Oral Prodrug Of 5-fluorouracil Research Articles

Spotlight on capecitabine for the treatment of unresectable or metastatic carcinoma of various origin: A retrospective study of 25 dogs.

Capecitabine, the oral prodrug of 5-fluorouracil, is indicated in people to treat various malignant epithelial cancers. In dogs, capecitabine has not been extensively evaluated. The aim of this retrospective study was to investigate toxicity and preliminary efficacy of single agent capecitabine in dogs with advanced malignant epithelial cancers of any site, for which no effective therapy existed, conventional treatment failed or was declined. Capecitabine was administered orally at 750 mg/m2 from day 1 to 14, followed by 1-week rest period, given as 3-week cycles. Safety evaluation was performed after 2 cycles, and every 2-3 cycles thereafter. Tumour response was determined every 2-3 cycles. Twenty-five dogs with hepatocellular carcinoma (n = 6), lung papillary carcinoma (n = 4), anal sac adenocarcinoma (n = 3), colic adenocarcinoma (n = 2), and other individually represented epithelial cancers (n = 10) were included. Dogs received a median of 4 cycles (range, 2-43) for a median of 84 days (range, 42-913). Toxicity occurred in 17 (68.0%) dogs; the most frequent adverse events were gastrointestinal, with the majority being self-resolving and of mild grade. Of the 22 dogs with macroscopic disease, 3 (13.6%) achieved partial remission, 16 (72.7%) were stable and 3 (13.6%) progressed; overall clinical benefit rate was 86.4%. Median progression-free interval was 93 days (95% CI 42-154; range, 1-521) and median tumour-specific survival was 273 days (95% CI 116-482; range 45-913). These findings suggest that capecitabine is an attractive option for the treatment of several types of carcinomas in dogs. Prospective studies are warranted to optimize the scheduling of capecitabine and confirm its efficacy.

Association of Single-Nucleotide Polymorphisms in Capecitabine Bioactivation Pathway with Adjuvant Therapy Safety in Colorectal Cancer Patients.

Capecitabine, an oral prodrug of 5-fluorouracil (5-FU), is part of the standard treatment of colorectal cancer (CRC). Severe adverse dose limiting reactions that impair treatment safety and lead to treatment suspension remain a relevant concern. Single-nucleotide polymorphisms (SNPs) in genes involved in the activation of capecitabine may alter the bioavailability of 5-FU and thereby affect therapy outcomes. The aim of this study was to evaluate the association of these SNPs with severe toxicity and treatment suspension in patients with CRC treated with capecitabine-based therapy. An ambispective cohort study was conducted, including 161 patients with CRC. SNPs were analyzed using real-time PCR with TaqMan® probes. Toxicity was assessed according to the National Cancer Institute Common Terminology Criteria for Adverse Events v.5.0. CES1 rs71647871-A was associated with a severe hand-foot syndrome (p = 0.030; OR = 11.92; 95% CI = 1.46-73.47; GG vs. A). CDA rs1048977-CC (p = 0.030; OR = 2.30; 95% CI 1.09-5.00; T vs. CC) and capecitabine monotherapy (p = 0.003; OR = 3.13; 95% CI 1.49-6.81) were associated with treatment suspension due to toxicity. SNPs CES1 rs71647871 and CDA rs1048977 may act as potential predictive biomarkers of safety in patients with CRC under capecitabine-based adjuvant therapy.

Development of a UPLC-MS/MS Assay for the Quantitative Determination of Capecitabine, 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5'-fluorouracil (5-FU), and α-fluoro-β-alanine (FBAL).

Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-β-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples. Capecitabine is an anticancer agent and is the oral prodrug of 5-fluorouracil (5-FU). In this study, an ultra-high performance liquid chromatography coupled to turbo ion spray tandem mass spectrometry (UPLC-MS/MS) method was developed and validated to quantify capecitabine and its metabolites including 5'-deoxy-5-fluorocytidine (5'-dFCR), 5'-deoxy-5-fluorouridine (5'-dFUR), 5-FU, and fluoro-β-alanine (FBAL) in lithium heparinized human plasma. Analytes were extracted by protein precipitation, chromatographically separated by Acquity UPLC HSS T3 column with gradient elution, and analyzed with a tandem mass spectrometer equipped with an electrospray ionization source. Capecitabine and 5'-dFCR were quantified in positive ion mode and 5'-dFUR, 5-FU, and FBAL were quantified in negative ion mode. The total chromatographic run time was 9 min. Stable isotopically labeled internal standards were used for all analytes. The assay was validated over the range from 25.0 to 2,500 ng/mL for capecitabine, 10.0 to 1,000 ng/mL for 5'-dFCR, 5'-dFUR, and 5-FU and 50 to 5,000 ng/ mL for FBAL in human plasma. Validation results have shown the developed assay allows for reliable quantitative analysis of capecitabine, 5'-dFCR, 5'-dFUR, 5-FU, and FBAL in plasma samples.

Influence of age on pharmacokinetics of capecitabine and its metabolites in older adults with cancer: a pilot study.

Capecitabine is an oral chemotherapy prodrug of 5-fluorouracil (5-FU) with unpredictable toxicity, especially in older adults. The aim of this study was to evaluate the pharmacokinetics (PK) of capecitabine and its metabolites in younger adults (< 70years) and older adults (≥ 70years) receiving capecitabine for solid cancer. Eligible participants receiving capecitabine had 2 venous samples collected on day 14 of cycle 1 and cycle 2 of their treatment. Capecitabine and metabolite concentrations were determined using liquid chromatography with tandem mass spectrometry. A Bayesian estimation approach was used to generate individual estimates of PK parameters for 5-FU. A linear mixed-effect analysis of variance (ANOVA) model was used to compare dose-normalised log-transformed PK parameters between age groups. Correlations were determined by linear regression and logistic regression analyses. Of the total 26 participants, 58% were male with a median age of 67years (range, 37-85) with 54% aged < 70years and 46% aged ≥ 70years. Participants aged ≥ 70years, compared to those aged < 70years, had a greater 5-FU exposure based on area under the concentration-time curve (AUC) of 17% (90% CI 103-134%; 0.893 vs. 0.762mg h/L) and 14% increase in maximal concentration, Cmax (90% CI 82.1-159%; 0.343 vs. 0.300mg/L). The 5-FU Cmax was positively associated with time up and go (TUG) (Pearson's correlation 0.77, p = 0.01), but not other geriatric assessment domains or severe toxicity. 5-FU exposure was significantly increased in older adults compared to younger adults receiving equivalent doses of capecitabine, and is a possible cause for increased toxicity in older adults.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema.

Stroke-like presentation of acute toxic leukoencephalopathy due to capecitabine treatment with extensive intramyelinic edema.

Oral Capecitabine Exposures and Use of Uridine Triacetate: A 20-Year Retrospective Analysis.

Capecitabine is an oral prodrug of 5-fluorouracil. Toxicity can occur during therapy as well as acutely with overdose and particular genetic susceptibilities. Uridine triacetate is an effective antidote if given within 96h of exposure. This study seeks to characterize accidental and intentional capecitabine exposures and uridine triacetate use, about which little has been published. A retrospective review of capecitabine exposures from 30 April 2001 to 31 December 2021 reported to a statewide poison control center was performed. All single-substance oral exposures were included. In total, 81 of 128 reviewed cases were included, with a median age of 63years. In total, 49 were acute-on-chronic exposures and 32 were acute exposures in capecitabine-naïve patients, 29 of which were accidental. Fifty-six (69%) were managed at home. Of these, none later recontacted the poison control center to report symptoms or were known to have later had healthcare facility evaluations. Of the 25 cases presenting for healthcare facility evaluation, 4 were acutely symptomatic. Thirteen were eligible for uridine triacetate, and six received it; no new or progressive toxicity was reported after. Three developed mild latent toxicity; otherwise, no morbidity or mortality was reported. Accidental acute-on-chronic and acute ingestions of capecitabine appear to be well tolerated; most cases were managed at home. Unfortunately, little is known regarding the threshold at which toxicity may present following exposures. The threshold may vary individually given genetic susceptibilities. Management was heterogeneous, likely reflecting inadequate guidelines. Further research is needed to better delineate at-risk populations and treatment strategies.

