Capecitabine-induced Hand-foot Syndrome Research Articles

Topical Diclofenac for Prevention of Capecitabine-Associated Hand-Foot Syndrome: A Double-Blind Randomized Controlled Trial.

Hand-foot syndrome (HFS) is a dose-limiting side effect of capecitabine. Celecoxib prevents HFS by inhibiting cyclooxygenase-2 (COX-2) that is upregulated because of the underlying associated inflammation. However, systemic side effects of celecoxib have limited routine prescription. Topical diclofenac inhibits COX-2 locally with minimal risk of systemic adverse events. Therefore, we conducted this study to assess the efficacy of topical diclofenac in the prevention of capecitabine-induced HFS. In this single-site phase III randomized double-blind trial, we enrolled patients with breast or GI cancer who were planned to receive capecitabine-based treatment. Participants were randomly assigned in a 1:1 ratio to receive topical diclofenac or placebo gel for 12 weeks or until the development of HFS, whichever occurred earlier. The primary end point was the incidence of grade 2 or 3 HFS (Common Terminology Criteria for Adverse Events version 5), which was compared between the two groups using simple logistic regression. In total, 264 patients were randomly assigned to receive topical diclofenac gel (n = 131) or placebo (n = 133). Grade 2 or 3 HFS was observed in 3.8% of participants in the diclofenac group compared with 15.0% in the placebo group (absolute difference, 11.2%; 95% CI, 4.3 to 18.1; P = .003). Grade 1-3 HFS was lower in the diclofenac group than in the placebo group (6.1% v 18.1%; absolute risk difference, 11.9%; 95% CI, 4.1 to 19.6). Capecitabine dose reductions because of HFS were less frequent in the diclofenac group (3.8%) than in the placebo group (13.5%; absolute risk difference, 9.7%; 95% CI, 3.0 to 16.4). Topical diclofenac prevented HFS in patients receiving capecitabine. This trial supports the use of topical diclofenac to prevent capecitabine-associated HFS.

Predictive factors for the development of capecitabine-induced hand-foot syndrome: a retrospective observational cohort study.

Capecitabine-induced hand-foot syndrome (HFS) is a common condition that significantly affects patients' quality of life. The exact underlying mechanisms are currently not clearly understood. Therefore, the study of predictive factors for HFS is of critical importance. This prognostic factor research used a retrospective observational cohort as the study design. Data collected from the medical records of 205 patients treated with capecitabine between January 2019 and June 2022 were subjected to univariable and multivariable regression analysis to determine the predictive factors for the development of grade 2 and grade 3 HFS. The incidence of grade 2 and grade 3 HFS was 26.8%. The independent predictive factors, such as age over 60 years (OR 4.80, 95% CI: 2.16-10.68, P<0.001), capecitabine dose greater than 3000mg/day (OR 2.47, 95% CI: 1.09-5.59, P=0.030), and the number of cycles five or more in the total capecitabine regimen (OR 2.94, 95% CI: 1.29-6.71, P=0.01), were significantly associated with the development of grade 2 and grade 3 HFS. Independent predictive factors for the development of grade 2 and grade 3 HFS in patients treated with capecitabine include age over 60, capecitabine dose greater than 3000mg/day, and patients who plan to undergo five or more cycles in the total capecitabine regimen. This knowledge can be valuable for guiding clinical monitoring and follow-up of patients.

Risk Factors of Capecitabine-Induced Hand-Foot Syndrome: A Single-Institution, Retrospective Study

