihydropyrimidine dehydrogenase (DPD) deficiency detection and adverse events in patients receiving fluoropyrimidine-based therapy in a pancreatic and biliary tract cancer cohort

Background

Pancreatic and biliary tract cancers (BTCs) are associated with extremely poor prognoses due to patients frequently presenting at an advanced stage, limited treatment options and lack of screening programmes. Treatment for these malignancies may involve a 5-fluorouracil (5-FU)-based chemotherapy regimen. 5-fluorouracil requires Dihydropyrimidine dehydrogenase (DPD) for catabolism. Dihydropyrimidine dehydrogenase deficiency occurs due to a Dihydropyrimidine dehydrogenase gene (DPYD) mutation and increases the risk of patients experiencing 5-FU toxicity and adverse effects. This retrospective study aimed to determine the DPD deficiency frequency in patients with pancreatic and BTCs (all stages) who received 5-FU-based treatment in a tertiary referral centre and assessed adverse events (AEs) as per the Common Terminology Criteria for Adverse Events (CTCAE) version 5.

Methods

Patients commencing 5-FU-based chemotherapy for pancreatic and BTCs were identified. The institution database was used to access patient records, review evidence of DPYD mutation, type of cancer, and assessment of tolerance to treatment as per the CTCAE version 5.
Patients with pancreatic or BTC who had been tested for DPD deficiency were eligible for the study. Details of chemotherapy regimens for each patient and evidence of any subsequent alteration in the dose of 5-FU-based treatment was also reviewed.

Results

Between 06/07/2020 and 19/04/2021, all (100%) of 291 patients starting a 5-FU-based chemotherapy regimen were tested for DPD deficiency. Of the 198 patients with pancreatic cancer, 83.8% of patients received treatment in the palliative setting, 8.6% adjuvant and 8.1% neoadjuvant. Of the 93 patients with BTC, 60.2% of patients received treatment in the palliative setting, 37.6% adjuvant and 2.2% neoadjuvant.

Of the total cohort tested, 9.3% had a DPD deficiency; 17 of 198 patients (8.6%) with pancreatic cancer and 10 of 93 patients (10.8%) with BTCs had a DPD deficiency (all underwent a 50% reduction of 5-FU starting dose). Three DPYD gene mutations were identified in the overall cohort: c.1129-5923C>G (15 patients (5.2%)), c.2846A>T (9 patients (3.1%)), and c.1905+1G>A (3 patients (1.0%)).

In the entire cohort of patients with DPD deficiency who received 5-FU at 50% dose (N = 21, (N = 10 adjuvant and N = 11 palliative)), 90% experienced AEs; 73.7% of patients experienced a grade 1 AE, 47.7% a grade 2 AE, and 36.8% a grade 3 AE. The most common grade 3 AEs were diarrhoea, neutropenia, and thrombocytopenia. No patients experienced a grade 4 AE. Furthermore, 11.1% of these 21 patients were given and tolerated a dose escalation to 75% of the standard dose, 7.4% patients required a dose decrease, and 19% required treatment-related cessation of 5-FU-based therapy. No patients tolerated a dose increase to 100%.

Conclusions

This study provides reference DPD frequencies and associated AEs for patients with pancreas and BTC receiving 5-FU-based chemotherapy. In the entire cohort, 9.3% had a DPD deficiency; 36.8% of these patients experienced treatment-related grade 3 AEs even with the reduced 50% dose of 5-FU, with some patients requiring either a further dose reduction or cessation of 5-FU. However, a minority of patients tolerated a dose increase to 75%.