Impact of S-1 adjuvant chemotherapy longer than 6months on survival in patients with resected pancreatic cancer: a nationwide survey by the Japan Pancreas Society based on real-world data.

Based on the Japan Adjuvant Study Group of Pancreatic Cancer 01 study, the standard duration of adjuvant chemotherapy with S-1 (an oral 5-fluorouracil prodrug consisting of tegafur, gimeracil, and oteracil) in patients with resected pancreatic ductal adenocarcinoma (PDAC) was considered to be 6months, but the impact of increasing its duration on postoperative survival was unknown. Here, the authors investigated this question by reviewing real-world data from a large cohort of patients with PDAC. In total, 3949 patients who underwent surgery for PDAC during the study period followed by S-1 adjuvant chemotherapy in board-certified institutions were included. Based on the duration of S-1 chemotherapy, two subgroups were defined: a standard-duration group that included patients who were treated for 180±30days and a longer duration group that included patients who received treatment for >210days. The median duration of S-1 chemotherapy was 167days, with a mean±standard deviation of 200±193days. After excluding patients who had a recurrence within 210days after the initiation of adjuvant chemotherapy, postoperative recurrence-free survival (RFS) and overall survival (OS) in the standard-duration group (n=1473) and the longer duration group (n=975) were compared. RFS and OS did not differ significantly between the standard-duration and longer duration groups (5-year RFS: 37.8% vs. 36.2% respectively; p=.6186; 5-year OS: 52.8% vs. 53.4%, respectively; p=.5850). The insignificant difference was verified by multivariate analysis and propensity-score matching analysis. The current findings suggest that extending S-1 adjuvant chemotherapy beyond 6months has no significant additional effect on survival in patients with PDAC. This could be useful in determining whether to extend S-1 chemotherapy in patients who have completed the standard 6-month treatment.

Editor’s Letter

Capecitabine (Xeloda; CAP) is a recently developed oral antineoplastic prodrug of 5-fluorouracil (5-FU) with enhanced tumor selectivity. Previous studies have shown that CAP activation follows a pathway with three enzymatic steps and two intermediary metabolites, 5′-deoxy-5-fluorocytidine (5′-DFCR) and 5′-deoxy-5-fluorouridine (5′-DFUR), to form 5-FU preferentially in tumor tissues. In the present work, we investigated all fluorinated compounds present in liver, bile, and perfusate medium of isolated perfused rat liver (IPRL) and in liver, plasma, kidneys, bile, and urine of healthy rats. Moreover, data obtained from rat urine were compared with those from mice and human urine. According to a low cytidine deaminase (3.5.4.5) activity in rats, 5′-DFCR was by far the main product in perfusate medium from IPRL and plasma and urine from rats. Liver and circulating 5′-DFCR in perfusate and plasma equilibrated at the same concentration value in the range 25 to 400 μM, which supports the involvement of es-type nucleoside transporter in the liver. 5′-DFUR and α-fluoro-β-ureidopropionic acid (FUPA) + α-fluoro-β-alanine (FBAL) were the main products in urine of mice, making up 23 to 30% of the administered dose versus 3 to 4% in rat. In human urine, FUPA + FBAL represented 50% of the administered dose, 5′-DFCR 10%, and 5′-DFUR 7%. Since fluorine-19 nuclear magnetic resonance spectroscopy gives an overview of all the fluorinated compounds present in a sample, we observed the following unreported metabolites of CAP: 1) 5-fluorocytosine and its hydroxylated metabolite, 5-fluoro-6-hydroxycytosine, 2) fluoride ion, 3) 2-fluoro-3-hydroxypropionic acid and fluoroacetate, and 4) a glucuroconjugate of 5′-DFCR.

A Physiologically Based Pharmacokinetic-Pharmacodynamic Model for Capecitabine in Colorectal Cancer Rats: Simulation of Antitumor Efficacy at Various Administration Schedules.