Introduction: This retrospective study was conducted to identify risk factors for developing hand-foot syndrome (HFS) and to determine new strategies for improving quality of life (QoL) in patients undergoing chemotherapy. Methods: Between April 2014 and August 2018, we enrolled 165 cancer patients at our outpatient chemotherapy center who were undergoing capecitabine chemotherapy. Variables related to the development of HFS were extracted from the clinical records of patients for use in regression analysis. HFS severity was assessed at the time of completing capecitabine chemotherapy. The degree of HFS was classified in accordance with the National Cancer Institute Common Terminology Criteria for Adverse Events version 5. Multivariate ordered logistic regression analysis was performed to identify risk factors for the development of HFS. Results: Risk factors for the development of HFS included concomitant use of a renin-angiotensin system (RAS) inhibitor (odds ratio [OR] = 2.85, 95% confidence interval [CI] = 1.20–6.79; p = 0.018), body surface area (BSA) (high) (OR = 12.7, 95% CI = 2.29–70.94; p = 0.004), and albumin (low) (OR = 0.44, 95% CI = 0.20–0.96; p = 0.040). Discussion/Conclusion: Concomitant use of RAS inhibitor, high BSA, and low albumin were identified as risk factors for the development of HFS. The identification of potential risk factors of HFS may assist in the development of strategies that can be used to improve QoL in patients receiving chemotherapy regimens that include capecitabine.

Capecitabine-induced hand-foot syndrome: A pharmacogenetic study beyond DPYD

Aim of the studyOccurrence of hand-foot syndrome (HFS) during capecitabine treatment often results in treatment interruptions (26 %) or treatment discontinuation (17 %), and can severely decrease quality of life. In this study, we investigated whether single nucleotide polymorphisms (SNPs) in genes involved in capecitabine metabolism – other than DPYD – are associated with an increased risk for capecitabine-induced HFS. MethodsPatients treated with capecitabine according to standard of care were enrolled after providing written informed consent for genotyping purposes. Prospectively collected blood samples were used to extract genomic DNA, which was subsequently genotyped for SNPs in CES1, CES2 and CDA. SNPs and clinical baseline factors that were univariably associated with HFS with P ≤ 0.10, were tested in a multivariable model using logistic regression. ResultsOf the 446 patients eligible for analysis, 146 (32.7 %) developed HFS, of whom 77 patients (17.3 %) experienced HFS ≥ grade 2. In the multivariable model, CES1 1165–33 C>A (rs2244613, minor allele frequency 19 %) and CDA 266 + 242 A>G (rs10916825, minor allele frequency 35 %) variant allele carriers were at higher risk of HFS ≥ grade 2 (OR 1.888; 95 %CI 1.075–3.315; P = 0.027 and OR 1.865; 95 %CI 1.087–3.200; P = 0.024, respectively). ConclusionsWe showed that CES1 1165–33 C>A and CDA 266 + 242 A>G are significantly associated with HFS grade 2 and grade 3 in patients treated with capecitabine. Prospective studies should assess whether this increased risk can be mitigated in carriers of these SNPs, when pre-emptive genotyping is being followed by dose adjustment or by alternative treatment by a fluoropyrimidine that is not substrate to CES1, such as S1.

Capecitabine induces hand-foot syndrome through elevated thymidine phosphorylase-mediated locoregional toxicity and GSDME-driven pyroptosis that can be relieved by tipiracil.

Hand-foot syndrome (HFS) is a serious dose-limiting cutaneous toxicity of capecitabine-containing chemotherapy, leading to a deteriorated quality of life and negative impacts on chemotherapy treatment. The symptoms of HFS have been widely reported, but the precise molecular and cellular mechanisms remain unknown. The metabolic enzyme of capecitabine, thymidine phosphorylase (TP) may be related to HFS. Here, we investigated whether TP contributes to the HFS and the molecular basis of cellular toxicity of capecitabine. TP-/- mice were generated to assess the relevance of TP and HFS. Cellular toxicity and signalling mechanisms were assessed by in vitro and in vivo experiments. TP-/- significantly reduced capecitabine-induced HFS, indicating that the activity of TP plays a critical role in the development of HFS. Further investigations into the cellular mechanisms revealed that the cytotoxicity of the active metabolite of capecitabine, 5-DFUR, was attributed to the cleavage of GSDME-mediated pyroptosis. Finally, we demonstrated that capecitabine-induced HFS could be reversed by local application of the TP inhibitor tipiracil. Our findings reveal that the presence of elevated TP expression in the palm and sole aggravates local cell cytotoxicity, further explaining the molecular basis underlying 5-DFUR-induced cellular toxicity and providing a promising approach to the therapeutic management of HFS.

