Feasibility of implementing a pharmacist-led DPYD gene testing service for patients commencing 5-fluorouracil (5FU) or capecitabine.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e18644-e18644
Author(s):  
Benjamin Lee ◽  
Sarah Glewis ◽  
Marliese Alexander ◽  
Danny Rischin ◽  
Prudence A. Francis ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Program Implementation ◽  
Dihydropyrimidine Dehydrogenase ◽  
European Medicines Agency ◽  
Buccal Swab ◽  
Dpyd Gene ◽  
Testing Service ◽  
Gene Testing ◽  
Timely Access ◽  
Grade 3

e18644 Background: Polymorphisms in the DPYD gene, which encodes for dihydropyrimidine dehydrogenase (DPD), may impair DPD metabolism of fluoropyrimidines (FP) and cause life-threatening toxicities. The European Medicines Agency (EMA) recommend testing for DPD activity before FP therapy, but the Australian Therapeutic Goods Administration and the US Food and Drug Administration do not currently recommend this. At our hospital, pre-emptive DPYD gene screening was established in response to 7 cases of severe FP-toxicity and significant challenges for timely access to the life-saving antidote, uridine triacetate (UT), in the preceding 3 years. This study assessed the feasibility of a pharmacist-led DPYD gene testing service in an Australian cancer centre. Methods: Patients planned for FP therapy, without previous FP exposure, were referred to the Clinical Pharmacogenetics (CPGx) pharmacist for consenting, before a blood or buccal swab sample was taken. An external genomics company screened for the five Clinical Pharmacogenetics Implementation Consortium (CPIC) recommended gene variants (c.1905+1G > A, c.1679T > G, c.2846A > T, c.1236G > A and c.557A > G). Dose recommendations based on CPIC guidelines and phenotype were made to the treating clinician. Patients were followed-up for toxicity (graded according to CTCAE v5.0) at 3-5 days post first FP exposure and pre-cycle 2. Results: Between 16 December 2019 and 11 December 2020, 311 patients were planned for FP therapy. Genetic testing did not occur for 13 patients, in the first two months of program implementation mostly due to unfamiliarity with procedures. Of the 298 genotyped patients (median age 59.5 years, 52.7% female, 67.8% Upper and Lower Gastrointestinal, 18.1% Breast), 274 (91.9%) were seen by the CPGx pharmacist within 1 day of referral. Median time from samples being taken to result availability was 6 days. 286 patient (96.0%) results were reported and acted upon prior to the planned cycle 1 FP commencement date. Overall, 1 patient (0.3%, 95%CI 0.1-1.9) was identified as a poor metaboliser and avoided FP therapy. Ten patients (3.4%, 95%CI 1.8-6.0) were identified as intermediate metabolisers, of which 2 patients did not receive chemotherapy due to changes in goals of care, 1 patient received only one cycle at 100% of the full dose but passed away due to disease progression, 1 patient required UT administration after cycle 2 despite 50% dose reductions for both cycles and 6 patients received an initial 50% dose reduction, where for subsequent cycles, 3 continued at this dose level, 2 had dose increases and 1 had a further dose reduction. 17 patients experienced at least one grade 3/4 toxicity pre-cycle 2; all had normal metaboliser phenotypes. Conclusions: A pharmacist-led DPYD gene testing service is feasible, with acceptable test result turnaround times and phenotype identification rates similar to that reported by the EMA.

Prevalence of DPYD gene mutations among patients receiving 5-FU therapy.

2013 ◽  
Vol 31 (4_suppl) ◽  
pp. 447-447
Author(s):  
Jennifer Saam ◽  
Karla Bowles ◽  
Laurie Korst ◽  
Kendel Kline ◽  
Benjamin Roa ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Gene Mutations ◽  
European Ancestry ◽  
Severe Toxicity ◽  
Sequencing Data ◽  
Dpyd Gene ◽  
Commercial Laboratory ◽  
Gene Testing ◽  
Exposure Levels ◽  
Grade 3