Capecitabine is an oral prodrug of 5-fluorouracil and is widely used for colorectal cancer (CRC) treatment. However, knowledge of its antitumor efficacy after modification of the dosing schedule is insufficient. The aim of this study was to predict the antitumor efficacy of capecitabine using a physiologically based pharmacokinetic-pharmacodynamic (PBPK-PD) model based on metabolic enzyme activities. CRC model rats were administrated 180mg/kg of capecitabine for 2weeks. Blood samples were collected at 0, 0.25, 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, and 8h following capecitabine administration. Plasma concentrations of capecitabine and its metabolites were measured on days 1, 7, and 14. Metabolic enzyme activities were determined in vitro using the liver and small intestine of the CRC model rats. A PBPK-PD model was developed based on metabolic enzyme activities. The antitumor efficacy of capecitabine after regimen modification was simulated using the PBPK-PD model. Capecitabine antitumor efficacy was dose-dependent. A dose of >500μmol/kg was needed to inhibit tumor growth. After capecitabine regimen modification, a 1-week postponement of capecitabine administration was more efficacious than a reduction in the dosage to 80%. The PBPK-PD model could simulate the antitumor efficacy at various capecitabine administration schedules. PBPK-PD models can contribute to the development of an appropriate CRC chemotherapy regimen with capecitabine.

Synthesis and Kinetic Study of Novel Coumarin- Based Mutual Prodrug of 5-fluorouracil and 5-ethynyluracil

The oral use of 5-fluorouracil is being deserted in the last decades due to its atypical intestinal absorption, which is primarily attributed to the mutable activity of dihydropyrimidine dehydrogenase located in the gastrointestinal mucosa. In this work, a coumarin-based prodrug system was utilized to synthesize a novel mutual prodrug of 5-fluorouracil and 5-ethynyluracil. This prodrug was designed to afford a concurrent release of these two active drugs resulting in the improvement of the therapeutic efficacy of both. The synthetic pathway involved 7 linear steps starting from coumarin. The chemical structures of the intermediates and prodrug were established by analyzing their FTIR, 1H-NMR, and 13C-NMR spectra. The in vitro chemical stability of the synthesized prodrug was tested in the HCl buffer (pH 1.2) and phosphate-buffered saline (pH 6.8), while its ability to release the active moieties was studied in human serum. The outcomes of these in vitro studies revealed that the prodrug showed a significant stability in the HCl buffer and phosphate-buffered saline with half-lives of 33.19 h and 18.13 hr respectively, obeying pseudo-first-order kinetics. Also, the prodrug was able to release the two active components in human serum with a half-life of 4.62 h obeying zero-order kinetics. It is concluded that the synthesized prodrug represents a promising oral prodrug of 5-fluorouracil and 5-ethynyluracil to serve better in therapeutics.

Pumpless, unidirectional microphysiological system for testing metabolism-dependent chemotherapeutic toxicity.

Drug development is often hindered by the failure of preclinical models to accurately assess and predict the efficacy and safety of drug candidates. Body-on-a-chip (BOC) microfluidic devices, a subset of microphysiological systems (MPS), are being created to better predict human responses to drugs. Each BOC is designed with separate organ chambers interconnected with microfluidic channels mimicking blood recirculation. Here, we describe the design of the first pumpless, unidirectional, multiorgan system and apply this design concept for testing anticancer drug treatments. HCT-116 colon cancer spheroids, HepG2/C3A hepatocytes, and HL-60 promyeloblasts were embedded in collagen hydrogels and cultured within compartments representing "colon tumor", "liver," and "bone marrow" tissue, respectively. Operating on a pumpless platform, the microfluidic channel design provides unidirectional perfusion at physiologically realistic ratios to multiple channels simultaneously. The metabolism-dependent toxic effect of Tegafur, an oral prodrug of 5-fluorouracil, combined with uracil was examined in each cell type. Tegafur-uracil treatment induced substantial cell death in HCT-116 cells and this cytotoxic response was reduced for multicellular spheroids compared to single cells, likely due to diffusion-limited drug penetration. Additionally, off-target toxicity was detected by HL-60 cells, which demonstrate that such systems can provide useful information on dose-limiting side effects. Collectively, this microscale cell culture analog is a valuable physiologically-based pharmacokinetic drug screening platform that may be used to support cancer drug development.

