ESTRO 2024 - Abstract Book

S1888

Clinical - Mixed sites, palliation

ESTRO 2024

Purpose/Objective:

5-Fluoruracil (5-FU) and its oral prodrug capecitabine are a mainstay in many tumor entities treated with combined chemoradiotherapy regimens. It is metabolized by the dihydropyrimidine dehydrogenase (DPYD). Pathogenic variants in DPYD gene cause a reduction in DPYD activity, leading to severe and possibly lethal toxicity [1]. With a prevalence of relevant genetic variants in Europe ranging at 9% [2], all patients scheduled for 5-FU/capecitabine based chemoradiotherapy are tested prior to treatment initiation. However, there is limited clinical data on treatment protocol adjustments and tolerability in patients with reduced DPYD activity receiving combined chemoradiotherapy.

In this report, rate of DPYD deficiency in patients at our department was analyzed. Treatment protocol adjustments, toxicity profiles and oncological outcome in patients with reduced DPYD activity were reviewed.

Material/Methods:

For all patients receiving 5-FU/Capecitabine based chemoradiotherapy, DPYD activity were routinely tested. Genotyping of four DPYD variants (DPYD*2A, DPYD*13, c.2846A>T, and haplotype B3 [3]) was conducted according to the recommendation of the German society for hematooncology (DGHO), using Taq-Man Hydrolysis PCR (QuantStudy 3, Thermo FisherScientific, Darmstadt). DPYD variants and activity score as well as clinical data (tumor entity, treatment protocol, chemotherapy adjustments, toxicity (hematological, neurological, cardiological and mucosal; common terminology criteria for adverse events, CTCAE)) and oncological outcome of patients presenting with a DPYD alteration was reported.

Results:

Between January 2020 and August 2023, 199 patients scheduled for 5-FU based chemoradiotherapy were tested for DPYD deficiency, which was observed in 15 patients (7.5%). Tumor entities included rectal cancer (n=7), anal cancer (n=4), and carcinomas of the oral cavity, larynx or gastroesophageal junction (n=4). Apart from one patient, most presented with a heterozygous DPYD variant, of which haplotype B3 was most prevalent (n=11; 73.3%). Median DPYD activity score was 1.27 (range 0- 1,5). Based on genetic findings, physicians’ assessment and patients’ wishes, 5-FU was omitted from chemotherapy regimens in 3 cases with alternatives applied (mitomycin, cisplatin) . 12 patients received dose-adapted 5-FU (50-75%). Treatment-related toxicity included elevated liver enzymes, hematological toxicity CTCAE grade 1, and mild mucositis. Only in one case, pronounced leukocytopenia (CTCAE grade 3) and elevated serum creatinine were observed. No CTCAE grade 4 toxicities were reported.

Conclusion:

In our cohort, the observed rate of DPYD variants of 7.5% was in accordance with reported rates in European populations (9%). Heterozygous haplotype B3 were most common. DPYD activity score was at least 0.5 in heterozygous patients, corresponding with a residual DPYD activity. In patients receiving dose adapted chemotherapy regimens, no CTCAE grade 4 toxicities were observed. Our clinical data suggests that dose adapted 5 FU/capecitabine chemoradiotherapy regimens can be considered in patients with heterozygous clinically relevant DPYD variants and an activity score of at least 0.5. However, treatment adaptations and toxicity profiles need to be