71P Capecitabine-induced adverse events: A pharmacogenetic study beyond DPYD

Capecitabine treatment is frequently accompanied by adverse events such as hand-foot syndrome (HFS), leading to interruption --or even discontinuation-- of treatment in approximately 26% of patients. These adverse events can be mitigated with pre-emptive dose reductions in case of single nucleotide polymorphisms (SNPs) in DPYD, encoding the main fluoropyrimidine-metabolizing enzyme dihydropyrimidine dehydrogenase. However, HFS still occurs in 53-77% of patients treated with capecitabine. In this study, we investigated if SNPs in other genes involved in capecitabine metabolism are predictive for capecitabine-induced HFS.

Pharmacological prevention strategy for capecitabine‐induced hand‐foot syndrome: A network meta‐analysis of randomized control trials

Capecitabine-induced hand-foot syndrome (HFS) is common in clinical practice. There are many regimens used to prevent HFS. However, the most effective preventive regimen has not yet been identified. Thus, we conducted a network meta-analysis to investigate the best preventive regimen for HFS. The PRISMA-NMA guidelines were used in this study. The PubMed, Cochrane, and Embase databases were searched. The main endpoint was set as HFS of National Cancer Institute grade 2 or more. We included only randomized control trials. The P-score was used to rank the regimens. Among all the regimens, topical silymarin had the best preventive ability compared with the placebo (OR: 0.08; 95% CI: 0.01-0.71). The other identified effective regimen included pyridoxine (400 mg) and celecoxib; compared with the placebo, the odds ratio was 0.27 (95% CI: 0.08-0.91) and 0.41 (95% CI: 0.18-0.95), respectively. Topical silymarin is the most useful regimen for preventing capecitabine-induced HFS.

Study protocol of a single-arm phase 2 study evaluating the preventive effect of topical hydrocortisone for capecitabine-induced hand-foot syndrome in colorectal cancer patients receiving adjuvant chemotherapy with capecitabine plus oxaliplatin (T-CRACC study)

BackgroundsClinical evidence of the preventive effectiveness of medium-class topical corticosteroids for capecitabine-induced hand foot syndrome (HFS) is limited. Although the pathogenesis and mechanism of HFS are unclear, inflammatory reactions are thought to be involved in HFS development. This study aimed to evaluate the preventive effect of medium-class topical corticosteroids (hydrocortisone butyrate 0.1% topical therapy) for capecitabine-induced HFS in patients with colorectal cancer receiving adjuvant chemotherapy with capecitabine plus oxaliplatin.MethodsThis is a single-center, single-arm, phase 2 study. Patients with colorectal cancer scheduled to receive adjuvant chemotherapy with capecitabine plus oxaliplatin are enrolled, and topical hydrocortisone butyrate 0.1% is applied prophylactically in addition to standard moisturizing therapy. The primary endpoint is the incidence of grade ≥ 2 HFS within three months. The secondary endpoints are the time to onset of HFS, rates of dose reduction, schedule delay, discontinuation caused by capecitabine-induced HFS, and other adverse events. All adverse events are evaluated by clinical pharmacists and attending physicians.DiscussionThis study is expected to contribute to the establishment of new supportive care for preventing HFS, not only for colorectal cancer patients receiving adjuvant chemotherapy, but also for various cancer patients receiving capecitabine-based chemotherapy.Trial registration: This trial was registered in the Japan Registry of Clinical Trials (jRCT) as jRCTs031220002. Registered 5 April 2022, https://jrct.niph.go.jp/searchProtocol version V.1.0, 16 February 2022.

Prophylactic strategies for hand-foot syndrome/skin reaction associated with systemic cancer treatment: a meta-analysis of randomized controlled trials.