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.

5-Fluorouracil degradation rate as a predictive biomarker of toxicity in breast cancer patients treated with capecitabine

Capecitabine is an oral prodrug of 5-fluorouracil with a relevant role in the treatment of breast cancer. Severe and unexpected toxicities related to capecitabine are not rare, and the identification of biomarkers is challenging. We evaluate the relationship between dihydropyrimidine dehydrogenase, thymidylate synthase enhancer region and methylenetetrahydrofolate reductase polymorphisms, 5-fluorouracil degradation rate and the onset of G3-4 toxicities in breast cancer patients. Genetic polymorphisms and the 5-fluorouracil degradation rate of breast cancer patients treated with capecitabine were retrospectively studied. Genetic markers and the 5-fluorouracil degradation rate were correlated with the reported toxicities. Thirty-seven patients with a median age of 58 years old treated with capecitabine for stages II-IV breast cancer were included in this study. Overall, 34 (91.9%) patients suffered from at least an episode of any grade toxicity while nine patients had G3-4 toxicity. Homozygous methylenetetrahydrofolate reductase 677TT was found to be significantly related to haematological toxicity (OR = 6.5 [95% IC 1.1-37.5], P = 0.04). Three patients had a degradation rate less than 0.86 ng/mL/106 cells/min and three patients greater than 2.1 ng/mL/106 cells/min. At a univariate logistic regression analysis, an altered value of 5-fluorouracil degradation rate (values < 0.86 or >2.10 ng/mL/106 cells/min) increased the risk of G3-4 adverse events (OR = 10.40 [95% IC: 1.48-7.99], P = 0.02). A multivariate logistic regression analysis, adjusted for age, comorbidity and CAPE-regimen, confirmed the role of 5-fluorouracil degradation rate as a predictor of G3-4 toxicity occurrence (OR = 10.9 [95% IC 1.2-96.2], P = 0.03). The pre-treatment evaluation of 5-fluorouracil degradation rate allows to identify breast cancer patients at high risk for severe 5-FU toxicity.

3118 Case of Capecitabine-Induced Diarrhea Leading to Renal Failure Requiring Hemodialysis

INTRODUCTION: Capecitabine is a cytotoxic oral prodrug of 5-fluorouracil used as a chemotherapeutic adjuvant in the treatment of colorectal cancer. The most common adverse effects reported are hand-foot-syndrome and diarrhea. Incidence of diarrhea has been reported in up to 67% of patients. The pathophysiology of capecitabine induced diarrhea is not well understood with most cases being attributed to drug toxicity and overexpression of inflammatory cytokines. Chemotherapy induced diarrhea (CID) can be deleterious and, in some cases, life threatening. The subsequent case presents the development of acute renal failure requiring hemodialysis after treatment with capecitabine. CASE DESCRIPTION/METHODS: Case of a 50-year-old man with stage 3B T2N2M0 moderately differentiated adenocarcinoma of the rectum who presented with non-bloody diarrhea after recently starting his first chemotherapy treatment with CAPOX-Oxaliplatin and Capecitabine. Laboratory studies were significant for acute kidney failure with creatinine of 2.9 mg/dL and non-anion gap metabolic acidosis with bicarbonate of 18 mmol/L. Physical examination was unremarkable. Infectious workup for diarrhea was negative. Patient's renal function progressively worsened and ultimately required hemodialysis. After a negative colonoscopy and multiple bowel regimens, including lomotil, questran, octreotide and budesonide, his diarrhea was deemed to be secondary to Capecitabine therapy and only started to resolve after initiation of budesonide. Upon interval follow up with gastroenterology his diarrhea had completely resolved, and creatinine was at baseline. DISCUSSION: Grade 3–4 diarrhea occurs in 11.4% of patients treated with capecitabine monotherapy. However, when used in combination with other chemotherapeutic drugs also known to cause diarrhea such as oxaliplatin, the incidence increases to 18.2%. In general, treatment is conservative and limited to IV hydration, electrolyte replacement, and medications such as, loperamide and octreotide. However, in cases with standard treatment failure, it has been proven that budesonide effectively reduces the effects of 5-FU on the intestinal mucosa. In the literature, no other cases have been reported of acute renal failure requiring hemodialysis after treatment with capecitabine. Given the unpredictability of the effects of chemotherapy induced diarrhea and its potential to increase morbidity and mortality, it is essential to maintain close monitoring of such patients and provide adequate supportive treatment.

