Adoption of a DPYD variant screening panel and treatment dosing protocol in South East London Cancer patients undergoing fluoropyrimidine chemotherapy is workable safe and effective.


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Julien de Naurois1, Kalliopi Michoglou1, Dimity Ball1, Muhammad Khan1, Ketevan Eremeishvili1, Jose Roca1, Asad Qureshi1, Nick Maisey1, Kiruthikah Thillai1, Miguel Reis Ferreira1, Sarah Ngan1, Kasia Owczarczyk1, Debashis Sarker1, Ailsa Sita-Lumsden1, Vasiliki Michalarea1, Jessica Brady1, Irene DeFrancesco1, Tony Marinaki1, Paul Ross1
1Guy’s and St Thomas’ NHS Foundation Trust

Abstract

Background

5-8% of the general population carry DPYD polymorphisms, risking severe toxicity from fluoropyrimidine (FP)-based chemotherapy at standard doses. In November 2018, Guy’s and St Thomas’ Hospital established a regional protocol mandating DPYD screening for all patients starting FP-based therapy. 5 common variants associated with FP toxicity were screened. Patients with variant alleles commenced dose modified FP chemotherapy, with re-escalation allowed in the absence of toxicity.

Method

From February 2019 to July 2020, 1462 patients from 3 Hospital Trusts in South East London were screened, of which 129 had a DPYD variant (8.9%), the largest cohort being Colorectal cancer (57), followed by Oesophago-gastric (19), Pancreas (18), Breast (11), Oral and Head & Neck (10), Anal (8), CUP (2), and NET (1). Records were taken of chemotherapy and radiotherapy treatments, FP dose modifications, toxicity and response assessments, admissions and deaths, until 1st June 2021.

Results

In total, 121 FP-based treatments were administered, 71 first line, 33 second and third line chemotherapy, and 17 FP-containing Chemo-RT.

Protocol compliance was 98.3%. Across FP-based chemotherapy, serious G3/4 toxicity was acceptable with neutropenia of 19.2%, diarrhoea of 9.6%, mucositis of 3.8%, and PPE of 1%. FP-containing Chemo-RT was well tolerated with G3/4 neutropenia of 5.9%. 25 chemotherapy-related admissions occurred. 15 were caused by DPD deficiency (14 on 1st line), with 7 due to neutropenic sepsis, and 5 due to G3 diarrhoea. 5 deaths occurred, of which only 2 due to DPD deficiency, with neutropenic sepsis following palliative CAPOX.

Adequate efficacy was demonstrated with response rates to 1st line chemotherapy of 69.2% for 14 metastatic Colorectal, and of 58.8% for 17 locally advanced/ metastatic Oesophago-gastric patients.

20 patients experienced dose escalations, with 16 safe outcomes, but 4 admissions , 2 due to G3 diarrhoea (CAPOX and Capecitabine), 2 due neutropenic sepsis (CAPOX and GemCap), with one death (CAPOX).

Conclusion

Compliance with the DPYD dose-reduction protocol was good, and chemotherapy related toxicity acceptable. FP dose-escalation was safe in a significant subgroup of patients, although caution is advised. Further prospective data is warranted to ensure continued safety and equivalent efficacy of FP regimens between wildtype and variant DPYD patients.

Impact statement