447 Background: Dihydropyrimidine dehydrogenase (DPYD) is the major enzyme that metabolizes 5-Fluoruracil (5-FU), a component of many chemotherapy regimens. Patients with a DPYD gene mutation have higher 5-FU plasma levels, leading to a 50-60% risk of a grade 3-4 toxicity. DPYD mutations have an estimated prevalence of 3-5% in the general population, but full sequencing is rarely performed in published studies. Analyses of the largest set of full DPYD gene sequencing test results from a commercial laboratory database are presented. Methods: A set of 3,083 patients was analyzed. Patient demographics (age, gender, ethnicity) and pre-test grade 3-4 toxicity status (none, 5-FU related, other) were obtained from the test request form. Descriptive analyses were performed to estimate mutation prevalence overall, and by toxicity and ancestry classifications, as well as to characterize mutations of interest. A subset of 24 patients tested for DPYD mutations in response to high 5-FU exposure levels was also analyzed. Results: The overall DPYD mutation prevalence was 7.3%. Mutations were present in 4.7% and 10.3% of patients experiencing none and at least one 5-FU related toxicity pre-test, respectively. Among patients with toxicities pre-test, the prevalence increased from 7.8% to 31.6% for those experiencing a single to all four toxicity types. Among 5-FU related toxicities, mutation prevalence was highest (18.5%) for hematopoietic events. The previously reported founder mutation IVS14+1G>A had a relative prevalence 42.7%, but 30.9% of these mutations were seen in patients not reporting a Western/Northern European ancestry. Among the subset of patients with high 5-FU exposure levels, 29% had a DPYD mutation showing a genetic causality. Conclusions: 5-FU in chemotherapy regimens remains widespread, yet DPYD gene testing utilization remains minimal. Most testing occurs post-treatment in response to a severe toxicity rather than pre-treatment, which would permit physicians to adapt treatment and reduce toxicity risk. Compared to previous studies, this study using full sequencing data from 3083 patients provides robust estimates of DPYD mutation prevalence and helps characterize DPYD mutations of particular interest.

Germline pharmacogenomics in patients with dihydropyrimidine dehydrogenase (DPD) deficiency.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 521-521
Author(s):  
Moh'd M. Khushman ◽  
Peter Joel Hosein ◽  
Daniel Cameron ◽  
David Roland Clarkson ◽  
Thomas Wayne Butler ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Nucleotide Polymorphisms ◽  
Test Results ◽  
Single Nucleotide ◽  
Gastrointestinal Malignancies ◽  
Exact Test ◽  
Dpyd Gene ◽  
Gene Testing ◽  
Grade 3 ◽  
Dose Limiting Toxicity

521 Background: DPD deficiency is a pharmacogenetic syndrome associated with dose-limiting toxicity to fluoropyrimidines. Oncologists are expected to recognize and diagnose this syndrome, as toxicities could be fatal. Over 40 single nucleotide polymorphisms (SNPs) and deletions have been identified within the DPYD gene. IVS14+1G>A (DPYD*2A) is the most common (40-50%) and best studied of these SNPs. Yet, it showed a median sensitivity of 30% and is absent in Japanese, Korean and African Americans. Overall, the data on DPYD testing is insufficient to provide enough guidance to diagnose DPD deficiency. Herein we describe our experience with germline pharmacogenomics in patients with DPD deficiency. Methods: Between 2011 and 2015, 35 patients with gastrointestinal malignancies were tested for DPYD mutations; 17 were tested after developing toxicities to treatment and 18 were tested prior to treatment. IVS14+1G>A (DPYD*2A) was tested in all patients. DPYD c.85T>C (DPYD*9A), DPYD c.1679T>G (DPYD*13A), DPYD c.-1590T>C, and DPYD c.2846A>T were tested in 24 patients (69%) only. We explored the association between DPYD mutations and fluoropyrimidine-related toxicity using Fisher’s exact test. Results: Median age was 60 years, 43% were male, 80% were Caucasian and 20% were African American. Capecitabine-based regimens (71%) and 5-Fluorouracil-based regimens (29%). 14 out of 35 patients (40%) had DPYD mutations. Grade 3 toxicities were encountered in 64% of patients with DPYD mutation and 48% of patients with no DPYD mutation. In patients who received full dose fluoropyrimidines (57% of patients with DPYD mutation and 81% of patients with no DPYD mutation), DPYD mutations were associated with a significantly higher rate of grade 3 diarrhea (p=0.026). In patients with DPYD mutation, 2 (14%) had DPYD*A2 mutation and 12 (86%) had DPYD*9A mutation. Conclusions: In patients treated with fluoropyrimidines, the rate of grade 3 diarrhea was significantly higher in patients with mutated DPYD gene. Testing for DPYD*2A alone to diagnose DPD deficiency is suboptimal. Testing for other DPYD mutation variants including DPYD*9A provides a more comprehensive approach. These data should further be validated in prospective clinical trials.

