Dataset Information

Evaluation of patient-reported severity of hand-foot syndrome under capecitabine using a Markov modeling approach.

ABSTRACT:

Purpose

The inclusion of the patient's perspective has become increasingly important when reporting adverse events and may assist in management of toxicity. The relationship between drug exposure and toxicity can be quantified by combining Markov elements with pharmacometric models. A minimal continuous-time Markov model (mCTMM) was applied to patient-reported outcomes using hand-foot syndrome (HFS) induced by capecitabine anti-cancer therapy as an example.

Methods

Patient-reported HFS grades over time of 150 patients from two observational studies treated with oral capecitabine were analyzed using a mCTMM approach. Grading of HFS severity was based on the Common Terminology Criteria for Adverse Events. The model was evaluated by visual predictive checks (VPC). Furthermore, a simulation study of the probability of HFS severity over time was performed in which the standard dosing regimen and dose adjustments according to HFS severity were investigated.

Results

The VPC of the developed dose-toxicity model indicated an accurate description of HFS severity over time. Individual absolute daily dose was found to be a predictor for HFS. The simulation study demonstrated a reduction of severe HFS using the recommended dose adjustment strategy.

Conclusion

A minimal continuous-time Markov model was developed based on patient-reported severity of hand-foot syndrome under capecitabine. Thus, a modeling framework for patient-reported outcomes was created which may assist in the optimization of dosage regimens and adjustment strategies aiming at minimizing symptom burden during anti-cancer drug therapy.

SUBMITTER: Schmulenson E

PROVIDER: S-EPMC7478943 | biostudies-literature | 2020 Sep

REPOSITORIES: biostudies-literature

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Publications

Evaluation of patient-reported severity of hand-foot syndrome under capecitabine using a Markov modeling approach.

Schmulenson Eduard E Krolop Linda L Simons Sven S Ringsdorf Susanne S Ko Yon-Dschun YD Jaehde Ulrich U

Cancer chemotherapy and pharmacology 20200827 3

<h4>Purpose</h4>The inclusion of the patient's perspective has become increasingly important when reporting adverse events and may assist in management of toxicity. The relationship between drug exposure and toxicity can be quantified by combining Markov elements with pharmacometric models. A minimal continuous-time Markov model (mCTMM) was applied to patient-reported outcomes using hand-foot syndrome (HFS) induced by capecitabine anti-cancer therapy as an example.<h4>Methods</h4>Patient-reporte ...[more]

PMID: 32852627

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Project description:Importance:Hand-foot syndrome (HFS) is a common adverse effect of capecitabine treatment. Objective:To compare the incidence and time to onset of grade 2 or greater HFS in patients receiving pyridoxine vs placebo and to identify biomarkers predictive of HFS. Design, Setting, and Participants:This single-center, randomized double-blind, placebo-controlled phase 3 trial conducted at National Cancer Centre Singapore assessed whether oral pyridoxine could prevent the onset of grade 2 or higher HFS in 210 patients scheduled to receive single-agent capecitabine chemotherapy for breast, colorectal, and other cancers. Interventions:Patients were randomized to receive concurrent pyridoxine (200 mg) or placebo daily for a maximum of 8 cycles of capecitabine, with stratification by sex and use in adjuvant or neoadjuvant vs palliative setting. Patients were withdrawn from the study on development of grade 2 or higher HFS or cessation of capecitabine. Main Outcomes and Measures:Primary end point was the incidence of grade 2 or higher HFS in patients receiving pyridoxine. Secondary end points included the time to onset (days) of grade 2 or higher HFS and identification of biomarkers predictive of HFS, including baseline folate and vitamin B12 levels, as well as genetic polymorphisms with genome-wide arrays. Results:In this cohort of 210 patients (median [range] age, 58 [26-82] years; 162 women) grade 2 or higher HFS occurred in 33 patients (31.4%) in the pyridoxine arm vs 39 patients (37.1%) in the placebo arm (P?=?.38). The median time to onset of grade 2 or higher HFS was not reached in both arms. In univariate analysis, the starting dose of capecitabine (odds ratio [OR], 1.99; 95% CI, 1.32-3.00; P?=?.001), serum folate levels (OR, 1.27; 95% CI, 1.10-1.47; P?=?.001), and red blood cell folate levels (OR, 1.25; 95% CI, 1.08-1.44; P?=?.003) were associated with increased risk of grade 2 or higher HFS. In multivariate analyses, serum folate (OR, 1.30; 95% CI, 1.12-1.52; P?<?.001) and red blood cell folate (OR, 1.28; 95% CI, 1.10-1.49; P?=?.001) were the only significant predictors of grade 2 or higher HFS. Grade 2 or higher HFS was associated with 300 DNA variants at genome-wide significance (P?<?5?×?10-8), including a novel DPYD variant (rs75267292; P?=?1.57?×?10-10), and variants in the MACF1 (rs183324967, P?=?4.80?×?10-11; rs148221738, P?=?5.73?×?10-10) and SPRY2 (rs117876855, P?<?1.01?×?10-8; rs139544515, P?=?1.30?×?10-8) genes involved in wound healing. Conclusions and Relevance:Pyridoxine did not significantly prevent or delay the onset of grade 2 or higher HFS. Serum and red blood cell folate levels are independent predictors of HFS. Trial Registration:clinicaltrials.gov Identifier: NCT00486213.

