Abstract 2204: DPD for dummies: efficacy and toxicity in digestive cancer patients with pharmacogenetic-driven adaptive dosing of 5-FU.
Authors: Ciccolini Joseph , Dahan Laetitia , Evrard Alexandre , Duluc Muriel , Norguet Emmanuelle , Lacarelle Bruno , Seitz Jean-François 
Published: August 2014

5-FU remains the backbone of most regimen in digestive oncology. Drug-related toxicity is a major concern at bedside that shows in 10-20% of patients administered with standard 5-FU. In particular, patients presenting with DPD-deficiency, a pharmacogenetic syndrome resulting in the partial or total lack of ability to detoxify 5-FU in the liver, will experience severe or lethal toxicities. Pre-therapeutic screening for DPD-deficiency should help to improve the efficacy/toxicity balance of 5-FU through adaptive dosing strategies. In this POC study, a total of 40 adult patients with a variety of digestive cancers scheduled for 5-FU-based regimen were included. DPD-deficiency was screened primiraly using a simple and rapid surrogate phenotypic test based upon the UV-HPLC monitoring of the endogenous U to UH2 ratio in plasma. In addition, search for the DPYD*2A allelic variant was scheduled. 5-FU doses were tailored (ie, up to 50% cut in dosing) according to DPD functional status. 5-FU administration was precluded in patients displaying total DPD-deficiency. Toxicity was monitored using standard CTC 2.0. grading. Efficacy was evaluated at 3-month using standard RECIST criteria. Seven out of 40 patients (ie, 17%) displayed mild (4 patients, 10%), strong (2 patients, 5%) and severe (1 patient, 2.5%) DPD-deficiency. No patient with total deficiency was observed. Accordingly, no patient bearing the IVS14+1G&gt;A polymorphism was found. 5-FU dosage was cut by 15% to 50% in patients with DPD-deficiency. As a result, mean 5-FU total dose was 3643 ± 1484 mg in normal patients, and 2257 ± 1310 mg in the other group (ie, -38%, p=0.011). Despite the marked differences in dosing, efficacy in DPD-deficient patients whom dosage had been cut displayed a response rate (CR+PR: 57%) similar to that of patients with full dosage (CR+PR: 45%). G1-G2 toxicities were recorded in 82% of patients with normal DPD status and given standard dosage, and in 72% of patients with DPD-deficiency administered with reduced dosing. No severe toxicities were encountered in both groups. Here, we have demonstrated that rapid and cost-effective pre-therapeutic screening for DPD-deficiency associated with a simple and geometric scale for tailoring 5-FU dosing can reduce the risk of drug-related toxicities. Despite the significantly lower doses administered in patients showing mild to severe DPD-deficiency, no loss of clinical efficacy was observed. Additionally, no &gt;G2 toxicities was recorded, whereas 5-FU normally leads to 10-20% of severe toxicities. This study suggests that the efficacy/toxicity balance of 5-FU can been improved indeed, and that immediate clinical benefit can be achieved in patients. Despite the small sample-size and the heterogeneity of the regimen, this pilot study advocates for the pre-therapeutic screening of DPD-deficiency in patients scheduled for any 5-FU-based therapy.

Citation Format: Joseph Ciccolini, Laetitia Dahan, Alexandre Evrard, Muriel Duluc, Emmanuelle Norguet, Bruno Lacarelle, Jean-François Seitz. DPD for dummies: efficacy and toxicity in digestive cancer patients with pharmacogenetic-driven adaptive dosing of 5-FU. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2204. doi:10.1158/1538-7445.AM2013-2204