Dihydro pyrimidine dehydrogenase deficiency in patients treated with capecitabine-based regimens: A retrospective tertiary care centre experience.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 712-712
Author(s):  
Arvind Sahu ◽  
Vikas S. Ostwal ◽  
Anant Ramaswamy
Keyword(s):  
Dose Reduction ◽  
Dose Range ◽  
Dihydropyrimidine Dehydrogenase ◽  
Tertiary Care ◽  
Tertiary Care Centre ◽  
Exon 2 ◽  
Hand Foot Syndrome ◽  
Life Threatening ◽  
Grade 3 ◽  
Oncology Unit

712 Background: Capecitabine is an integral part of treatment of gastrointestinal cancers. Dihydropyrimidine dehydrogenase (DPD) enzyme is rate limiting in the metabolism of capecitabine, deficiency of which leads to myelsuppression, mucositis, diarrhea, hand foot syndrome (HFS) and rarely, death. Data regarding the toxicity of capecitabine in patients with DPD deficiency in the Indian context is scarce. Methods: 506 patients were treated with capecitabine containing regimens with a dose range of 1250 mg/m2/day to 2000 mg/m2/day during the period from June 2013 to May 2015 in the Gastrointestinal Medical Oncology Unit of our institution. Patients with Grade 3/4 toxicities requiring in-patient care (life threatening complications) were planned for DPD activity testing by Peripheral Blood PCR sequencing. Results: 27 patients developed Gr 3/4 toxicities during cycle 1 of capecitabine. It included mucositis in 22 (81.5 %), diarrhea in 25 (92.6%), HFS in 10 (37%) and myelosuppression in 4 (14.8%). 19 were found to be DPD deficient with 5 patients negative for DPD mutation. 3 patients did not do the DPD analysis as advised. Homozygous mutations were seen in 9 (33.3%) and heterozygous mutations in 10 (27%) of patients. More than one mutation was seen in 10 patients (37%). The relative frequencies of mutation were Exon 14 (44.4%), Exon 2 (25.9%), Exon 13 (25.9%), Exon 6 (11.1%) and Exon 18 (7.4 %). Post Cycle 1 of capecitabine, the drug was stopped in 5 patients (18.5%), regimen changed in 2 (7.4%) and dose reduction by 50% of the drug was done in the remaining patients. Despite dose reduction and change in therapy during Cycle 2, patients still had Grade 3/4 toxicities including mucositis in 7(25.9%), diarrhoea in 10 (37%), HFS in 7 (25.9 %) and myelosuppression in 6 (22%) of patients. Conclusions: Capecitabine can also lead to severe toxicities in DPD-deficient patients. Dose reduction of capecitabine in DPD deficient patients may not completely ameliorate the future risk of life – threatening complications. Screening for DPD deficiency prior to administration of capecitabine in toxicity prone nutritionally deficient Indian patients should be further evaluated based on this data.

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

2020 ◽  
Vol 28 (1) ◽  
pp. 94-97
Author(s):  
Lauren E. Winquist ◽  
Michael Sanatani ◽  
Richard B. Kim ◽  
Eric Winquist
Keyword(s):  
Cancer Patients ◽  
Patient Outcomes ◽  
Anticancer Agents ◽  
Potential Benefit ◽  
Dihydropyrimidine Dehydrogenase ◽  
Standard Of Care ◽  
Near Miss ◽  
European Medicines Agency ◽  
Current Standard ◽  
Dpyd Gene

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.

Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2056-2056
Author(s):  
R. Mehra ◽  
L. K. Mattison ◽  
L. Ledbetter ◽  
H. Ezzeldin ◽  
R. B. Diasio ◽  
...  
Keyword(s):  
Dihydropyrimidine Dehydrogenase ◽  
Memory Loss ◽  
Altered Mental Status ◽  
Heterozygous Mutation ◽  
High Dose ◽  
Dpyd Gene ◽  
Genotypic Analysis ◽  
Grade 3 ◽  
Rate Limiting

2056 Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique. [Table: see text]

Lonsurf (trifluridine/tipiracil): Assessing the impact of dose related toxicities and progression free survival in (refractory) metastatic colorectal cancer

2021 ◽  
pp. 107815522110179
Author(s):  
Olivia R Court
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Progression Free Survival ◽  
Electronic Patient Records ◽  
Free Survival ◽  
Length Of Treatment ◽  
Common Grade ◽  
Grade 3 ◽  
The Impact

In the RECOURSE trial which lead to its accreditation, Lonsurf (trifluridine/tipiracil) was shown to extend progression free survival (PFS) by 1.8 months in metastatic colorectal cancer. This Trust audit aims to assess the average quantity of cycles of Lonsurf received by participants and the length of time it extends PFS. Similarly, to identify how many participants required a dose-reduction or experienced toxicities which necessitated supportive therapies. Quantitative data was collected retrospectively from all participants who had received ≥1 cycle of Lonsurf from The Clatterbridge Cancer Centre (CCC) from 2016 until June 2020. Participant electronic patient records were accessed to identify toxicity grading, length of treatment received, the date progression was identified, if dose reductions were applied and if supportive therapies were administered. Lonsurf extends PFS in patients with metastatic colorectal cancer at CCC by 3.0 months (95% CI: 2.73–3.27) and average treatment length was 2.4 months. However, 78 participants (41.5%) received a dose reduction due to toxicities. A total of 955 toxicities were recorded by participants; the most commonly reported toxicities irrespective of grade were fatigue (33.8%), diarrhoea (13.8%) and nausea (12.3%). The most common grade ≥3 toxicities were constipation and infection. The most frequently utilised supportive therapies were loperamide (49.6%) and domperidone (49.1%). Granulocyte colony stimulating factor (GCSF) was required by patients on 5 occasions (0.3%) in total. Lonsurf extends median PFS in patients with metastatic colorectal cancer by 3.0 months. The most common grade ≥3 toxicities which necessitated supportive therapies or a dose reduction were gastrointestinal and infection.

Cost effectiveness of DPYD genotyping to screen for dihydropyrimidine dehydrogenase (DPD) deficiency prior to adjuvant chemotherapy for colon cancer.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. 55-55
Author(s):  
Gabriel A. Brooks ◽  
Stephanie Tapp ◽  
Allan T. Daly ◽  
Jonathan Busam ◽  
Anna N.A. Tosteson
Keyword(s):  
Colon Cancer ◽  
Cost Effectiveness ◽  
Adjuvant Chemotherapy ◽  
Transition Probabilities ◽  
Dihydropyrimidine Dehydrogenase ◽  
Sensitivity Analyses ◽  
Dpyd Gene ◽  
Cancer Screen ◽  
The Cost ◽  
The U.S

