Dataset Information

DPD status and fluoropyrimidines-based treatment: high activity matters too.

ABSTRACT:

Background

Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution.

Methods

Lymphocytic DPD activity was assessed in a group of 136 patients receiving FP-based chemotherapy from 2004 to 2016. There were 105 digestive (77.2%), 24 breast (17.6%) and 7 head and neck cancers (5.2%). Cox or logistic regression models were applied with adjustment on all confounding factors that could modify OS, PFS or response. All models were stratified on the three cancer locations. A cut-off for DPD activity was assessed graphically and analytically.

Results

An optimal cut-off for DPD activity at 0.30?nmol/min/mg protein was identified as the best value for discriminating survivals and response. In multivariate analysis, individual lymphocytic DPD activity was significantly related to overall survival (p?=?0.013; HR: 3.35 CI95%[1.27-8.86]), progression-free survival (p?ConclusionsDPD status screening should result in a two-pronged approach with FP dose reduction in case of low intrinsic DPD and, inversely, an increased FP dose for high intrinsic DPD. In a context of personalized FP-based treatment, this innovative strategy needs to be prospectively validated.

SUBMITTER: Chamorey E

PROVIDER: S-EPMC7236295 | biostudies-literature | 2020 May

REPOSITORIES: biostudies-literature

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Publications

DPD status and fluoropyrimidines-based treatment: high activity matters too.

Chamorey Emmanuel E Francois Eric E Etienne Marie-Christine MC Ferrero Jean-Marc JM Peyrade Frederic F Barranger Emmanuel E Bozec Alexandre A Largillier Rémy R Cassuto Ophelie O Viotti Julien J Schiappa Renaud R Milano Gérard G

BMC cancer 20200518 1

<h4>Background</h4>Dihydropyrimidine dehydrogenase (DPD) status is an indicator of a marked risk for toxicity following fluoropyrimidine (FP)-based chemotherapy. This notion is well-established for low DPD status but little is known about the clinical impact of high DPD activity. This study examined the possible link between high intrinsic lymphocytic DPD activity and overall survival, progression free survival and response to FP-based treatment in patients treated in our institution.<h4>Methods ...[more]

PMID: 32423482

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Project description:IntroductionThe fluoropyrimidines (FP) (5-Fluorouracil, capecitabine, and tegafur) are commonly used anti-cancer drugs, but lead to moderate to severe toxicity in about 10-40% of patients. DPD testing [either the enzyme activity of dihydropyrimidine dehydrogenase (DPD) or the DPYD genotype] identifies patients at higher risk for toxicity who may be treated more safely with a lower drug dose. The Netherland's National guideline for colon carcinoma was updated in 2017 to recommend DPYD genotyping before treatment with FP. Pretreatment DPYD genotyping identifies approximately 50% of the patients that will develop severe FP toxicity. The aim of the study was to assess the uptake of DPD testing in the Amsterdam University Medical Centers over time and to evaluate stakeholder experiences to indicate barriers and facilitators of implementation in routine clinical care.Materials and methodsWe used a mixed-method approach involving electronic patient records of 753 unique patients and pharmacy information systems analyses and fifteen semi-structured interviews with oncologists, pharmacists, and patients. The constellation perspective was used to identify barriers and facilitators at the level of practice, culture and structure. The proportion of FP users who were DPD tested pretreatment showed an increase from 1% (1/86) in Q2-2017 up to 87% (73/84) in Q4-2018. Unlike a landmark paper published in 2015, the National guideline for colorectal carcinoma followed by meetings to achieve local consensus led to this steep increase in the proportion of patients tested.ResultsFacilitating factors for stakeholders to implement testing included the existence of clear protocols, (anecdotal) evidence of the utility, being aware that peers are adhering to standard practice and clear and simple procedures for ordering and reporting. Main barriers included the lack of clear divisions of responsibilities, the lack of consensus on a test approach, long turn-around times and non-user-friendly IT-infrastructures. More professional education on the utility and limitations of pharmacogenetic testing was desired by most stakeholders.ConclusionWhile the evidence for DPD testing was sufficient, only after the update of a National guideline and local consensus meetings the proportion of FP users that were DPD tested pretreatment rose to 87%. The implementation of personalized medicine requires stakeholders involved to attune practice, culture and structure.

Project description:BackgroundCurrent prognostic scores for status epilepticus (SE) may not be adequate for patients in ICU who usually have more severe systemic conditions or more refractory episodes of SE. We aimed to compare the prognostic performance of two SE scores, Status Epilepticus Severity Score (STESS) and Epidemiology-Based Mortality Score in Status Epilepticus (EMSE) score, with four systemic severity scores, Acute Physiology and Chronic Health Evaluation 2 (APACHE-2), Simplified Acute Physiology Score 2 (SAPS-2), Sequential Organ Failure Assessment (SOFA) score, and Inflammation, Nutrition, Consciousness, Neurologic function and Systemic condition (INCNS) score in critically ill patients with SE.MethodsThis retrospective observational study of a prospectively identified SE cohort was conducted in the ICU at a tertiary-care center. The area under the receiver operating characteristic curve (AUC), sensitivity, specificity, positive predictive value, negative predictive value, accuracy, and associations with outcomes of STESS, EMSE, INCNS, APACHE-2, SAPS-2, and SOFA score for the prediction of in-hospital mortality and no return to baseline condition were assessed.ResultsBetween January 2015 and December 2020, 166 patients with SE in ICU were included in the study. In predicting in-hospital death, APACHE-2 (0.72), SAPS-2 (0.73), and SOFA score (0.71) had higher AUCs than STESS (0.58) and EMSE (0.69). In predicting no return to baseline condition, the AUC of APACHE-2 (0.75) was the highest, and the AUC of INCNS (0.55) was the lowest. When the specificity approached 90%, the sensitivity values of these scores were not quite acceptable (< 40%). Neither SE scores nor systemic severity scores had desirable prognostic power. In the multivariate logistic regression analyses, the best combinations of scores always included at least one or more systemic severity scores.ConclusionsSTESS and EMSE were insufficient in outcome prediction for SE patients in ICU, and EMSE was marginally better than STESS. Systemic illness matters in ICU patients with SE, and SE scores should be modified to achieve better accuracy in this severely ill population. This study mostly refers to severely ill patients in the ICU.

Dataset Information

DPD status and fluoropyrimidines-based treatment: high activity matters too.

Background

Methods

Results

Publications

DPD status and fluoropyrimidines-based treatment: high activity matters too.

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