Hand-foot syndrome (HFS) and hand-foot skin reaction (HFSR) are common toxicities of several systemic cancer treatments. Multikinase inhibitor-induced HFSR is distinguished from chemotherapy-induced HFS in terms of pathogenesis, symptomatology, and treatment. Multiple trials have investigated the efficacy of preventive strategies such as COX-inhibitors, pyridoxine, and urea cream; however, no consensus has been made. This meta-analysis evaluated data from high-quality trials to provide strong evidence in forming recommendations to prevent systemic cancer therapy-induced HFS/HFSR. A systematic search of PubMed, Embase, Cochrane, clinical trials databases, and hand searching were utilized to identify randomized trials (RCTs) investigating prophylactic strategies for HFS/HFSR in cancer patients receiving systemic treatment. Trials published until August 2021 were included. Using the random effects model, pooled odds ratios were calculated for rates of all-grade and severe HFS/HFSR. Subgroup analysis based on type of cancer treatment given was done. Sixteen RCTs were included (N=2814). For all-grade HFS/HFSR, celecoxib (OR 0.52, 95% CI 0.32-0.85, p=0.009) and urea cream (OR 0.48, 95% CI 0.39-0.60, p<0.00001) both showed statistically significant risk reduction. Celecoxib was effective in preventing HFS in patients who received capecitabine (50.5% vs 65%, p=0.05), while urea cream was effective in both capecitabine HFS (22.3% vs 39.5%, p=0.02) and sorafenib-induced HFSR (54.9% vs 71.4%, p<0.00001). Pyridoxine at higher doses showed a trend towards benefit in preventing all grade HFS (69.6% vs 74.1%, p=0.23). Urea cream and celecoxib are both effective in preventing HFS/HFSR in patients receiving systemic cancer treatment. Particularly, celecoxib is more effective in preventing all-grade capecitabine-induced HFS, while urea cream shows more benefit in preventing moderate to severe sorafenib-induced HFSR. Studies investigating optimal dosing for celecoxib and urea cream are recommended. There is inadequate evidence to make recommendations regarding pyridoxine.

Proton Pump Inhibitors Ameliorate Capecitabine-induced Hand-Foot Syndrome in Patients With Breast Cancer: A Retrospective Study

Hand-foot syndrome (HFS) is the most common adverse event associated with capecitabine, and its pathogenesis is known to be associated with inflammation. Proton pump inhibitors (PPIs) reportedly exert anti-inflammatory effects; however, the impact of PPIs on capecitabine-induced HFS needs to be clarified in the clinical setting. In the present study, we retrospectively investigated the efficacy and safety of PPIs in patients with breast cancer receiving capecitabine. We analyzed the effects of PPIs on the development of severe HFS (grade ≥2), progression-free survival (PFS), and overall survival (OS) in 195 patients who received capecitabine chemotherapy for breast cancer. In total, 50 patients (26%) were treated with PPIs, while 145 patients (74%) did not receive PPIs. The incidence of severe HFS was significantly lower in patients who received PPIs (18%) than in patients who did not receive PPIs (43%, p=0.001), and the discontinuation rate of capecitabine therapy due to HFS was also lower in patients receiving PPIs than in those who did not receive PPIs (p=0.003). Multivariate analysis revealed that concomitant PPIs use was an independent factor that significantly contributed to the prevention of severe HFS (odds ratio (OR)=0.265, p=0.003). Meanwhile, no significant difference in median PFS and OS values was observed between patients treated with and without PPIs. Concomitant use of PPIs could ameliorate capecitabine-induced HFS in patients with breast cancer.

Topical heparin as an effective and safe treatment for patients with capecitabine-induced hand-foot syndrome: results of a phase IIA trial supported by proteomic profiling of skin biopsies.

