Dataset Information

Near Miss or Standard of Care? DPYD Screening for Cancer Patients Receiving Fluorouracil.

ABSTRACT: 5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes.

SUBMITTER: Winquist LE

PROVIDER: S-EPMC7816174 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Near Miss or Standard of Care? DPYD Screening for Cancer Patients Receiving Fluorouracil.

Winquist Lauren E LE Sanatani Michael M Kim Richard B RB Winquist Eric E

Current oncology (Toronto, Ont.) 20201218 1

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU t ...[more]

PMID: 33704179

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Project description:BackgroundThe maternal near-miss concept has been developed as an instrument for assisting health systems to evaluate and improve their quality of care. Our study aimed at studying the characteristics and quality of care provided to women with severe complications in Baghdad through the use of the World Health Organization (WHO) near-miss approach for maternal health.MethodsThis is a facility-based, cross-sectional study conducted in 6 public hospitals in Baghdad between March 1, 2010 and the June 30, 2010. WHO near-miss approach was utilized to analyze the data in terms of indicators of maternal near miss and access to and quality of maternal care.ResultsThe maternal near-miss rate was low at 5.06 per 1,000 live births, while the overall maternal near miss: mortality ratio was 9:1. One third of the near-miss cases were referred from other facilities and the mortality index was the same for referred women and for in-hospital women (11%). The intensive care unit (ICU) admission rate was 37% for women with severe maternal outcomes (SMO), while the overall admission rate was 0.28%. Anemia (55%) and previous cesarean section (45%) were the most common associated conditions with severe maternal morbidity. The use of magnesium sulfate for treatment of eclampsia, oxytocin for prevention and treatment of postpartum hemorrhage, prophylactic antibiotics during caesarean section, and corticosteroids for inducing fetal lung maturation in preterm birth is suboptimum.ConclusionsThe WHO near-miss approach allowed systematic identification of the roadblocks to improve quality of care and then monitoring the progress. Critical evidence-based practices, relevant to the management of women experiencing life-threatening conditions, are underused. In addition, possible limitations in the referral system result in a very high proportion of women presenting at the hospital already in a severe health condition (i.e. with organ dysfunction). A shortage of ICU beds leading to women taken care of without admission to ICU may also contribute to a high proportion of maternal deaths and organ dysfunction.

Project description:Previous studies have suggested the potential importance of three DPYD variants (DPYD*2A, D949V, and I560S) with increased 5-FU toxicity. Their individual associations, however, in 5-FU-based combination therapies, remain controversial and require further systematic study in a large patient population receiving comparable treatment regimens with uniform clinical data. We genotyped 2886 stage III colon cancer patients treated adjuvantly in a randomized phase III trial with FOLFOX or FOLFIRI, alone or combined with cetuximab, and tested the individual associations between functionally deleterious DPYD variants and toxicity. Logistic regressions were used to assess univariate and multivariable associations. All statistical tests were two-sided. In 2594 patients with complete adverse event (AE) data, the incidence of grade 3 or greater 5FU-AEs in DPYD*2A, I560S, and D949V carriers were 22/25 (88.0%), 2/4 (50.0%), and 22/27 (81.5%), respectively. Statistically significant associations were identified between grade 3 or greater 5FU-AEs and both DPYD*2A (odds ratio [OR] = 15.21, 95% confidence interval [CI] = 4.54 to 50.96, P < .001) and D949V (OR = 9.10, 95% CI = 3.43 to 24.10, P < .001) variants. Statistical significance remained after adjusting for multiple variables. The DPYD*2A variant statistically significantly associated with the specific AEs nausea/vomiting (P = .007) and neutropenia (P < .001), whereas D949V statistically significantly associated with dehydration (P = .02), diarrhea (P = .003), leukopenia (P = .002), neutropenia (P < .001), and thrombocytopenia (P < .001). Although two patients with I560S had grade≥3 5FU-AEs; a statistically significant association could not be demonstrated because of its low frequency (P = .48). In the largest study to date, statistically significant associations were found between DPYD variants (DPYD*2A and D949V) and increased incidence of grade 3 or greater 5FU-AEs in patients treated with adjuvant 5-FU-based combination chemotherapy.

Dataset Information

Near Miss or Standard of Care? DPYD Screening for Cancer Patients Receiving Fluorouracil.

Publications

Near Miss or Standard of Care? <i>DPYD</i> Screening for Cancer Patients Receiving Fluorouracil.

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