Capecitabine for the treatment of pancreatic cancer

ABSTRACTIntroduction: Capecitabine is an oral prodrug of 5-fluorouracil (5-FU) which is converted to 5FU by a series of reactions catalyzed by different enzymes, the last of the enzymes being thymidine phosphorylase (TP). TP is found to be elevated in tumor cells in comparison to normal cells, which consequently tumor-localizes the production of 5-FU, thereby limiting its systemic toxicity. Today, capecitabine is extensively used for the treatment of many solid malignancies, with a particular focus in breast and gastrointestinal tumors, but also in pancreatic cancer.Areas covered: This review summarizes the pharmacology and the clinical evidence relevant to the use of capecitabine in the treatment of pancreas cancer. The authors provide, furthermore, provide their expert perspectives on its use.Expert opinion: Capecitabine has the advantage over other therapeutics in so much that it has both convenient oral administration and a favorable toxicity profile. Current data has promised the use of capecitabine in all stages of pancreatic cancer. However, predictive markers for outcome and toxicity remain to be validated.

Clinical implications of dihydropyrimidine dehydrogenase expression in patients with pancreatic cancer who undergo curative resection with S-1 adjuvant chemotherapy.

The predictive roles of dihydropyrimidine dehydrogenase (DPD) in patients who undergo curative resection and adjuvant chemotherapy with S-1, which is the oral 5-fluorouracil prodrug tegafur combined with oteracil and gimeracil, remain unclear. In the present study, the clinical data from 66 consecutive patients who underwent curative resection and received adjuvant chemotherapy with S-1 for the treatment of pancreatic cancer at Kanagawa Cancer Center (Yokohama City, Japan) from April 2005 to March 2014 were retrospectively analyzed. The association between the DPD status and the survival and clinicopathological features were investigated. Of the 66 patients, 34 patients exhibited positive DPD expression (51.5%). Although a significant increase in DPD expression in male patients was observed, no significant differences were identified for other clinicopathological parameters, including tumor factor or node factor, between the DPD-positive expression group and the DPD-negative expression group. The median follow-up period of the present study was 29.2 months. There was no significant difference in the 3-year overall survival (OS) rates following surgery, which were 12.6 and 14.5% in the DPD-positive and DPD-negative expression groups, respectively (P=0.352). However, in a subgroup analysis, a significant difference in the 3-year OS rates following surgery was noted, which were 58.9 and 14.5% in the DPD-high and DPD-low expression groups, respectively (P=0.019). The intratumoral DPD expression in curatively resected pancreatic cancer patients treated with S-1 adjuvant chemotherapy was identified to not be useful as a predictive marker, whereas the level of DPD expression is a potential predictive marker. The results of the present study require confirmation in another cohort or in a prospective multicenter study.

Novel Genetic Variants in Carboxylesterase 1 Predict Severe Early-Onset Capecitabine-Related Toxicity.