55 Background: Fluoropyrimidine chemotherapy agents, including 5-fluorouracil and capecitabine, are the backbone of adjuvant treatment for colon cancer, and adjuvant chemotherapy substantially reduces recurrence and mortality after surgical resection of stage 3 colon cancer. While fluoropyrimidine chemotherapy is generally safe, the risk of severe, potentially fatal chemotherapy toxicity is substantially increased for the 2-3% of U.S. patients with DPD deficiency caused by pathogenic variants in the DPYD gene. DPYD genotype testing is readily available in the U.S. but has not been widely adopted. We evaluated the cost effectiveness of DPYD genotyping prior to adjuvant chemotherapy for colon cancer in the U.S. Methods: We constructed a Markov model to simulate screening for DPD deficiency with DPYD genotyping (versus no screening) among patients receiving fluoropyrimidine-based adjuvant chemotherapy for stage 3 colon cancer. Screen-positive patients were modeled to receive dose-reduced fluoropyrimidine chemotherapy. Model transition probabilities for treatment-related toxicities were derived from published clinical trial data with annotation of DPYD genotype and chemotherapy dosing strategy. Our analysis is from the healthcare perspective, with a time horizon of five years and an annual discount rate of 3% for future costs and benefits. Direct healthcare costs and health utilities were estimated from published sources and converted to 2020 US dollars, and post-treatment survival was modeled from SEER data. The primary outcome was the incremental cost-effectiveness ratio (ICER), defined as dollars per quality-adjusted life year (QALY). We used a value of $100,000/QALY as the cost-effectiveness threshold. One-way sensitivity analyses were used to examine model uncertainty. Results: Compared with no screening, screening for DPD deficiency with DPYD genotyping increased per-patient costs by $106 and improved quality-adjusted survival by 0.0028 QALYs, leading to an ICER of $37,300/QALY. In one-way sensitivity analyses, the ICER exceeded $100,000/QALY when the carrier frequency of pathogenic DPYD gene variants was less than 1.17%, and when the specificity of DPYD genotyping was less than 98.9%. Cost-effectiveness estimates were not sensitive to the cost of DPYD genotyping, the cost of toxicity-related hospitalizations, or the health utility associated with grade 3-4 toxicity. Conclusions: Among patients receiving adjuvant chemotherapy for stage 3 colon cancer, screening for DPD deficiency with DPYD genotyping is a cost-effective strategy for preventing infrequent but severe, sometimes fatal toxicities of fluoropyrimidine chemotherapy.

scholarly journals Patient Benefit and Risk in Anticancer Drug Development: A Systematic Review of the Ixabepilone Trial Portfolio

2019 ◽  
Author(s):  
Benjamin Carlisle ◽  
James Mattina ◽  
Tiger Zheng ◽  
Jonathan Kimmelman
Keyword(s):  
Combination Therapy ◽  
Ex Vivo ◽  
Human Subjects ◽  
Large Fraction ◽  
Phase 1 ◽  
Objective Response ◽  
Tumour Response ◽  
European Medicines Agency ◽  
Clinical Value ◽  
Grade 3

AbstractOBJECTIVETo describe the patient burden and benefit, and the dynamics of trial success in the development of ixabepilone—a drug that was approved in the US but not in Europe.DATA SOURCESTrials were captured by searching Embase and MEDLINE on July 27, 2015.STUDY SELECTIONInclusion: 1) primary trial reports, 2) interventional trials, 3) human subjects, 4) phase 1 to phase 3, 5) trials of ixabepilone in monotherapy or combination therapy of 6) pre-licensure cancer indications. Exclusion: 1) secondary reports, 2) interim results, 3) meta-analyses, 4) retrospective/observational studies, 5) laboratory analyses (ex vivo tissues), 6) reviews, 7) letters, editorials, guidelines, interviews, abstract-only and poster presentations.DATA EXTRACTION AND SYNTHESISData were independently double-extracted and differences between coders were reconciled by discussion.MAIN OUTCOMES AND MEASURESWe measured risk using the number of drug-related adverse events that were grade 3 or higher, benefit by objective response rate and trial outcomes by whether studies met their primary endpoint with acceptable safety.RESULTSWe identified 39 publications of ixabepilone monotherapy and 23 primary publications of combination therapy, representing 5615 patients and 1598 patient-years of involvement over 11 years and involving 17 different malignancies. In total, 830 patients receiving ixabepilone experienced objective tumour response (16%, 95% CI 12.5%–20.1%), and 74 died from drug-related toxicites (2.2%, 95% CI 1.6%–2.9%). Responding indications and combinations were identified very quickly; thereafter, the search for additional responding indications or combinations did not lead to labelling additions. A total of 11 “uninformative” trials were found, representing 27% of studies testing efficacy, 208 grade 3–4 events and 226 patient-years of involvement (21% and 26% of the portfolio total, respectively). After the European Medicines Agency rejected ixabepilone for licensing, all further trial activity involving ixabepilone was pursued outside of Europe.DISCUSSIONRisk/benefit for patients who enrolled in trials of non-approved indications of ixabepilone did not improve over the course of the drug’s development. Clinical value was discovered very quickly; however, a large fraction of trials were uninformative.