Background:Hand-foot syndrome (HFS) is a common adverse reaction associated with capecitabine chemotherapy that significantly affects the quality of life of patients. This study evaluates the safety and effectiveness of a topical heparin (TH) treatment on the clinical manifestations and anatomopathological alterations of capecitabine-induced HFS. In addition, we performed proteome profiling of skin biopsies obtained from patients with HFS at baseline and after heparin treatment.Methods:Patients with grade ⩽ 2 HFS associated with capecitabine were included in this study. The primary end point was the effectiveness of TH in reducing HFS of any grade. Clinical improvement was evaluated by clinicians, and an improvement was perceived by patients who performed a weekly visual analog scale questionnaire. Secondary end points included a comparative histological analysis and protein expression in skin biopsies at baseline and after 3 weeks of HT treatment. Proteomic profiling was carried out using quantitative isobaric labelling and subsequently validated by a T-array.Results:Twenty-one patients were included in the study. The median TH treatment time was 7.6 weeks (range = 3.6–41.6 weeks), and the median response time was 3.01 weeks (95% CI = 2.15–3.97). At the end of treatment, 19 of 21 patients (90.48%) responded to treatment with a decrease in one or more grades of HFS. None of the patients experienced adverse effects related to TH usage, nor did they suspend chemotherapy treatment. The main findings observed in skin biopsies after treatment were a decrease in hyperkeratosis and lymphocytic infiltrates. The proteomic analysis showed altered expression of 34 proteins that were mainly related to wound healing, cell growth, and the immune response.Conclusion:Based on our results, topical heparin is an effective and safe treatment for clinical manifestations of HFS, probably due to the restauration of skin homeostasis after heparin treatment, as supported by our proteomics-derived data.Trial registration:EudraCT 2009-018171-13

Creme de dexpantenol à base de lanolina, hidrocortisona tópica ou observação na prevenção da síndrome mão-pé induzida por capecitabina: um estudo de fase III

INTRODUCTION: The use of capecitabine is associated with hand-foot syndrome (HFS). Since there is anecdotal evidence that lanolin-based creams and topical steroids are useful for the treatment of HFS, we conducted a three- arm phase III trial to compare observation, lanolin-based cream with dexpanthenol (L-D), and topical hydrocortisone in the prevention of HFS. MATERIAL AND METHODS: Patients with breast or colorectal cancer with indication to use capecitabine as a single agent or in combination were randomized in an open-label fashion to one of the three arms. The initial capecitabine dose was 1,000 or 1,250mg/m2, according to the physicians discretion and clinical practice, and dose adjustments followed the local label. The primary endpoint was the frequency of HFS of any grade in the intent-to-treat population, whereas quality of life (QoL), change from baseline in performance status and adverse events were secondary endpoints. RESULTS: Mean age among the 595 patients randomized was 58 years, and 69% were women. 37% of patients had advanced breast cancer and 63% of patients had colorectal cancer. Capecitabine was used as a single agent in 67% of patients; among the remaining 33% of patients, 82% were treated with oxaliplatin-based combinations. HFS of any grade was seen in 35.6% of patients in the observation group, 24.9% with L-D, and 34.3% with hydrocortisone (p=0.039). The unadjusted odds ratio for the frequency of HFS in the arm treated with L-D was 0.60 (95%CI, 0.39 to 0.92). Only between 2.6% and 9.4% of patients had grade 3 HFS. There were no statistically significant differences in mean change from baseline in any of the QoL scores, the distribution of performance status, or the frequency of adverse events among the three arms. CONCLUSION: L-D could be considered a standard strategy in the attempt to prevent capecitabine-induced HFS.

Use of omeprazole, the proton pump inhibitor, as a potential therapy for the capecitabine-induced hand-foot syndrome

Hand-foot syndrome (HFS), also known as palmar-plantar erythrodysesthesia (PPE), is a major side effect of capecitabine. Although the pathogenesis of HFS remains unknown, some studies suggested a potential involvement of inflammation in its pathogenesis. Proton pump inhibitors (PPIs) have been reported to have anti-inflammatory effects. In this study, we investigated the ameliorative effects of omeprazole, a PPI on capecitabine-related HFS in mice model, and a real-world database. Repeated administration of capecitabine (200 mg/kg, p.o., five times a week for 3 weeks) increased fluid content, redness, and tumor necrosis factor (TNF)-α substance of the mice hind paw. Co-administration of omeprazole (20 mg/kg, p.o., at the same schedule) significantly inhibited these changes induced by capecitabine. Moreover, based on the clinical database analysis of the Food and Drug Administration Adverse Event Reporting System, the group that has used any PPIs had a lower reporting rate of capecitabine-related PPE than the group that has not used any PPIs. (6.25% vs. 8.31%, p < 0.0001, reporting odds ratio (ROR) 0.74, 95% confidence interval (CI) 0.65–0.83). Our results suggest that omeprazole may be a potential prophylactic agent for capecitabine-induced HFS.