An important concern with the anticancer drug capecitabine (Cp), an oral prodrug of 5-fluorouracil, are dose-limiting adverse effects, in particular hand-foot syndrome (HFS) and diarrhea. Here we evaluated the association of genetic variability in all enzymes of the Cp-activation pathway to 5-fluorouracil with Cp-related early-onset toxicity in 144 patients receiving Cp. We identified a haplotype encompassing five variants in the carboxylesterase 1 (CES1) gene region including an expression quantitative trait locus associated with early-onset Cp-toxicity (Haplotype A3: ORadditive = 2.2, 95% CI 1.2-4.0, Padjusted = 0.012; ORrecessive = 10.3, 95% CI 2.1-49.4, Padjusted = 0.0038). Furthermore, the association of two linked cytidine deaminase (CDA) promoter variants (c.1-451C>T: ORdominant = 4.3, 95% CI 1.3-14.2, Padjusted = 0.017; and c.1-92A>G: ORdominant = 4.4, 95% CI 1.3-14.5, Padjusted = 0.015) with Cp-related diarrhea was replicated. This first study identifying an association of genetic variation in CES1 with Cp-related toxicity provides further evidence for the existence of a functional noncoding CES1-variant with a possible regulatory impact.

Possible Pathways of Capecitabine-Induced Hand-Foot Syndrome.

Capecitabine, an oral prodrug of 5-fluorouracil, inhibits DNA synthesis and has received FDA approval for treatment of metastatic colorectal and breast cancers. Hand-foot syndrome (HFS) is a serious dose-limiting toxicity and the most frequently reported side effect of capecitabine. Because of the lack of knowledge about the causative mechanism of HFS, scarce information is available for effective treatment or prevention. Data are based on published literatures and reports available from the HFS development program database. The purpose of this Review is to provide information regarding definition, clinical manifestation, and the possible mechanisms of HFS induced by capecitabine. Ethnic variations in the clinical presentation of HFS warrant further attention. Several physiological and pharmacological mechanisms have been investigated, such as cyclooxygenase (COX) inflammatory-type reaction, accumulation of capecitabine metabolites, and enzymes and transporters involved in the metabolism and absorption. Although current studies describe the possible mechanisms of HFS induced by capecitabine, much remains to be determined. It appears from this scientific evidence that additional study is needed to determine the effect of skin-mediated metabolism in the possible mechanism of HFS induced by capecitabine.

Self-identification and management of hand-foot syndrome (HFS): effect of a structured teaching program on patients receiving capecitabine-based chemotherapy for colon cancer.

Capecitabine is an oral prodrug of 5-fluorouracil and is commonly used oral chemotherapeutic drugs for advanced gastric and colorectal cancer. However, hand-foot syndrome (HFS) has high incidence, and once developed, the symptoms significantly impair quality of life (QOL), leading to a reduction in the dosage or discontinuation of the treatment. Effective health education should be offered to patients to promote self-identification and management on how to recognize HFS and use self-management techniques at the very beginning of chemotherapy. The present study intended to evaluate the effectiveness of structured teaching program on knowledge related to self-identification and management of HFS among patients receiving chemotherapy for colon cancer at tertiary cancer care center. Participants who fulfilled the criteria were selected using non-probability purposive sampling. The sample selected were 40 participants (20 participants in experimental group and 20 participants in control group). Among the group of 40 patients, 17 (85%) participants in the experimental group and 17 (85%) participants in the control group were receiving capecitabine and oxaliplatin (CAPOX) chemotherapy treatment protocol. Five (25%) participants in the experimental group and ten (50%) participants in the control group were receiving drug capecitabine at a dose of 2500mg. The mean knowledge (knowledge related to self-identification and management of HFS) pretest score was 6.75 and mean knowledge posttest score was 10.25 in the experimental group which was statistically significant (p = 0.000) (p < 0.05). The mean knowledge pretest score of participants was 6.45 and mean knowledge posttest score of participants was 6.75 in the control group which was not statistically significant (p = 0.67) (p > 0.05). The study showed a statistically significant improvement in knowledge scores of participants that occurred due to intervention of structured teaching program. This can be used to assess reduction in incidence of HFS in the future.

Effect of DPYD gene polymorphisms on pharmacokinetics of capecitabine in Chinese cancer patients.

e13561 Background: Capecitabine (Xeloda, Roche) is an oral prodrug of 5-Fluorouracil (5-FU) that is widely used in the treatment for patients with cancers of the gastrointestinal tract, breast, hea...