Project description:BackgroundBreast cancer is a global problem, and a large number of new cases are diagnosed every year. Capecitabine is effective in patients with metastatic breast cancer (MBC). Hand-foot syndrome (HFS) is a common adverse effect of capecitabine. In this study, we investigated the association between single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism pathways and capecitabine-induced HFS in Chinese patients with MBC to identify some predictive genetic biomarkers.MethodsWe selected 3 genes involved in capecitabine metabolism and screened genetic variants in these target genes. We genotyped a total of 22 SNPs in the thymidylate synthase gene (TYMS), the methylene tetrahydrofolate reductase gene (MTHFR), and the ribonucleotide reductase M1 gene (RRM1) in 342 MBC patients treated with capecitabine-based chemotherapy. The genotype distributions of each SNP in patients with and without HFS were assessed using Pearson's χ2 test, and the relationship between HFS and genotypes of SNPs was determined using logistic regression analysis. The association between SNPs and their corresponding gene expression was analyzed using the Blood expression quantitative trait loci (eQTL) browser online tools.ResultsWe found 4 positive sites for HFS in the TYMS and MTHFR genes: TYMS rs2606241 (P = 0.022), TYMS rs2853741 (P = 0.019), MTHFR rs3737964 (P = 0.029), and MTHFR rs4846048 (P = 0.030). Logistic regression analyses showed that the genotype AG of MTHFR rs3737964 [odds ratio (OR) = 0.54, 95% confidence interval (CI) 0.31-0.97, P = 0.038] and MTHFR rs4846048 (OR = 0.54, 95% CI 0.30-0.98, P = 0.042) were protective factors of HFS, whereas the genotype CT of TYMS rs2853741 (OR = 2.25, 95% CI 1.31-3.87, P = 0.012) increased the risk of HFS. The association between the genotype GT of TYMS rs2606241 (OR = 1.27, 95% CI 0.73-2.23, P = 0.012) and HFS was uncertain. Further eQTL analyses confirmed that the alleles of rs3737964 and rs4846048 affected the gene expression levels of MTHFR in cis.ConclusionsWe have identified four potentially useful pharmacogenetic markers, TYMS rs2606241, TYMS rs2853741, MTHFR rs3737964, and MTHFR rs4846048 to predict capecitabine-induced HFS in MBC patients.

Project description:BackgroundHand, foot, and mouth disease (HFMD) is an epidemic infectious disease in China. Relationship of neighborhood greenness with human health has been widely studied, yet its association with severe HFMD has not yet been established.MethodsIndividual HFMD cases that occurred in Guangdong province in 2010 were recruited and were categorised into mild and severe cases. Residential greenness was assessed using global land cover data. We used a case-control design (i.e., severe versus mild cases) with logistic regression models to assess the association between neighborhood greenness and HFMD severity. Effect modification was also examined.ResultsA total of 131,606 cases were included, of whom 130,840 were mild cases and 766 were severe cases. In an unadjusted model, HFMD severity increased with higher proportion of neighborhood greenness (odds ratio, OR = 1.029, 95%CI: 1.009-1.050). The greenness-HFMD severity association remained (OR = 1.031, 95%CI: 1.006-1.057) after adjusting for population density, demographic variables and climate variables. Both population density (Z = 4.148, P < 0.001) and relative humidity (Z = -4.297, P < 0.001) modified the association between neighborhood greenness and HFMD severity. In the stratified analyses, a protective effect (OR = 0.769, 95%CI: 0.687-0.860) of greenness on HFMD severity were found in the subgroup of population density being lower than and equal to 5 ln(no.)/km2. While in both the subgroups of population density being higher than 5, the greenness had hazard effects (subgroup of > 5 & ≤7: OR = 1.071, 95%CI: 1.024-1.120; subgroup of > 7: OR = 1.065, 95%CI: 1.034-1.097) on HFMD severity. As to relative humidity, statistically significant association between greenness and HFMD severity was only observed in the subgroup of being lower than and equal to 76% (OR = 1.059, 95%CI: 1.023-1.096).ConclusionsOur study found that HFMD severity is associated with the neighborhood greenness in Guangdong, China. This study provides evidence on developing a prevention strategy of discouraging the high-risk groups from going to the crowded green spaces during the epidemic period.

Dataset Information

Evaluation of patient-reported severity of hand-foot syndrome under capecitabine using a Markov modeling approach.

Purpose

Methods

Results

Conclusion

Publications

Evaluation of patient-reported severity of hand-foot syndrome under capecitabine using a Markov modeling approach.

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