Fluoropyrimidine-induced toxicity and DPD deficiency.. A case report of early onset, lethal capecitabine-induced toxicity and mini review of the literature. Uridine triacetate: Efficacy and safety as an antidote. Is it accessible outside USA?

2019 ◽  
Vol 26 (3) ◽  
pp. 747-753 ◽  
Author(s):  
Dimitra Ioanna Lampropoulou ◽  
Konstantinos Laschos ◽  
Anna-Lea Amylidi ◽  
Ariadni Angelaki ◽  
Nikolaos Soupos ◽  
...  
Keyword(s):  
Early Onset ◽  
Dehydrogenase Deficiency ◽  
Colorectal Cancer Patient ◽  
Dihydropyrimidine Dehydrogenase ◽  
Efficacy And Safety ◽  
Review Of The Literature ◽  
Time Restrictions ◽  
Timely Access ◽  
Life Threatening ◽  
Chemotherapy Dose

Fluoropyrimidine-based regimens are among the most commonly used chemotherapy combinations for the treatment of solid tumors. Several genetic polymorphisms that are implicated with fluoropyrimidine anabolism and catabolism have been associated with the development of life-threatening toxicities. Uridine triacetate is an FDA-approved antidote for 5-fluorouracil or capecitabine overdose and early-onset, life-threatening toxicity within 96 h of last chemotherapy dose. To date, it is not accessible for Greek patients as per the current summary of product characteristic's time restrictions. We report and discuss the course and outcome of capecitabine toxicity in a 66-year-old female colorectal cancer patient with heterozygous dihydropyrimidine dehydrogenase deficiency. This paper highlights the difficulty in timely access of this lifesaving medication for Greek and possibly other European patients.

scholarly journals Cost Implications of Reactive Versus Prospective Testing for Dihydropyrimidine Dehydrogenase Deficiency in Patients With Colorectal Cancer: A Single-Institution Experience

Dose-Response ◽  
2018 ◽  
Vol 16 (4) ◽  
pp. 155932581880304 ◽  
Author(s):  
Con Murphy ◽  
Stephen Byrne ◽  
Gul Ahmed ◽  
Andrew Kenny ◽  
James Gallagher ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Dihydropyrimidine Dehydrogenase ◽  
Cost Savings ◽  
Cost Effective ◽  
Public Hospitals ◽  
Severe Toxicity ◽  
Care Payer ◽  
Input Variables ◽  
Grade 3 ◽  
The Cost

Background: Severe toxicity is experienced by a substantial minority of patients receiving fluoropyrimidine-based chemotherapy, with approximately 20% of these severe toxicities attributable to polymorphisms in the DPYD gene. The DPYD codes for the enzyme dihydropyrimidine dehydrogenase (DPD) important in the metabolism of fluoropyrimidine-based chemotherapy. We questioned whether prospective DPYD mutation analysis in all patients commencing such therapy would prove more cost-effective than reactive testing of patients experiencing severe toxicity. Methods: All patients experiencing severe toxicity from fluoropyrimidine-based chemotherapy for colorectal cancer in an Irish private hospital over a 3-year period were tested for 4 DPYD polymorphisms previously associated with toxicity. The costs associated with an index admission for toxicity in DPD-deficient patients were examined. A cost analysis was undertaken comparing the anticipated cost of implementing screening for DPYD mutations versus current usual care. One-way sensitivity analysis was conducted on known input variables. An alternative scenario analysis from the perspective of the Irish health-care payer (responsible for public hospitals) was also performed. Results: Of 134 patients commencing first-line fluoropyrimidine chemotherapy over 3 years, 30 (23%) patients developed grade 3/4 toxicity. Of these, 17% revealed heterozygote DPYD mutations. The cost of hospitalization for the DPYD-mutated patients was €232 061, while prospectively testing all 134 patients would have cost €23 718. Prospective testing would result in cost savings across all scenarios. Conclusions: The cost of hospital admission for severe chemotherapy-related toxicity is significantly higher than the cost of prospective DPYD testing of each patient commencing fluoropyrimidine chemotherapy.

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