O-0019 Severe Fluoropyrimidines Toxicities: A Simple and Effective Way to Avoid Them. Screen Effectively for DPD Deficiencies.

Abstract

ABSTRACT Introduction Severe, even fatal toxicities which occur during the first course of fluoropyrimidines chemotherapy treatments pose a serious public health problem. This family of chemotherapy molecules is used in over 60% of protocols, in adjuvant and metastatic settings. In adjuvant therapies, using fluoropyrimidines engenders a toxic (even fatal) risk to a patient who is possibly in remission, if not cancer-free. Even protocols using orally-administered molecules (capecitabine, UFT, others) cause the same toxicities. The results of more than 11,000 patients, assessing risk in the prevalence of severe toxicities by the search for mutations in the DPD and phenotyping are included in this study. Methods From April 2001 to December 2011, 11,351 patients were screened for the risk of severe toxic reaction to fluoropyrimidines. Chemotherapy protocols were 5-Fluorouracil based (e.g., FEC, LV5FU2, FOLFOX, FOLFIRI), as well as orally- delivered fluoropyrimidines (capecitabine and UFT.) 11,104 patients were screened before treatment, as has been the regular protocol in our institution. 247 blood samples were received from other institutions from patients who, after having received their first treatment, showed signs of severe (grade III-IV) toxicity, or had died. The evaluation of risk associates genotyping for mutations on the DPYD gene (1) and phenotyping (dihydrouracil and plasmatic uracil) (2). The calculations were made via the ODPM Tox (ODPM, Angers, France), and every patient whose screening before treatment showed risk received an individually-adapted dose via ODPM Protocol (ODPM, Angers, France). Results The frequencies of mutations observed in the total population are presented in Table I. The frequencies of mutations involved in serious toxicities with fluoropyrimidine are shown in Figure 1. In the patient population screened after toxicity occurred (247 patients): 27 patients (11%) died from toxicity. 16 patients (59%) had one or more genetic mutations and 11 presented with no mutation, but a phenotype characteristic of DPD deficit (ODPM Tox). 220 patients (89%) showed grade III – IV toxicity after first treatment (hematological, diarrhea, etc). Among these patients, 66 (30%) presented with genetic mutation and 148 (67%) showed altered phenotype (ODPM Tox). In population screened before treatment (11, 104): no patients died and none presented with grade III-IV toxicity. Among this population, 264 (2.4%) patients carried one or more risk-related mutations and 956 showed a phenotype characteristic of DPD deficiency. All of these patients received chemotherapy treatments using the ODPM Tox dose-adjustment and all subsequent rounds were dose-adjusted using ODPM Protocol. Conclusion The dual approach to DPD deficiency screening using genotype and phenotype (ODPM Tox) before treatment avoided all severe toxicities. This system has been used in our institution for the past 10 years on a routine basis. Only 8 patients (.07%), of which 2 presented with cardiac toxicity, neither carried a known mutation nor showed a phenotype for risk of toxicity. Thus, the technique has over 99.9% reliability. All of the patients who carried a known risk for toxicity were either treated by another protocol without fluoropyrimidines, or the 5-Fluorouracile treatments were dose-adjusted (ODPM Protocol). Download : Download full-size image Figure 1 . Frequencies of mutations involved in serious toxicities with fluoropyrimidne. Table I . Mutation frequency