Polymorphisms in TYMS for Prediction of Capecitabine-Induced Hand-Foot Syndrome in Chinese Patients with Colorectal Cancer.

PurposeCapecitabine is an extensively used oral prodrug of 5-fluorouracil in treatment of colon cancer and is known to cause hand-foot syndrome (HFS). As the target enzyme for capecitabine, thymidylate synthase (TYMS) plays a key role for 5-fluorouracil metabolism and has been associated with some side effects caused by capecitabine. The aim of our study is to identify the possible genetic predictors of capecitabine-induced HFS (CAP-HFS) in Chinese colorectal cancer patients.Materials and MethodsWhole exons of TYMS were sequenced for 288 extreme phenotype HFS patients, including 144 severe or early-onset (first 2 cycles) moderate HFS extreme cases and 144 extreme controls with no reported HFS. The associations between polymorphisms and CAP-HFS were analyzed using logistic regression under an additive model.ResultsWe identified a novel risk mutation (c.1A>G, chr18:657743), was associated with severe HFS in an extreme case who was affected during the first cycle of treatment. Moreover, we identified three new variants, rs3786362, rs699517, rs2790, and two previously reported variants, 5’VNTR 2R/3R and 3′-untranslated region 6-bp ins-del, which were significantly associated with CAP-HFS (p < 0.05). In silico analysis revealed that the effect of these polymorphisms in the TYMS region on the development of HFS might not be restricted solely to the regulation of TYMS expression, but also the TYMS catalytic activity through the indirect effect on ENOSF1 expression.ConclusionThis study identified new polymorphisms in TYMS gene significantly associated with CAP-HFS, which may serve as useful genetic predictors for CAP-HFS and help to elucidate the underlying mechanism of HFS.

Henna Application in the Prevention of Capecitabine-Induced Hand-Foot Syndrome in Breast and Colorectal Cancer Patients.

AIMThis study investigates the prophylactic effect of henna on the occurrence of hand-foot syndrome (HFS) in patients receiving capecitabine for breast and colorectal cancer.METHODThis experimental study was carried out between May 2014 and May 2015. In this self-control experimental study, 52 patients with breast and colorectal cancer were included on the first day of capecitabine treatment and had a minimum follow-up of 3 cycles. One hand/foot of each patient constituted the study hand/foot, whereas the others constituted the control. Henna was administered to the study hand/foot on the first day of treatment and application renewed weekly. Development of grade 1–3 toxicity was set as the termination criterion for study.RESULTSPainful skin changes such as rawness, intumescence and bulla formation, blocking the daily activities or self-care were observed in 26.9% of the patients in the 3rd or 4th cycles of treatment. Development time and severity of skin changes over time did not differ significantly between the study and the control hand/foot.CONCLUSIONFurther studies with a larger sample size are needed to conclude on the prophylactic effect of henna in the management of the HFS.

Regulatory CDH4 Genetic Variants Associate With Risk to Develop Capecitabine-Induced Hand-Foot Syndrome.

Capecitabine-induced hand-foot syndrome (CiHFS) is a common dermatological adverse reaction affecting around 30% of patients with capecitabine-treated cancer, and the main cause of dose reductions and chemotherapy delays. To identify novel genetic factors associated with CiHFS in patients with cancer, we carried out an extreme-phenotype genomewide association study in 166 patients with breast and colorectal capecitabine-treated cancer with replication in a second cohort of 85 patients. We discovered and replicated a cluster of four highly correlated single-nucleotide polymorphisms associated with susceptibility to CiHFS at 20q13.33 locus (top hit=rs6129058, hazard ratio=2.40, 95% confidence interval=1.78-3.20; P=1.2×10-8 ). Using circular chromosome conformation capture sequencing, we identified a chromatin contact between the locus containing the risk alleles and the promoter of CDH4, located 90 kilobases away. The risk haplotype was associated with decreased levels of CDH4 mRNA and the protein it encodes, R-cadherin (RCAD), which mainly localizes in the granular layer of the epidermis. In human keratinocytes, CDH4 downregulation resulted in reduced expression of involucrin, a protein of the cornified envelope, an essential structure for skin barrier function. Immunohistochemical analyses revealed that skin from patients with severe CiHFS exhibited low levels of RCAD and involucrin before capecitabine treatment. Our results uncover a novel mechanism underlying individual genetic susceptibility to CiHFS with implications for clinically relevant risk prediction.

