Dataset Information

A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.

ABSTRACT:

Background

Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant allele carriers versus wild type).

Methods

A systematic review/meta-analysis of original publications indexed in Ovid Medline, Ovid Embase, and the Cochrane CENTRAL (Wiley) library from inception to 7-Dec-2020. Eligible studies evaluated at least one pre-defined treatment outcome measures (toxicity/hospitalisations/survival/overall response/quality of life).

Results

Of 1090 identified publications, 17 met predefined eligibility criteria. The meta-analysis observed reduced incidence of grade 3/4 overall toxicity (Risk Ratio [RR] 0.32 [95% Cl 0.27-0.39], p < 0.00001) and grade 3/4 diarrhoea (RR 0.38 [95% Cl 0.24-0.61], p < 0.0001) among PGD versus non-PGD cohorts. Within PGD cohorts, there was no statistical differences for overall response rates (complete/partial) (RR 1.31 [95% Cl 0.93-1.85], p = 0.12). Similar results were found with stable disease (RR 1.27 [95% Cl 0.66-2.44], p = 0.47).

Conclusion

PGD improves patient outcomes in terms of grade 3/4 toxicity, in particular overall toxicity and diarrhoea, without impacting on treatment response.

Registration number

The study is registered with PROSPERO, registration number CRD42020223768.

SUBMITTER: Glewis S

PROVIDER: S-EPMC9276780 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.

Glewis Sarah S Alexander Marliese M Khabib Muhammad N H MNH Brennan Annabelle A Lazarakis Smaro S Martin Jennifer J Tie Jeanne J Lingaratnam Senthil S Michael Michael M

British journal of cancer 20220319 1

<h4>Background</h4>Serious and potentially life-threatening toxicities can occur following 5-fluorouracil/capecitabine exposure. Patients carrying Dihydropyrimidine Dehydrogenase (DPYD) variant alleles associated with decreased enzymatic function are at a greater risk of early/severe 5-fluorouracil/capecitabine toxicity. The objective of this systematic review/meta-analysis was to evaluate treatment outcomes between Pharmacogenetics Guided Dosing (PGD) versus non-PGD and within PGD (DPYD variant ...[more]

PMID: 35306539

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Project description:Background: Fluoropyrimidine toxicity is often due to variations in the gene (DPYD) encoding dihydropyrimidine dehydrogenase (DPD). DPYD genotyping can be used to adjust doses to reduce the likelihood of fluoropyrimidine toxicity while maintaining therapeutically effective drug levels. Methods: A multiplex QPCR assay was locally developed to allow genotyping for six DPYD variants. The test was offered prospectively for all patients starting on fluoropyrimidines at the BC Cancer Centre in Vancouver and then across B.C., Canada as well as retrospectively for patients suspected to have had an adverse reaction to therapy. Dose adjustments were made for variant carriers. The incidence of toxicity in the first three cycles was compared between DPYD variant allele carriers and non-variant carriers. Subsequent to an initial implementation phase, this test was made available province-wide. Results: In 9 months, 186 patients were tested and 14 were found to be heterozygous variant carriers. Fluoropyrimidine-related toxicity was higher in DPYD variant carriers. Of 127 non-variant carriers who have completed chemotherapy, 18 (14%) experienced severe (grade ≥3, Common Terminology Criteria for Adverse Events version 5.0). Of note, 22% (3 patients) of the variant carriers experienced severe toxicity even after DPYD-guided dose reductions. For one of these carriers who experienced severe thrombocytopenia within the first week, DPYD testing likely prevented lethal toxicity. In DPYD variant carriers who tolerate reduced doses, a later 25% increase led to chemotherapy discontinuation. As a result, a recommendation was made to clinicians based on available literature and expert opinion specifying that variant carriers who tolerated two cycles without toxicity can have a dose escalation of only 10%. Conclusion: DPYD-guided dose reductions were a feasible and acceptable method of preventing severe toxicity in DPYD variant carriers. Even with dose reductions, there were variant carriers who still experienced severe fluoropyrimidine toxicity, highlighting the importance of adhering to guideline-recommended dose reductions. Following the completion of the pilot phase of this study, DPYD genotyping was made available province-wide in British Columbia.

