Prevention of 5-fluorouracil-induced early severe toxicity by pre-therapeutic dihydropyrimidine dehydrogenase deficiency screening: Assessment of a multiparametric approach

Publication date: Available online 11 February 2017
Source:Seminars in Oncology
Author(s): M. Boisdron-Celle, O. Capitain, R. Faroux, C. Borg, J.P. Metges, M.P. Galais, M. Kaassis, J. Bennouna, K. Bouhier-Leporrier, E. Francois, I. Baumgaertner, V. Guerin-Meyer, O. Cojocarasu, C. Roemer-Becuwe, C. Stampfli, L. Rosenfeld, T. Lecompte, V. Berger, A. Morel, E. Gamelin
Background5-FU-based treatments can lead to early-onset severe (4 to 5%) even fatal (0.3%) toxicities in patients with dihydropyrimidine dehydrogenase (DPD) deficiency. This multicenter prospective cohort study aimed to assess the clinical benefit of pre-therapeutic screening for DPD deficiency using a multiparametric approach.MethodsTwo parallel cohorts of patients treated with 5-FU-based chemotherapy for colorectal carcinoma were compared in a prospective non-randomized study. In Arm A, patients had DPD deficiency screening before treatment whereas in Arm B no pre-therapy screening was performed. Dosing was based on 5-FU administration guidelines of each institution. DPD deficiency screening was performed using a combined multiparametric approach (5-FU^{ODPM Tox}). The frequency of early grade 4-5 toxic events potentially induced by 5-FU was compared in the two groups.Results1142 patients (n=1116 evaluable) were enrolled. In Arm A, out of 718 evaluable patients, 9 grade 4 early toxicities potentially related to 5-FU were reported in 9 patients (1.2%) with no toxic death despite 1 complete DPD deficiency and 24 partial deficiencies. The 24 patients with partial deficiency had safe PK-monitored 5-FU. In Arm B, out of 398 evaluable patients, 17 grade 4-5 toxic early events potentially related to 5-FU were reported in 12 patients (4.2%). The incidence of early severe toxicity was significantly higher in Arm B, (p = 0.0019), confirming the positive impact of pre-therapeutic DPD assessment. The percent of patients with a toxicity grade 3 or higher observed in Arm A was 10.8% (n=78) compared to 17.55% (n=69) reported in Arm B (p=0.0497). The percentage of death was reduced from 2.5/1000 in Arm B to 0 in Arm A. The time to occurrence of all grade ≥3 toxicities was determined in both arms and the difference between the 2 arms was significant (P=0.047). Overall, one patient with complete DPD deficiency confirmed retrospectively died within 13 days from grade 5 multivisceral toxicity. Enrollment was prematurely closed after external experts' decision.ConclusionsMultiparametric pre-therapeutic DPD deficiency screening significantly lowered the risk of early severe toxicity and avoided an early toxic death. This approach should be used for safe administration of 5-FU-based treatments.



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