SNPs in the COX-2/PGES/EP signaling pathway are associated with risk of severe capecitabine-induced hand-foot syndrome.

Capecitabine is a widely used 5-fluorouracil oral prodrug. Hand-foot syndrome (HFS), one of the most common adverse events of capecitabine, impacts patients' quality of life seriously. The pathogenesis of HFS remains unclear but was usually considered as a type of inflammation conducted by cyclooxygenase-2 (COX-2). The COX-2/PGES/EP signaling pathway plays an important role in the inflammatory reaction. We hypothesized that the single nucleotide polymorphisms (SNPs) in this pathway may be associated with the risk of HFS induced by capecitabine. Using DNA from blood samples of 225 patients, we genotyped 19 SNPs in 6 core genes (COX-2, PGES, EP1, EP2, EP3, and EP4). Common Terminology Criteria for Adverse Events version 3.0 was used to grade hand-foot syndrome. We used logistic regression analysis to evaluate the correlations between genotype variants and occurrence of HFS. The cumulative incidence of HFS was assessed by Kaplan-Meier analysis. Among the 225 participants, 58.6% (132/225) patients developed into HFS, including 41.3% (93/225) grade 1 HFS, 10.2% (23/225) grade 2 HFS and 7.1% (16/225) grade 3 HFS. Multivariate logistic regression analysis showed the AG/GG genotype of rs3810255 to be associated with a significantly higher risk of grade 2/3 HFS, while the AG/AA genotype of rs17131450 to be associated with a significantly lower risk of grade 2/3 HFS (OR = 3.646, P = 0.011; and OR = 0.266, P = 0.036; respectively). Our study showed that rs3810255 AG/GG genotypes and rs17131450 GG genotypes to be associated with high risk of capecitabine-induced HFS.

Polymorphisms of MTHFR and TYMS predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer

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.

Capecitabine Induced Hand-Foot Syndrome: A Systematic Review of Case Reports

Objective: Capecitabine, a prodrug of 5-fluorouracil, is currently used in the treatment of metastatic colorectal and breast cancers. The aim of this study was to review the pharmacological mechanisms, treatment strategies, and documented case reports of capecitabine-induced hand–foot syndrome (HFS).Methods: All case reports documented in the PubMed, Web of Science, and Scopus databases up to February 2018 were searched and reviewed using the keywords capecitabine, hand-foot syndrome, and case report.Results: The database search identified 373 articles in the literature; of these, 88 articles (having 111 case reports) in the English or Turkish language having a full-text access were included in the study. The median duration of capecitabine-induced HFS was 28 (range, 7–140) days, and the daily dose of capecitabine ranged between 850 and 5000 mg/m2 in cases wherein capecitabine was applied as monotherapy(n=19). A dose reduction or treatment discontinuation, systemic or topical treatment alone or in combination, and the use of henna, vitamin E, or pyridoxine were preferred options in the treatment of HFS.Conclusion: Health care providers and patients should be aware of developing capecitabine-induced HFS and its risk factors. Early recognition and treatment initiation for HFS are important to maintain effective chemotherapy in patients with cancer.

Polymorphisms of MTHFR and TYMS to predict capecitabine-induced hand-foot syndrome in patients with metastatic breast cancer.

1085Background: Breast cancer is a global problem, and 1.7 million new cases are diagnosed per year. Capecitabine, an oral prodrug of fluorouracil, has been reported to be effective in patients wit...