Project description:Warfarin is the most common oral anticoagulant. Because of a narrow therapeutic range, interindividual differences in drug responses, and the risk of bleeding, there are many challenges in using warfarin. We need to predict the warfarin maintenance dose. However, ethnic-specific algorithms may be required, and some Chinese algorithms do not perform adequately. Therefore, we aimed to establish a Han Chinese appropriate algorithm.We recruited a study group consisting of 361 Han Chinese patients receiving warfarin treatment who had heart valve replacements. Genotyping of 38 single nucleotide polymorphisms (SNPs) in 13 candidate genes was carried out using the MassARRAY. In the derivation cohort, a multiple linear regression model was constructed to predict the warfarin dosage. We evaluated the accuracy of our algorithm in the validation cohort and compared it with the other 5 algorithms based on Han Chinese and other races.We established a Han Chinese-specific pharmacogenetic-guided warfarin dosing algorithm. Warfarin maintenance dosage (mg/day) = 1.787 - 0.023 × (Age) + 1.151 × (BSA [m]) + 0.917 × (VKORC1 AG) + 4.619 × (VKORC1 GG) + 0.595 × (CYP4F2 TT) + 0.707 × (CYP2C19 CC). It explained 58.3% of the variance in warfarin doses in Han Chinese patients and was superior to the other 5 algorithms. The ability of the 6 algorithms which estimate the required dose correctly was tested. Our model had a mean absolute error of 0.74 mg/day, the other 5 models have mean absolute error of 0.81 mg/day,1.05 mg/day, 1.24 mg/day, 1.18 mg/day, and 0.85 mg/day, respectively. Our model had a mean percentage error of 26.9%, the other 5 models have the mean percentage error of 27.7%, 27.2%, 52.3%, 45.7%, and 29.3%, respectively.Physicians can not adopt algorithm from other race directly to predict warfarin dose in patients with heart valve replacements, they should establish a new algorithm or adjust another algorithm to fit their patients. The algorithm established in this study has the potential to assist physicians in determining warfarin doses that are close to the appropriate doses.

Project description:Introduction: Dihydropyrimidine dehydrogenase (DPD), encoded by DPYD gene, is the rate-limiting enzyme responsible for fluoropyrimidine (FP) catabolism. DPYD gene variants seriously affect DPD activity and are well validated predictors of FP-associated toxicity. DPYD variants rs3918290, rs55886062, rs67376798, and rs75017182 are currently included in FP genetic-based dosing guidelines and are recommended for genotyping by the European Medicines Agency (EMA) before treatment initiation. In Greece, however, no data exist on DPYD genotyping. The aim of the present study was to analyze prevalence of DPYD rs3918290, rs55886062, rs67376798, rs75017182, and, additionally, rs1801160 variants, and assess their association with FP-induced toxicity in Greek cancer patients. Methods: Study group consisted of 313 FP-treated cancer patients. DPYD genotyping was conducted on QuantStudio ™ 12K Flex Real-Time PCR System (ThermoFisher Scientific) using the TaqMan® assays C__30633851_20 (rs3918290), C__11985548_10 (rs55886062), C__27530948_10 (rs67376798), C_104846637_10 (rs75017182) and C__11372171_10 (rs1801160). Results: Any grade toxicity (1-4) was recorded in 208 patients (66.5%). Out of them, 25 patients (12%) experienced grade 3-4 toxicity. DPYD EMA recommended variants were detected in 9 patients (2.9%), all experiencing toxicity (p = 0.031, 100% specificity). This frequency was found increased in grade 3-4 toxicity cases (12%, p = 0.004, 97.9% specificity). DPYD deficiency increased the odds of grade 3-4 toxicity (OR: 6.493, p = 0.014) and of grade 1-4 gastrointestinal (OR: 13.990, p = 0.014), neurological (OR: 4.134, p = 0.040) and nutrition/metabolism (OR: 4.821, p = 0.035) toxicities. FP dose intensity was significantly reduced in DPYD deficient patients (β = -0.060, p <0.001). DPYD rs1801160 variant was not associated with FP-induced toxicity or dose intensity. Triple interaction of DPYD*TYMS*MTHFR was associated with grade 3-4 toxicity (OR: 3.725, p = 0.007). Conclusion: Our findings confirm the clinical validity of DPYD reduced function alleles as risk factors for development of FP-associated toxicity in the Greek population. Pre-treatment DPYD genotyping should be implemented in clinical practice and guide FP dosing. DPYD*gene interactions merit further investigation as to their potential to increase the prognostic value of DPYD genotyping and improve safety of FP-based chemotherapy.

Dataset Information

A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.

Background

Methods

Results

Conclusion

Registration number

Publications

A systematic review and meta-analysis of toxicity and treatment outcomes with pharmacogenetic-guided dosing compared to standard of care BSA-based fluoropyrimidine dosing.

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